Cause-Specific Deaths in Non–Dialysis-Dependent CKD

CKD is associated with higher risk of death, but details regarding differences in cause-specific death in CKD are unclear. We examined the leading causes of death among a non–dialysis-dependent CKD population using an electronic medical record-based CKD registry in a large healthcare system and the Ohio Department of Health mortality files. We included 33,478 white and 5042 black patients with CKD who resided in Ohio between January 2005 and September 2009 and had two measurements of eGFR<60 ml/min per 1.73 m² obtained 90 days apart. Causes of death (before ESRD) were classified into cardiovascular, malignancy, and non-cardiovascular/non-malignancy diseases and non–disease-related causes. During a median follow-up of 2.3 years, 6661 of 38,520 patients (17%) with CKD died. Cardiovascular diseases (34.7%) and malignant neoplasms (31.8%) were the leading causes of death, with malignancy-related deaths more common among those with earlier stages of kidney disease. After adjusting for covariates, each 5 ml/min per 1.73 m² decline in eGFR was associated with higher risk of death due to cardiovascular disease (hazard ratio [HR], 1.10; 95% confidence interval [95% CI], 1.08 to 1.12) and non-cardiovascular/non-malignancy diseases (HR, 1.12; 95% CI, 1.09 to 1.14) but not to malignancy. In the adjusted models, blacks had overall-mortality hazard ratios similar to those of whites but higher hazard ratios for cardiovascular deaths. Further studies to confirm these findings and explain the mechanisms for differences are warranted. In addition to lowering cardiovascular burden in CKD, efforts to target known risk factors for cancer at the population level are needed.     

The Tricky Tear Trough: A Review of Topical Cosmeceuticals for Periorbital Skin Rejuvenation

There is a growing demand for noninvasive anti-aging products for which the periorbital region serves as a critical aspect of facial rejuvenation. This article reviews a multitude of cosmeceutical ingredients that have good scientific data, specifically for the periorbital region. Topical treatment options have exponentially grown from extensively studied retinoids, to recently developed technology, such as growth factors and peptides. With a focus on the periorbital anatomy, the authors review the mechanisms of action of topical cosmeceutical ingredients, effectiveness of ingredient penetration through the stratum corneum, and validity of clinical trials.Due to the Baby Boomer’s continual pursuit to maintain a youthful appearance, there is a new paradigm in treating the signs of aging. The periorbital region serves as a window to a person’s chronological age. Aging photodamaged skin demonstrates epidermal atrophy, pigmentary changes, and the formation of dynamic and resting rhytides. Patients are commonly concerned about the appearance of dark circles, crow’s feet, eyelid bags, dry skin, thin skin, and just “looking tired.” They often seek advice about which treatments are most effective for periorbital rejuvenation. Although aging is inevitable, there are certain features of the periorbital skin that can be addressed to minimize the aged appearance.There are many effective treatment options including surgical measures and nonsurgical modalities, such as fillers, neuromodulators, lasers, and light technology, but these are costly and have the potential for greater side effects. Therefore, a minimally invasive treatment, such as a topical cosmeceutical, is often the desired first line of defense.A search for “crow’s feet” on Amazon.com revealed 2,471 products. The upper limit of the price range was more than $1,000 for a 15mL eye serum claiming to “eliminate wrinkles, reduce dark circles, and hydrate the skin around the eyes.” This helps elucidate the demand for products to address these common concerns in the periorbital region.What follows is a review of the common ingredients in topical cosmeceuticals utilized for periorbital rejuvenation.     

Outcomes of Delayed Graft Function in Kidney Transplant Recipients Stratified by Histologic Biopsy Findings

Delayed graft function (DGF) after kidney transplantation is associated with an increased risk of graft failure. We studied the histologic findings among adult kidney transplant recipients transplanted between January 2000 and June 2015 who had DGF and had a kidney biopsy within 14 days of transplant. Death censored graft failure (DCGF) and death at 1 and 3 years after transplant were examined. A total of 269 transplant recipients fulfilled our selection criteria, of which 152 (56.51%) had acute tubular necrosis (ATN), 44 (16.4%) had acute rejection (AR), mainly T-cell mediated rejection (n = 31), 35 (13%) had ATN with AR (mainly T-cell mediated rejection, n = 26), and 38 (14.1%) had other pathology. Compared with those with ATN alone, kidney transplant recipients with AR alone had a significantly higher risk of DCGF at 1 year post transplant (adjusted hazard ratio = 3.70; 95% confidence interval 1.5-9.5; P = .006). Those with AR alone had an increased risk of DCGF at 3 years post transplant (hazard ratio = 3.10; 95% confidence interval 1.3-8.5; P = .01) in crude analyses. There was no association between DGF etiology and mortality. Early renal biopsy can be used to distinguish AR, which has protocolized treatments, from other etiologies. This could potentially alter allograft survival within 1 year of transplant complicated by DGF.     

Surgical management of a pulsatile chest wall mass secondary to an ascending aortic aneurysm in a patient with bovine arch

Ascending aortic pseudoaneurysms are rare, but life‐threatening conditions, that often require intervention. While endovascular techniques have advanced significantly, the majority of these clinical scenarios preclude endovascular options and the primary treatment modality remains open surgical repair. Repair of an aortic pseudoaneurysm eroding through the sternum resulting in a pulsatile chest wall mass is technically challenging. We report the successful repair of a large ascending aortic pseudoaneurysm in a 62‐year‐old male with bovine arch anatomy and prior Type A dissection repair, presenting with contained rupture and a pulsatile chest wall mass.     

Genetic aberrations of NAT2 and chromosome 8: their association with progression in transitional cell carcinoma of the urinary bladder

INTRODUCTION/OBJECTIVE: N-acetyltransferase 2 (NAT2), mapped to 8p22, is a polymorphic enzyme which metabolizes aromatic amines. Loss of heterozygosity of 8p22 is associated with an increased risk of bladder cancer. This study evaluated NAT2 and chromosome 8 in sequential tumours from bladder cancer patients to determine if NAT2 alterations increase the risk of progression. MATERIALS AND METHODS: Thirty-seven sequential carcinomas from 19 patients were assessed using fluorescence in situ hybridization. RESULTS: Five carcinomas showed loss of NAT2; 4 of these were from pTa/pT1 tumours. Polysomy 8 was observed in 4 of 14 (29%) primary carcinomas (pTa/pT1), in 4 of 12 (33%) pTa/pT1 recurrences, and in 90% (9/10) of the detrusor muscle invasive tumours (pT2+). 6 of 8 (75%) locally invasive tumours with polysomy 8 were from patients who subsequently developed disease progression (pT2+). In total, 13.5% (5/37) of the carcinomas were abnormal for NAT2, and 46% (17/37) were abnormal for chromosome 8 copy number. Polysomy 8 was associated with high grade (p = 0.01) and stage (p = 0.03) and disease progression (p = 0.03). CONCLUSION: Whilst there does not appear to be an association between loss of NAT2 and risk of progression in transitional cell carcinoma, the high rate of polysomy of chromosome 8 implies that other genes on this chromosome significantly influence disease progression.     

Ventromedial Hypothalamic Nitric Oxide Production Is Necessary for Hypoglycemia Detection and Counterregulation

OBJECTIVE

The response of ventromedial hypothalamic (VMH) glucose-inhibited neurons to decreased glucose is impaired under conditions where the counterregulatory response (CRR) to hypoglycemia is impaired (e.g., recurrent hypoglycemia). This suggests a role for glucose-inhibited neurons in the CRR. We recently showed that decreased glucose increases nitric oxide (NO) production in cultured VMH glucose-inhibited neurons. These in vitro data led us to hypothesize that NO release from VMH glucose-inhibited neurons is critical for the CRR.

RESEARCH DESIGN AND METHODS

The CRR was evaluated in rats and mice in response to acute insulin-induced hypoglycemia and hypoglycemic clamps after modulation of brain NO signaling. The glucose sensitivity of ventromedial nucleus glucose-inhibited neurons was also assessed.

RESULTS

Hypoglycemia increased hypothalamic constitutive NO synthase (NOS) activity and neuronal NOS (nNOS) but not endothelial NOS (eNOS) phosphorylation in rats. Intracerebroventricular and VMH injection of the nonselective NOS inhibitor N^G-monomethyl-l-arginine (l-NMMA) slowed the recovery to euglycemia after hypoglycemia. VMH l-NMMA injection also increased the glucose infusion rate (GIR) and decreased epinephrine secretion during hyperinsulinemic/hypoglycemic clamp in rats. The GIR required to maintain the hypoglycemic plateau was higher in nNOS knockout than wild-type or eNOS knockout mice. Finally, VMH glucose-inhibited neurons were virtually absent in nNOS knockout mice.

CONCLUSIONS

We conclude that VMH NO production is necessary for glucose sensing in glucose-inhibited neurons and full generation of the CRR to hypoglycemia. These data suggest that potentiating NO signaling may improve the defective CRR resulting from recurrent hypoglycemia in patients using intensive insulin therapy.Intensive insulin therapy significantly reduces the onset and progression of hyperglycemia-related complications in patients with type 1 and advanced type 2 diabetes. However, intensive insulin therapy also causes a clinically adverse effect: hypoglycemia (1). Powerful neuroendocrine and autonomic counterregulatory mechanisms protect the brain from hypoglycemia (2,3). These protective mechanisms, known as the counterregulatory response (CRR) to hypoglycemia, involve the release of hormones (e.g., glucagon, epinephrine) that restore euglycemia by stimulating hepatic glucose production and inhibiting peripheral glucose uptake (3). Although the physiology of the CRR is well understood, the underlying cellular mechanisms by which the brain senses hypoglycemia and initiates the CRR remain elusive.During hypoglycemia, central and peripheral glucose sensors detect declining glucose levels (4). In the brain, the ventromedial hypothalamus, which includes the arcuate nucleus and the ventromedial nucleus (VMN), is important in the initiation of the CRR (5–7). This region contains specialized glucose-sensing neurons (GSNs). Ventromedial hypothalamic (VMH) GSN electrical activity is regulated by physiologically relevant changes in extracellular glucose levels (8–11). Glucose-excited neurons decrease, whereas glucose-inhibited neurons increase, their input resistance, membrane potential, and action potential frequency when extracellular glucose is reduced (10). Many studies suggest that VMH glucose-inhibited neurons play a critical role in the control of the CRR (4). For example, the response of VMH glucose-inhibited neurons to decreased glucose is impaired under conditions where the CRR is impaired (e.g., recurrent hypoglycemia) (12,13).Nitric oxide (NO) is a gaseous messenger produced by NO synthase (NOS). Two classes of NOS have been identified in the brain: the inducible NOS (iNOS) and the constitutive NOS, which includes the neuronal NOS (nNOS) and endothelial NOS (eNOS) isoforms (14). Hypothalamic NO is involved in the regulation of food intake and glucose homeostasis (15–18). In support of this, we have recently shown that VMH glucose-inhibited neurons produce NO via nNOS in response to decreased extracellular glucose levels (19,20). Therefore, in this study, we test the hypothesis that NO production by VMH glucose-inhibited neurons is necessary for the CRR to hypoglycemia. We tested this hypothesis using a combination of in vivo and in vitro techniques in wild-type rats and mice as well as in transgenic nNOS and eNOS knockout mice.     

The Constipation Severity Instrument: A Validated Measure

Purpose This study was designed to develop and test the validity and reliability of the Constipation Severity Instrument. Methods Scale development was conducted in two stages: 1) 74 items were generated through a literature review and focus groups of constipated patients and medical providers; and 2) a preliminary instrument was administered to 191 constipated patients and 103 healthy volunteers. Test-retest reliability of the constipated group was assessed (N = 90). Content, convergent, divergent, and discriminant validity were evaluated by using other validated measures by performing one-way analysis of variance and Pearson correlations. Results Exploratory and confirmatory factor analysis revealed three subscales: obstructive defecation, colonic inertia, and pain. Internal consistency (α = 0.88–0.91) and test-retest reliability (intraclass correlation coefficients = 0.84–0.91) were high for all subscales. Constipated patients were grouped by Rome II criteria: functional constipation (22 percent), pelvic floor dyssynergia (15 percent), constipation predominant irritable bowel syndrome (23 percent), and no specific criteria (40 percent). Those with constipation predominant irritable bowel syndrome or pelvic floor dyssynergia scored higher on the Obstructive Defecation and Colonic Inertia subscales than those with functional constipation or no specific criteria (P = 0.001–0.058). Subjects with functional constipation had much lower scores on the pain subscale than constipation predominant irritable bowel syndrome, functional constipation, or no specific criteria (P < 0.009).The Constipation Severity Instrument subscale and total score correlated very highly with the subscales and total score of the Patient Assessment of Constipation Symptom measure. The Constipation Severity Instrument subscales discriminated well between constipated patients and healthy volunteers (P < 0.001) and demonstrated excellent divergent validity. Higher Constipation Severity Instrument scores inversely correlated with general quality of life. Conclusions The Constipation Severity Instrument is a reliable and valid instrument for assessing constipated patients. Administration of the Constipation Severity Instrument to other constipated patients will further validate its use. Supported by the University of California San Francisco Hellman Family Award for Early Career Faculty. Read at the meeting of The American Society of Colon and Rectal Surgeons, St. Louis, Missouri, June 2 to 6, 2007. Reprints are not available.     

A videotape-based training method for improving the detection of depression in residents of long-term care facilities

PURPOSE: This article reviews the effectiveness of a new training program for improving nursing staffs' detection of depression within long-term care facilities. The course was designed to increase recognition of the Minimal Data Set (MDS) Mood Trigger items, to be brief, and to rely on images rather than didactics. DESIGN AND METHODS: This study used a delayed intervention design. Twenty nurses from two facilities participated in all four sessions of the study. RESULTS: Staff exposed to the intervention (Site 1) improved significantly in their ability to detect mood symptoms in videotaped patients after completing the training course compared with those exposed to the delayed intervention (Site 2). Improvement in detection skills at Site 2 following the training confirmed the intervention's utility. The improvement was demonstrated across levels of staff (licensed and unlicensed). Maintenance of skills was demonstrated at the 4-month follow-up. IMPLICATIONS: Staff successfully improved knowledge and skill of MDS mood triggers. This method may lend itself to other MDS domains.     

Restoration of Serotonin Neuronal Firing Following Long-Term Administration of Bupropion but Not Paroxetine in Olfactory Bulbectomized Rats

Background:

Olfactory bulbectomized rats generally manifest many of the neurochemical, physiological, and behavioral features of major depressive disorder in humans. Another interesting feature of this model is that it responds to chronic but not acute antidepressant treatments, including selective serotonin reuptake inhibitors. The purpose of the present study was first to characterize the firing activity of dorsal raphe serotonin neurons in olfactory bulbectomized rats and then examine the effects of 2 antidepressants, bupropion and paroxetine.

Methods:

Olfactory bulbectomy was performed by aspirating olfactory bulbs in anesthetized rats. Vehicle and drugs were delivered for 2 and 14 days via subcutaneously implanted minipumps. In vivo electrophysiological recordings were carried out in male anesthetized Sprague-Dawley rats.

Results:

Following ablation of olfactory bulbs, the firing rate of serotonin neurons was decreased by 36%, leaving those of norepinephrine and dopamine neurons unchanged. In olfactory bulbectomized rats, bupropion (30mg/kg/d) restored the firing rate of serotonin neurons to the control level following 2- and 14-day administration and also induced an increase in the tonic activation of serotonin_1A receptors; paroxetine (10mg/kg/d) did not result in a return to normal of the attenuated firing of serotonin neurons in olfactory bulbectomized rats. In the hippocampus, although at a higher dose of WAY 100635 than that required in bupropion-treated animals, paroxetine administration also resulted in an increase in the tonic activation of serotonin_1A receptors.

Conclusions:

The present results indicate that unlike paroxetine, bupropion administration normalized serotonin neuronal activity and increased tonic activation of the serotonin_1A receptors in hippocampus.