Brain Cancer Risk and Electromagnetic Fields (EMFs): Assessing the Geomagnetic Component

Cancer cluster studies in North Carolina identified several communities in which there existed an elevated risk of brain cancer. These findings prompted a series of case-control studies. The current article, which originated from the results of the 3rd of such studies, is focused on inclusion of the earth's own geomagnetic fields that interact with electromagnetic fields generated from distribution power lines. This article also contains an assessment of the contribution of confounding by residential (e.g., urban, rural) and case characteristics (e.g., age, race, gender). Newly diagnosed brain cancer cases were identified for a 4-county region of central North Carolina, which the authors chose on the basis of the results of earlier observations. A 3:1 matched series of cancer cases from the same hospitals in which the cases were diagnosed served as the comparison group. Extensive geographic information was collected and was based on an exact place of residence at the time of cancer diagnosis, thus providing several strategic geophysical elements for assessment. The model for this assessment was based on the effects of these two sources of electromagnetic fields for an ion cyclotron resonance mechanism of disease risk. The authors used logistic regression models that contained the predicted value for the parallel component of the earth's magnetic field; these models were somewhat erratic, and the elements were not merged productively into a single statistical model. Interpretation of these values was difficult; therefore, the modeled values for the model elements, at progressive distances from the nearest power-line segments, are provided. The results of this study demonstrate the merits of using large, population-based databases, as well as using rigorous Geographic Information System techniques, for the assessment of ecologic environmental risks. The results also suggest promise for exposure classification that is compatible with the theoretical biological mechanisms posited for electromagnetic fields.     

Inhibitory effects of sigma‐1 ligands on handling‐induced tachycardia in conscious tethered rats

We used conscious tethered Sprague‐Dawley rats to evaluate the cardiovascular effects of four sigma‐1 (σ₁) agonists and five antagonists, given alone or in combination. All drugs were administered as a single intraperitoneal dose. The agonists were given at doses reported as efficacious in rodent cognition models, while the antagonists were administered at doses neutralizing agonist effects in vivo. Systolic blood pressure (SBP) and heart rate (HR) were continuously recorded for 20 min before and 60 min postadministration. Immediately after injection, a sudden, transitory increase in HR and SBP was noted in all animals, because of the stress induced by handling. For both parameters, a peak value (ΔHR_max and ΔSBP_max) and an area under the curve of changes from baseline over the period 5–20 min postinjection (ΔHR_AUC_{5–20 min} and ΔSBP_AUC_{5–20 min}) were calculated. Three of the four σ₁ agonists (SKF‐10,047, dehydroepiandrosterone (DHEAS), Compound 14) significantly reduced ΔHR_AUC_{5–20 min} value without changing ΔHR_max, while the fourth one, SA‐4503, had no significant effect. None of the antagonists (haloperidol, rimcazole, NE‐100, and BD1047) reduced, and even one (progesterone) enhanced the stress‐induced effects on HR. No changes in SBP were noted with any compound. When the antagonist NE‐100 was administered just before SKF‐10,047, it completely reversed the inhibitory effects of the σ₁ agonist on HR increase. In conclusion, we demonstrated for the first time the involvement of σ₁ receptors in the regulation of handling‐induced tachycardia in the conscious rat. Although additional investigations are needed to fully understand this role, it might offer new therapeutic perspectives to σ₁ ligands in the cardiovascular sphere.     

Effect of mixed hematopoietic chimerism on cardiac allograft survival in cynomolgus monkeys

BACKGROUND: We have previously reported the successful induction of mixed chimerism and long-term acceptance of renal allografts in MHC-mismatched nonhuman primates after nonmyeloablative conditioning and donor bone marrow transplantation. In this study, we extended our regimen to cardiac allotransplantation and compared the immunological responses of heart and kidney allograft recipients. METHODS: Five cynomolgus monkeys were conditioned with low-dose total body irradiation (1.5 Gy on days -6 and -5), supplemental thymic irradiation (7 Gy on day -1), antithymocyte globulin (50 mg/kg on days -2, -1, and 0), splenectomy (day 0), donor bone marrow transplantation (day 0), and a 4-week posttransplant course of cyclosporine. Heart allografts from MHC-mismatched donors were transplanted heterotopically on day 0. RESULTS: Two monkeys failed to develop multilineage chimerism and rejected their allografts soon after cyclosporine was stopped (postoperative days [PODs] 43 and 56). Three monkeys developed multilineage chimerism, which persisted 20 to 43 days posttransplant by flow cytometric analysis and to POD 124 by polymerase chain reaction analysis. Allograft survival in these recipients was prolonged to 138, 428, and 509 days, and in vitro mixed leukocyte reaction and cell-mediated lympholysis (CML) assays demonstrated donor-specific hyporesponsiveness. However, in contrast to kidney allograft recipients, long-term heart allograft recipients eventually developed humoral and cellular immunity against the donor and rejected the grafts. At the time of rejection, 1.3% to 9.5% of donor coronary arteries exhibited intimal proliferation. CONCLUSIONS: The induction of transient mixed hematopoietic chimerism leads to long-term heart allograft survival in MHC disparate monkeys without chronic immunosuppression. However, unlike kidney allografts, full tolerance to cardiac allografts was not achieved. Organ-specific modifications of the preparative regimen may be necessary to prevent the chronic cellular and humoral immune responses elicited by cardiac allografts.     

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 efficacy of drugs for the treatment of LUTS/BPH, a study in 6 European countries

OBJECTIVES: This paper profiles the usage and effectiveness of various LUTS/BPH drugs in real-life practice. METHOD: The TRIUMPH study recorded the treatment and outcomes of 2351 newly-presenting LUTS/BPH patients in 6 European countries over a 1-year follow-up period. At each visit the clinician recorded the treatment, co-morbidities, complications and drugs prescribed, and the patient completed an IPSS questionnaire. The results were analysed using change in IPSS as the primary outcome measure. RESULTS: Over the study period 74.9% of patients were prescribed medication, the majority (83% of those medicated) were prescribed only a single drug. Tamsulosin was the most commonly prescribed drug in all countries (38% of medicated cases), although with national variation from 24% in Poland to 70% in Italy. The alpha-blockers were the most effective, with a mean reduction of 6.3 IPSS points. Finasteride was slightly less effective (4.1 points). Significant improvements were seen in 43% of patients on phytotherapy with Serenoa repens or Pygeum africanum compared to 57% of those on finasteride and 68% on alpha-blockers. The only combination therapy found to produce a statistically significant improvement over the use of individual drugs was finasteride+tamsulosin (8.1 points compared to 6.7 for tamsulosin alone and 4.2 for finasteride alone). CONCLUSIONS: All drug treatments showed some improvement over watchful-waiting for most patients over the study period: the alpha-blockers were found to be the most effective. There were marked national differences in prescribing patterns, both in individual drug choice and in the use of combination therapies.     

Single-incision laparoscopic surgery in children: initial single-center experience

Background

In continued efforts to further improve the advantages of minimally invasive surgery to patients, surgeons have developed single-incision laparoscopic techniques. We report our initial experience in children with a variety of single-site procedures.

Method

A retrospective chart review was performed on patients who underwent a single-site procedure from April 2009 to April 2010.

Results

There were 142 consecutive procedures: 24 cholecystectomies, 103 appendectomies for nonperforated appendicitis, 2 splenectomies, 1 combined splenectomy/cholecystectomy, 8 ileocecectomies, 2 Meckel diverticulectomies, 1 small bowel duplication resection, and 1 jejunal stricture resection. There were 12 conversions to conventional laparoscopy: 10 during appendectomy and 2 during cholecystectomy. Mean operative time was 34 minutes for appendectomy, 73 minutes for cholecystectomy, 90 minutes for splenectomy, 116 minutes for combined splenectomy/cholecystectomy, 86 minutes for ileocecectomy, and 43 minutes for the small bowel procedures. The only complications were umbilical surgical site infections after appendectomy in 6 patients.

Conclusion

This institution's preliminary experience suggests that single-incision laparoscopic surgery in children has at least comparable outcomes to conventional laparoscopic surgery. However, prospective data are needed to prove that single-incision laparoscopic surgery is superior to conventional laparoscopy.