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Objective To investigate whether paresthesia of the lower extremities following exposure to the World Trade Center (WTC) disaster was associated with signs of neuropathy, metabolic abnormalities, or neurotoxin exposures. Methods Case-control study comparing WTC-exposed paresthesia cases with "clinic controls" (WTC-exposed subjects without paresthesias), and "community controls" (WTC-unexposed persons). Results Neurological histories and examination findings were significantly worse in cases than controls. Intraepidermal nerve fiber densities were below normal in 47% of cases and sural to radial sensory nerve amplitude ratios were less than 0.4 in 29.4%. Neurologic abnormalities were uncommon among WTC-unexposed community controls. Metabolic conditions and neurotoxin exposures did not differ among groups. Conclusions Paresthesias among WTC-exposed individuals were associated with signs of neuropathy, small and large fiber disease. The data support WTC-related exposures as risk factors for neuropathy, and do not support non-WTC etiologies.

OBJECTIVE To develop a disease-specific questionnaire for identifying domains having the greatest impact on the quality of life (QOL) of patients with neuroendocrine tumors (NETS). METHODS Patient responses to clinical interviews provided an 80-item initial pool for the development of the QOL-NET. The Delphi panel reviewed the items for content validity; the patient focus group reviewed the items for content/readability. Domains were derived from analysis of224 questionnaire responses. After principal components analysis, a scree plot suggested 7 domains. Exploratory factor analysis with forced 7-factor varimax rotation determined an ideal structure. Reliability/reproducibility was determined by test/retest 4 to 6 weeks apart. Logistic regression determined each domain score. RESULTS All 7 domains exhibited strong internal consistency (Cronbach alpha = 0.86-0.97). Physical functioning contributed 40% of the total QOL score, followed by flushing, gastrointestinal symptoms, respiratory, cardiovascular, depression, and attitude domains. Most items loaded 0.40 or higher. No significant differences in test and retest scores. The mean values for the total QOL and 4 of 7 factor scores were significantly higher (P < 0.05) for NETS than controls: sensitivity was 71.4% and specificity was 69.6% to discriminate the NETS from the controls. CONCLUSIONS We developed a 7-domain tool to determine QOL in NETS. Strong internal consistency exists within each domain of the QOL-NET. The QOL-NET is reliable and reproducible but weakly identifies NETS. Physical functioning is a greatest contributor to QOL impairment in NETS.

OBJECTIVES This supplement represents the proceedings of a panel of investigators whose goal was to assess the quality of evidence pertaining to current therapeutic approaches in the management of neuroendocrine tumors (NETs). It will examine the differences in opinions between expert faculty and community physicians. METHODS The Neuroendocrine Tumors Summit convened in December 2009 to address 6 statements prepared by panel members that reflect important questions in the management of NETs. RESULTS Panel members were polled on their acceptance of each statement, and those results were compared with community-based oncologists, gastroenterologists, and endocrinologists. CONCLUSIONS More education regarding the treatment of NETs, including pertinent studies, is needed for physicians. Additional multicenter, prospective, placebo-controlled trials are necessary to demonstrate the benefits of somatostatin analogs, including their ability to control symptoms and affect tumor growth, and their synergistic effect with other therapies. New trials should be reported consistently and include time to tumor progression and progression-free survival as primary or secondary end points.

Pheochromocytomas, intra-adrenal paraganglioma, and extra-adrenal sympathetic and parasympathetic paragangliomas are neuroendocrine tumors derived from adrenal chromaffin cells or similar cells in extra-adrenal sympathetic and parasympathetic paraganglia, respectively. Serious morbidity and mortality rates associated with these tumors are related to the potent effects of catecholamines on various organs, especially those of the cardiovascular system. Before any surgical procedure is done, preoperative blockade is necessary to protect the patient against significant release of catecholamines due to anesthesia and surgical manipulation of the tumor. Treatment options vary with the extent of the disease, with laparoscopic surgery being the preferred treatment for removal of primary tumors. Medullary thyroid cancer (MTC) is a malignancy of the thyroid C cells or parafollicular cells. Thyroid C cells elaborate a number of peptides and hormones, such as calcitonin, carcinoembryonic antigen, and chromogranin A. Some or all of these markers are elevated in patients with MTC and can be used to confirm the diagnosis as well as to follow patients longitudinally for recurrence. Medullary thyroid cancer consists of a spectrum of diseases that ranges from extremely indolent tumors that are stable for many years to aggressive types associated with a high mortality rate. Genetic testing for RET mutations has allowed identification of familial cases and prophylactic thyroidectomy for cure. The only curative treatment is complete surgical resection.

Objective Pancreastatin is a fragment of the chromogranin A (CgA) molecule. Existing pancreastatin assays, which depend on antibodies that cross-react in varying percents with the larger prohormone, may lack sensitivity and specificity to detect small changes in neuroendocrine tumor volume. Methods We developed a highly specific, sensitive pancreastatin assay. The antibody used recognizes the carboxyl terminal of the peptide hormone and was raised against a 17-amino acid porcine pancreastatin fragment with high homology with the carboxy-terminal amino acids 286-301 of the human CgA. Results Our assay measures more than 95% of circulating pancreastatin levels; has little or no cross-reactivity with CgA, even at plasma concentrations of 1000 ng/mL; and can detect pancreastatin levels of 17 pg/mL. Interassay reproducibility for the pancreastatin radioimmunoassay was determined from results of 3 quality control pools in 15 consecutive assays. Coefficients of variation for low, medium, and high pancreastatin levels were less than 20%. The sensitivity of serial pancreastatin assays to detect early liver tumor activity was demonstrated in 2 patients with slowly progressive neuroendocrine tumors and in patients undergoing surgical cytoreduction. Conclusions This highly specific, sensitive pancreastatin assay can detect small changes in liver tumor progression and is up to 100-fold more sensitive and specific than CgA assays in the United States.

Islet neogenesis-associated protein (INGAP) can enhance beta-cell mass to offset progression of diabetes. Identifying how transcription factors regulate INGAP gene expression could reveal key checkpoints governing islet neogenesis.Protein complex interactions at the INGAP promoter were detected using a beta-galactosidase reporter, these protein-DNA complexes being validated in competitive electrophoresis mobility shift assays. The relevance of the revealed promoter interactions was confirmed in small interfering RNA (siRNA) gene knockdown studies.Pdx-1 negatively regulates stimulation of the INGAP promoter by Pan-1/NeuroD. Independently, Pdx-1, Pan-1, and NeuroD bind to the INGAP promoter as revealed by electrophoresis mobility shift assay studies. In combination, Pdx-1 selectively displaces NeuroD from a DNA-binding complex with Pan-1 to form a non-DNA-binding unit. The importance of this interaction is shown in HIT cells that have a forced reduction of Pdx-1 expression. In siRNA/Pdx-1-depleted HIT cells, the interaction of Pan-1/NeuroD with the INGAP promoter is increased 6-fold. Furthermore, endogenous INGAP expression is detected in Pdx-1-depleted cells.These data reveal a dynamic interaction between Pdx-1, NeuroD, and Pan-1 for the regulation of INGAP promoter activity. Modulating molecular regulators of DNA expression may be a consideration in diabetic therapies that translate exogenous stimuli into new endogenous beta-cell mass.

In this review, we focus on the use of biochemical markers for the diagnosis of neuroendocrine tumors and exclusion of conditions that masquerade as neuroendocrine tumors. In addition, we outline the use of biochemical markers for follow-up, response to intervention, and determination of prognosis. Previous publications have focused only on markers specific to certain tumor types, but the uniqueness of this chapter is that it presents a new approach ranging from biochemical markers that relate to symptoms to the use of markers that facilitate decision making with regard to optimizing the choices of therapy from the complex arrays of intervention, The sequence of presentation in this chapter is first to provide the usual view, that is, biochemical markers of each tumor type and thereafter the diagnosis of the underlying condition or exclusion thereof and finally the algorithm for their use from the clinical presentation to the suspected diagnosis and the biochemical markers to monitor progression and therapeutic choice. There is also a specific description of the properties of the most important biochemical markers and 2 complications, bone metastasis and carcinoid heart disease, from the biochemical point of view.

OBJECTIVES Diabetes is a serious health problem. It has been proposed that islet neogenesis from pancreatic progenitor cells may restore insulin secretion in diabetic mammals. Islet neogenesis- associated protein (INGAP) stimulates islet neogenesis; therefore, we hypothesized that it would stimulate islet neogenesis in dogs. METHODS Forty nondiabetic beagle dogs were randomly divided into 4 groups. Group 1 received daily intramuscular injections of vehicle, whereas the other 3 groups received daily INGAP injections of 0.5, 1.5, or 10 mg/kg. After 30 days, pancreatic tissues were collected, and RNA and histological sections were analyzed. RESULTS In dogs treated with 1.5 mg/kg INGAP, there was a significant (P < 0.001) increase in the percentage of insulin-positive cells (P < 0.001) and insulin gene expression. There was a trend to increased insulin-positive cells and gene expression with treatments of 0.5 and 10 mg/kg peptide. Protein gene product 9.5-positive cells were increased with treatment. CONCLUSIONS These results indicate that INGAP stimulates cells in the pancreatic duct epithelium of healthy dogs (putative islet progenitor cells) to develop along a neuroendocrine pathway and form new islets in response to INGAP peptide. The INGAP might be an effective therapy for diabetes.

Purpose of reviewDiabetic neuropathies are a complex, heterogeneous group of disorders that include a wide range of abnormalities. They can be focal or diffuse, proximal or distal, affecting both somatic and autonomic nervous systems. Diabetic neuropathy causes considerable morbidity and mortality a

The objective of this study was to demonstrate that islet neogenesis-associated protein (INGAP) peptide, a pentadecapeptide containing the biologically active portion of native INGAP, increases functional beta-cell mass in normal animals and can be used therapeutically to reverse hyperglycemia in streptozotocin-induced diabetes.INGAP, a 175 amino acid pancreatic acinar cell protein, has been suggested to be implicated in beta-cell mass expansion.In the first part of this study, normoglycemic hamsters were administered either 500 microg INGAP peptide (n = 30) or saline (n = 20) intraperitoneally daily and sacrificed after 10 or 30 days of treatment. Blood glucose and insulin levels were measured, and a histologic and morphometric analysis of the pancreas was performed to determine the effect of INGAP peptide on the endocrine pancreas. In the second part of the study, 6- to 8-week-old C57BL/6J mice (n = 8) were administered multiple low doses of the beta-cell toxin streptozotocin (STZ) inducing insulitis and hyperglycemia. The mice were then injected with INGAP peptide (n = 4) or saline (n = 4) for 39 days and sacrificed at 48 days. Two additional groups of diabetic mice were administered either a peptide composed of a scrambled sequence of amino acids from INGAP peptide (n = 5) or exendin-4 (n = 5), an incretin that has been associated with amelioration of hyperglycemia.Islet cell neogenesis was stimulated in INGAP-treated hamsters by 10 days. At 30 days, the foci of new endocrine cells had the appearance of mature islets. There was a 75% increase in islet number, with normal circulating levels of blood glucose and insulin. Administration of INGAP peptide to diabetic mice reversed the diabetic state in all animals, and this was associated with increased expression of PDX-1 in duct cells and islet cell neogenesis with a reduction of insulitis in the new islets. Diabetic mice treated with exendin-4 or a scrambled INGAP peptide did not revert from hyperglycemia.Because there is a deficiency of beta-cell mass in both type-1 and type-2 diabetes, INGAP peptide stimulation of fully functional neoislet differentiation may provide a novel approach for diabetes therapy.

Background: Using identical methods, three simultaneous placebo-controlled trials of topiramate for painful diabetic neuropathy (PDN) did not reach significance. This independent yet concurrent placebo-controlled trial used different methods to assess topiramate efficacy and tolerability in PDN. Methods: This 12-week, multicenter, randomized, double-blind trial included 323 subjects with PDN and pain visual analog (PVA) score of at least 40 on a scale from 0 (no pain) to 100 (worst possible pain). Topiramate (n = 214) or placebo (n = 109) was titrated to 400 mg daily or maximum tolerated dose. Short-acting rescue analgesics were permitted only during the first 6 weeks. Results: Baseline characteristics were comparable between groups except for mean body weight (topiramate, 101.4 kg; placebo, 95.7 kg; p = 0.028). Twelve weeks of topiramate treatment reduced PVA scale score (from 68.0 to 46.2 mm) more effectively than placebo (from 69.1 to 54.0 mm; p = 0.038). Fifty percent of topiramate-treated subjects and 34% of placebo-treated subjects responded to treatment, defined as >30% reduction in PVA scale score ( p = 0.004). Topiramate monotherapy also reduced worst pain intensity ( p = 0.003 vs placebo) and sleep disruption ( p = 0.020 vs placebo). Diarrhea, loss of appetite, and somnolence were the most commonly reported adverse events in the topiramate group. Topiramate reduced body weight (−2.6 vs +0.2 kg for placebo; p Conclusions: Topiramate monotherapy reduced pain and body weight more effectively than placebo in patients with painful diabetic neuropathy.

Drugs acting via the same mechanism interact additively, whereas a supraadditive effect can result from an interaction of drugs with different mechanisms of action.Hypnotic midazolam-propofol and midazolam-thiopental interactions are supraadditive. In contrast to midazolam, the mechanisms of actions of propofol and thiopental are quite similar. The aim of this study was to test the hypothesis that similarity in the mechanisms of action of propofol and thiopental results in the additive hypnotic interaction. We studied the hypnotic effects of thiopental, propofol, and their combinations in 150 unpremedicated patients in a randomized, double-blind fashion. The ability to open eyes on command was used as an end point. Dose-response curves for the drugs given separately and in combinations at three different dose ratios between the drugs were determined by using a probit procedure, and the 50% effective dose values were compared by using isobolographic and algebraic (fractional) analysis. The hypnotic propofol-thiopental combination was additive with all dose ratios between components of the combination. The absence of propofol-thiopental synergy, as demonstrated with midazolam-thiopental or propofol-midazolam combinations, suggests that the mechanisms underlying the hypnotic effects of propofol and thiopental, in contrast to the above combinations with midazolam, are very similar and could be identical. Implications: The propofol-thiopental hypnotic interaction is additive. (Anesth Analg 1999;88:667-70)

Studies in experimental animals have demonstrated a rapidly developing acute tolerance to the analgesic effect of opioids administered by continuous i.v. infusion. The aim of the present study was to determine whether acute tolerance plays an important role in the analgesic effect of remifentanil provided by i.v. infusion to humans. The analgesic effect of remifentanil, infused at a constant rate of 0.1 microg x kg(-1) x min(-1) for 4 h, was evaluated by measuring pain tolerance with thermal (2 degrees C water) and mechanical (pressure) noxious stimulations in 13 paid volunteers. The constant-rate infusion of remifentanil resulted in a threefold increase in pain tolerance with both tests. After reaching its maximum in 60-90 min, the analgesic effect of remifentanil began to decline despite the constant-rate infusion, and after 3 h of infusion, it was only one fourth of the peak value. A comparative rate in the development of acute tolerance measured in terms of time to 50% recovery during infusion was 129 +/- 27 min (mean +/- SD) with the cold water test and 138 +/- 39 min with the pressure test. We conclude that the development of tolerance should be included in the calculations for target-controlled infusions.Our study shows that tolerance to analgesia during remifentanil infusion is profound and develops very rapidly. The administration of opioids during anesthesia based on target-controlled infusions should include corrections for the development of tolerance.

Background Bromocriptine‐ QR (a quick‐release formulation of bromocriptine mesylate), a dopamine D2 receptor agonist, is a US F ood and D rug A dministrration–approved treatment for type 2 diabetes mellitus ( T2DM ). A 3070‐subject randomized trial demonstrated a significant, 40% reduction in relative risk among bromocriptine‐ QR ‐treated subjects in a prespecified composite cardiovascular ( CV ) end point that included ischemic‐related (myocardial infarction and stroke) and nonischemic‐related (hospitalization for unstable angina, congestive heart failure [ CHF ], or revascularization surgery) end points, but did not include cardiovascular death as a component of this composite. The present investigation was undertaken to more critically evaluate the impact of bromocriptine‐ QR on cardiovascular outcomes in this study subject population by (1) including CV death in the above‐described original composite analysis and then stratifying this new analysis on the basis of multiple demographic subgroups and (2) analyzing the influence of this intervention on only the “hard” CV end points of myocardial infarction, stroke, and CV death (major adverse cardiovascular events [ MACE s]). Methods and Results Three thousand seventy T2DM subjects on stable doses of ≤2 antidiabetes medications (including insulin) with HbA1c ≤10.0 (average baseline HbA1c =7.0) were randomized 2:1 to bromocriptine‐ QR (1.6 to 4.8 mg/day) or placebo for a 52‐week treatment period. Subjects with heart failure ( N ew Y ork H eart C lasses I and II) and precedent myocardial infarction or revascularization surgery were allowed to participate in the trial. Study outcomes included time to first event for each of the 2 CV composite end points described above. The relative risk comparing bromocriptine‐ QR with the control for the cardiovascular outcomes was estimated as a hazard ratio with 95% confidence interval on the basis of C ox proportional hazards regression. The statistical significance of any between‐group difference in the cumulative percentage of CV events over time (derived from a K aplan– M eier curve) was determined by a log‐rank test on the intention‐to‐treat population. Study subjects were in reasonable metabolic control, with an average baseline HbA1c of 7.0±1.1, blood pressure of 128/76±14/9, and total and LDL cholesterol of 179±42 and 98±32, respectively, with 88%, 77%, and 69% of subjects being treated with antidiabetic, antihypertensive, and antihyperlipidemic agents, respectively. Ninety‐one percent of the expected person‐year outcome ascertainment was obtained in this study. Respecting the CV ‐inclusive composite cardiovascular end point, there were 39 events (1.9%) among 2054 bromocriptine‐ QR ‐treated subjects versus 33 events (3.2%) among 1016 placebo subjects, yielding a significant, 39% reduction in relative risk in this end point with bromocriptine‐ QR exposure ( P =0.0346; log‐rank test) that was not influenced by age, sex, race, body mass index, duration of diabetes, or preexisting cardiovascular disease. In addition, regarding the MACE end point, there were 14 events (0.7%) among 2054 bromocriptine‐ QR ‐treated subjects and 15 events (1.5%) among 1016 placebo‐treated subjects, yielding a significant, 52% reduction in relative risk in this end point with bromocriptine‐ QR exposure ( P Conclusions These findings reaffirm and extend the original observation of relative risk reduction in cardiovascular adverse events among type 2 diabetes subjects treated with bromocriptine‐ QR and suggest that further investigation into this impact of bromocriptine‐ QR is warranted. Clinical Trial Registration URL: http://clinicaltrials.gov . Unique Identifier: NCT00377676

The hypnotic effects of propofol, midazolam, alfentanil, and their binary and triple combinations, were studied in 130 unpremedicated patients in a randomized, double-blind fashion. The ability to open eyes on verbal command was used as an end-point. Dose-response curves for the three drugs given separately and in combination were determined with a probit procedure and the ED50 values were compared with an isobolographic analysis. The ratios of a single-drug fractional dose (ED50 = 1.0) to a combined fractional dose (in fractions of single-drug ED50 values) indicating the degree of superadditivity (synergism) were: 1.4 (P < 0.05) for propofol-alfentanil, 1.8 (P < 0.0005) for midazolam-propofol, 2.8 (P < 0.0001) for midazolam-alfentanil, and 2.6 (P < 0.0001) for propofol-midazolam-alfentanil. The results indicate that the propofol-midazolam-alfentanil interaction produces a profound hypnotic synergism which is not significantly different from that of the binary midazolam-alfentanil combination.

Partial obstruction of the hamster pancreas in the cellophane wrap model leads to the induction of duct and ductular proliferation followed by endocrine cell differentiation. This effect appears to be mediated by the local action of a growth factor. The purpose of the present study was to determine if cytosolic extract prepared from the wrapped pancreas had trophic activity on purified hamster pancreatic ductal epithelium in tissue culture. Cultures of purified pancreatic ducts were prepared by digestion of the hamster pancreas using a solution of collagenase type XI and chymotrypsin infused directly into the pancreatic duct. The ducts were separated and purified by a series of steel mesh filtrations. Ducts were embedded in 1.5% Seaplaque agarose and fed a liquid medium containing serum-free Dulbecco's Modified Eagle Medium/Nutrient Mixture F-12 Ham (DME/F-12), 12.5% cytosol extract+DME/F-12, or 25% cytosol extract+DME/F-12. The trophic effect of the extract on the tissue in culture was evaluated by the incorporation of tritiated thymidine ([3H]TdR) into DNA. Duct fragments cultured in medium supplemented with 12.5% cytosol showed no difference in their [3H]TdR uptake compared with control ducts (908 +/- 147 vs. 913 +/- 151 dpm/micrograms DNA). The incorporation of [3H]TdR by ducts maintained in medium supplemented with 25% cytosol extract was increased 78% over serum-free controls (1,632 +/- 386 vs. 913 +/- 147 dpm/micrograms DNA; p < 0.025). We conclude that a cytosol extract prepared from the partially obstructed cellophane-wrapped pancreas contains a factor(s) trophic for pancreatic ductal cells.

Psychiatric evaluations were completed on four patients who were treated for "idiopathic flushing" with a long-acting analogue of somatostatin. All four patients had symptom profiles consistent with a diagnosis of panic disorder. All four experienced clinically significant relief from panic-like attacks while on the experimental medication. These findings suggest a possible role for somatostatin in the pathophysiology and treatment of panic disorder.