Cytokeratin 19 is a powerful predictor of survival in pancreatic endocrine tumors

The prediction of the behavior of pancreatic endocrine tumors (PETs) is a difficult exercise. CK19, a marker of pancreatic ductal cells, does not stain normal islet cells. Our aim was to evaluate the prognostic value of traditional parameters, including the Capella classification, as well as CK19. We evaluated the clinicopathologic features of 101 curatively resected PETs. The influence on survival of size, functional status of tumor, growth pattern, nuclear grade, mitoses (>2/10 HPF), vascular and perineural invasion, and necrosis was determined. Immunohistochemistry for Ki-67 and CK19 was performed in 45 and 54 cases, respectively. Cases were categorized as per the Capella classification as: benign, borderline, low-grade, and high-grade malignant. The different variables were tested by standard univariate and multivariate analyses. Mitoses (P = 0.03), solid pattern (P = 0.04), necrosis (P = 0.01), vascular invasion (P = 0.003), perineural invasion (P = 0.02), CK19 staining (P = 0.0008), and Ki-67 (P = 0.02) were significant prognostic indicators by univariate analysis while the Capella classification was not significant. By multivariate analysis, only CK19 was significant (P = 0.0008). None of the CK19-negative cases died of disease, while 10 of 28 CK19-positive cases died of disease and 3 are alive with disease. The Capella classification includes malignant tumors in its benign and borderline categories. CK19 is a powerful predictor of survival and can potentially segregate benign and malignant PETs. We suggest that all PETs with any one of the following features be diagnosed as malignant: presence of necrosis, vascular invasion, perineural invasion, or CK19 positivity. We hypothesize that a subgroup of PETs may share a common histogenesis with pancreatic adenocarcinomas.     

Panniculectomy as an adjuvant to bariatric surgery

A large hanging panniculus can cause problems such as intertrigo, chronic infection, and immobility. Many patients undergoing weight reduction surgery can benefit from panniculectomy either done concomitantly with bariatric surgery or later after significant weight reduction. Over the last 5 years we performed 123 panniculectomies on patients (34 males, 89 females; mean age 44.5 +/- 10.3 years) undergoing bariatric surgery. The panniculectomy was either done at the same time as the bariatric surgery in 21 patients or after a time period of 17 +/- 11 months in 102 patients. The prebariatric surgery weight ranged from 107 to 341 kg (mean: 168.6 +/- 47.2 kg) with a mean body mass index (BMI) of 59 +/- 14 kg/m. After the bariatric surgery the patients had an average weight loss of 57.6 +/- 27 kg. The prepanniculectomy weight was 121.9 +/- 39.3 kg (BMI = 43.1 +/- 12.4 kg/m) for the patients who had the panniculectomy after the bariatric surgery. Ninety-two percent of the patients had multiple comorbidities. The weight of the panniculectomy specimen ranged from 4 to 54 kg. Any abdominal wall hernias (35.4% incisional and 8.9% umbilical) were fixed during the panniculectomy. Overall, patients who had panniculectomy simultaneously with the bariatric surgery had more complications than patients who had panniculectomy after their bariatric surgery. The wound infections were 48% versus 16% and respiratory distress was 24% versus 0%, respectively. The skin necrosis was 10% versus 6%, dehiscence was 33% versus 13%, and hematoma formation was 10% versus 2%, respectively. Overall, the patients had good outcomes, with 3 postoperative deaths in the group with panniculectomy at the same time of bariatric surgery. An interval of weight loss prior to the procedure makes this procedure safer and more effective.     

Pedometer accuracy in nursing home and community-dwelling older adults

PURPOSE: The accuracy of pedometers has not been thoroughly tested with older adult populations. The purpose of the present study was to examine the effects of walking speed and gait disorders on the accuracy of Yamax pedometers with nursing home residents (NH) relative to older adults living in the community. METHODS: Pedometer accuracy was evaluated against observed steps taken during a self-paced walking test (slow, normal, and fast speeds) in 26 NH residents and 28 seniors' recreation center members (SC). Devices were attached to clothing at the waist. Walking speed was ascertained from the timed walk and a gait assessment was conducted. Percent error was calculated as ([pedometer steps - observed steps]/observed steps) x 100. RESULTS: The walking speeds of both samples increased across self-selected paces (P < 0.0001). The community-dwelling older adults walked significantly faster (P < 0.0001) in all trials and had significantly higher (P < 0.0001) gait assessment scores (indicating fewer gait problems). Gait scores were positively associated with walking speed and pedometer percent error. Pedometers significantly underestimated NH residents' observed steps taken by 74% (slow), 55% (normal), and 46% (fast) paces (P < 0.0001). In the SC sample, the instruments failed to detect 25%, 13%, and 7% of actual steps taken, respectively (P < 0.0001). The magnitude of the error was greater for NH versus SC older adults (P < 0.0001) across all trials. CONCLUSIONS: Slow walking speed and gait disorders hamper the utility of pedometers for physical activity measurement in frail seniors, such as NH residents, when worn at the usual attachment site. Pedometers, however, can be confidently used with ostensibly healthy older adult populations for both assessment and motivation purposes.     

Mitochondrial DNA control region sequences from Nairobi (Kenya): inferring phylogenetic parameters for the establishment of a forensic database

Large forensic mtDNA databases which adhere to strict guidelines for generation and maintenance, are not available for many populations outside of the United States and western Europe. We have established a high quality mtDNA control region sequence database for urban Nairobi as both a reference database for forensic investigations, and as a tool to examine the genetic variation of Kenyan sequences in the context of known African variation. The Nairobi sequences exhibited high variation and a low random match probability, indicating utility for forensic testing. Haplogroup identification and frequencies were compared with those reported from other published studies on African, or African-origin populations from Mozambique, Sierra Leone, and the United States, and suggest significant differences in the mtDNA compositions of the various populations. The quality of the sequence data in our study was investigated and supported using phylogenetic measures. Our data demonstrate the diversity and distinctiveness of African populations, and underline the importance of establishing additional forensic mtDNA databases of indigenous African populations.     

Angiotensin II type 1 receptor activation increases microvascular hydraulic permeability

BACKGROUND: In addition to its vasoconstricting effects, angiotensin II (Ang II) has also demonstrated the ability to modulate microvessel permeability. We hypothesized that activation of the angiotensin II type 1 receptor (AT1) would increase hydraulic permeability. METHODS: Hydraulic permeability (L(p)) was measured in rat mesenteric venules using the Landis micro-occlusion technique. Paired measures of L(p) were obtained at baseline and after perfusion with the AT1 agonist, [Sar(1)]-angiotensin II, at 10 micromol/L (n=6) and 100 micromol/L (n=6). Activation of the AT1 receptor was also achieved by perfusion with 20 nmol/L Ang II plus the angiotensin II type 2 receptor (AT2) antagonist, PD123319. In these studies, 30 micromol/L (n=6) and 300 micromol/L (n=6) of PD123319 were used. RESULTS: [Sar(1)]-angiotensin II increased L(p) 2-fold with the 10 micromol/L dose (P=.04) and 4-fold with the 100 micromol/L dose (P < .001). The L(p) peak due to [Sar(1)]-angiotensin II occurred sooner than the peak observed with Ang II. PD123319 (30 micromol/L) plus 20 nmol/L Ang II increased L(p) 5-fold (P=.003), while PD123319 (300 micromol/L) plus 20 nmol/L Ang II increased L(p) 20-fold (P < .0001). The magnitude of the effect due to PD123319 (300 micromol/L) plus Ang II (20 nmol/L) was approximately twice the summation of effects due to PD123319 (300 micromol/L) alone and Ang II (20 nmol/L) alone. CONCLUSIONS: We conclude that endothelial cell Ang II receptors play an important role in modulating transendothelial fluid flux. Activating the AT1 receptor increases L(p); the AT2 receptor may operate to oppose this action. Pharmacologic manipulation of Ang II receptors may be beneficial during shock states to limit intravascular fluid loss.     

PYY3-36 reinforces insulin action on glucose disposal in mice fed a high-fat diet

Peptide YY(3-36) (PYY(3-36)) is released by the gut in response to nutrient ingestion. It modulates the activities of orexigenic neuropeptide Y (NPY) neurons and anorexigenic proopiomelanocortin (POMC) neurons in the hypothalamus to inhibit food intake. Because both NPY and POMC have also been shown to impact insulin action, we wondered whether PYY(3-36) could improve insulin sensitivity. To address this question, we examined the acute effect of intravenous PYY(3-36) on glucose and free fatty acid (FFA) flux during a hyperinsulinemic-euglycemic clamp in mice maintained on a high-fat diet for 2 weeks before the experiment. We also evaluated the effects of PYY(3-36) infusion on glucose uptake in muscle and adipose tissue in this experimental context. Under basal conditions, none of the metabolic parameters were affected by PYY(3-36). Under hyperinsulinemic conditions, glucose disposal was significantly increased in PYY(3-36)-infused compared with vehicle-infused mice (103.8 +/- 10.9 vs. 76.1 +/- 11.4 micromol.min(-1).kg(-1), respectively; P = 0.001). Accordingly, glucose uptake in muscle and adipose tissue was greater in PYY(3-36)-treated animals, although the difference with controls did not reach statistical significance in adipose tissue (muscle: 2.1 +/- 0.5 vs. 1.5 +/- 0.5 micromol/g tissue, P = 0.049; adipose tissue: 0.8 +/- 0.4 vs. 0.4 +/- 0.3 micromol/g tissue, P = 0.08). In contrast, PYY(3-36) did not impact insulin action on endogenous glucose production or FFA metabolism. These data indicate that PYY(3-36) reinforces insulin action on glucose disposal in mice fed a high-fat diet, through a mechanism that is independent of food intake and body weight. In contrast, it leaves glucose production and lipid flux largely unaffected in this experimental context.     

Angiotensin II type 2 receptor effect on microvascular hydraulic permeability

BACKGROUND: Angiotensin II (Ang II) is a potent vasoconstrictor that modulates microvascular permeability. Angiotensin II type 1 (AT1) and type 2 (AT2) receptors have been described with subsequent development of their respective antagonists. We hypothesized that the AT2 receptor modulates microvascular permeability. MATERIALS AND METHODS: Hydraulic permeability (L(p)) was measured in rat mesenteric venules using the Landis micro-occlusion technique. Following baseline L(p) measurements, paired measures of microvessel L(p) were obtained after perfusion with a test solution. The test solutions consisted of the AT2 receptor agonist CGP42112A at 10 microm (n = 6), 100 microm (n = 6), and 200 microm (n = 6), as well as the AT2 receptor antagonist PD-123319 at 3 microm (n = 6), 30 microm (n = 6), 300 microm (n = 6), and 600 microm (n = 6). RESULTS: From mean baseline L(p) of 0.99 +/- 0.03, 100 microm CGP42112A decreased L(p) to 0.76 +/- 0.02 (P = 0.005), and 200 microm CGP42112A decreased L(p) to 0.61 +/- 0.02 (P < 0.001). From mean baseline L(p) of 0.90 +/- 0.05, PD-123319 increased L(p) at 30 microm to 1.60 +/- 0.2 (P = 0.003), at 300 microm to 2.28 +/- 0.3 (P = 0.008), and at 600 microm to 4.30 +/- 0.9 (P = 0.03). Units for L(p) are mean +/- SEM x 10(-7) cm s(-1) cmH(2)O(-1). CONCLUSION: AT2 activation decreased L(p), while AT2 blockade increased L(p). These changes in L(p) may be explained by (1). a permeability-decreasing effect of the AT2 receptor that is induced by AT2 activation and inhibited by AT2 blockade; and/or (2). a permeability-increasing effect of the AT1 receptor observed during AT2 blockade and selective AT1 activation by endogenous locally released Ang II. These mechanisms would support the theories that the AT1 receptor increases microvascular permeability, while the AT2 receptor decreases microvascular permeability.     

Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome

Nephrotic syndrome (NS) represents the association of proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Steroid-resistant NS (SRNS) is defined by primary resistance to standard steroid therapy. It remains one of the most intractable causes of ESRD in the first two decades of life. Mutations in the NPHS2 gene represent a frequent cause of SRNS, occurring in approximately 20 to 30% of sporadic cases of SRNS. On the basis of a very small number of patients, it was suspected that children with homozygous or compound heterozygous mutations in NPHS2 might exhibit primary steroid resistance and a decreased risk of FSGS recurrence after kidney transplantation. To test this hypothesis, NPHS2 mutational analysis was performed with direct sequencing for 190 patients with SRNS from 165 different families and, as a control sample, 124 patients with steroid-sensitive NS from 120 families. Homozygous or compound heterozygous mutations in NPHS2 were detected for 43 of 165 SRNS families (26%). Conversely, no homozygous or compound heterozygous mutations in NPHS2 were observed for the 120 steroid-sensitive NS families. Recurrence of FSGS in a renal transplant was noted for seven of 20 patients with SRNS (35%) without NPHS2 mutations, whereas it occurred for only two of 24 patients with SRNS (8%) with homozygous or compound heterozygous mutations in NPHS2. None of 29 patients with homozygous or compound heterozygous mutations in NPHS2 who were treated with cyclosporine A or cyclophosphamide demonstrated complete remission of NS. It was concluded that patients with SRNS with homozygous or compound heterozygous mutations in NPHS2 do not respond to standard steroid treatment and have a reduced risk for recurrence of FSGS in a renal transplant. Because these findings might affect the treatment plan for childhood SRNS, it might be advisable to perform mutational analysis of NPHS2, if the patient consents, in parallel with the start of the first course of standard steroid therapy.