[Recurrent hypoglycemia due to an occult insulinoma]. / Okkultes Insulinom als Ursache rezidivierender Hypoglykämien.

A 64-year-old woman presented with a history of recurrent hypoglycemia. A prolonged fasting test revealed an increased "amended" insulin-glucose ratio. Transabdominal ultrasound (US), computed tomography (CT) scan, and magnetic resonance imaging (MRI) did not show abnormal results. An insulinoma was suspected based on a contrast-enhanced endoscopic US examination as well as a (68)gallium-DOTA-exendin-4 positron-emission tomography (PET)/CT. The diagnosis of an insulinoma was confirmed histologically after surgical removal of the tumor. Hypoglycemia did not occur during the postoperative period. The prolonged fasting test is the gold standard for the diagnosis of an insulinoma. Novel imaging procedures, such as contrast-enhanced endoscopic US or (68)gallium-DOTA-exendin-4 PET/CT are valuable additions to the diagnostic workup.

Hyperglycaemia is associated with impaired pulsatile insulin secretion: effect of basal insulin therapy.

AIM: Postprandial insulin pulsatility is impaired in patients with type 2 diabetes, but the effects of exogenous insulin therapy on pulsatile insulin secretion are not known. We addressed, whether pulsatile insulin secretion is related to glycaemic control, whether basal insulin supplementation increases postprandial insulin secretion, and if so, is this accomplished by a specific improvement in pulsatile insulin secretion? METHODS: Fourteen patients with type 2 diabetes underwent a mixed meal test before and after an 8-week treatment period with insulin glargine. Glucose, insulin and C-peptide levels were measured, and insulin pulsatility was determined by deconvolution analysis. RESULTS: Insulin treatment lowered fasting glycaemia from 179.6 ± 7.5 mg/dl to 117.6 ± 6.5 mg/dl (p < 0.001). Postprandial insulin and C-peptide levels increased significantly after the treatment period (p < 0.0001). The total calculated insulin secretion rate increased with insulin treatment (p = 0.0039), with non-significant increases in both pulsatile and non-pulsatile insulin secretion. Insulin pulse frequency was unchanged by the intervention. There was an inverse relationship between fasting and postprandial glycaemia and insulin pulse mass (r(2) = 0.51 and 0.56, respectively), whereas non-pulsatile insulin secretion was unrelated to either fasting or postprandial glucose concentrations (r(2) = 0.0073 and 0.031). CONCLUSIONS: Hyperglycaemia in type 2 diabetes is associated with a reduction in postprandial insulin secretion, specifically through a reduction in insulin pulsatility. Reducing chronic hyperglycaemia by basal insulin therapy enhances endogenous ß-cell function in the postprandial state. These data support the use of basal insulin regimens in the pharmacotherapy of overtly hyperglycaemic patients with type 2 diabetes.

Pancreatic diabetes manifests when beta cell area declines by approximately 65% in humans.

AIMS/HYPOTHESIS: Diabetes frequently develops in patients with pancreatic disorders. We aimed to determine the lower threshold of beta cell area for diabetes manifestation as well as the impact of insulin sensitivity on glucose homoeostasis in patients with pancreatic diabetes. METHODS: Eighty-two patients undergoing pancreatic surgery underwent pre-operative oral glucose challenge. Fractional pancreatic beta cell area was determined, and indices of insulin sensitivity and beta cell function were calculated. RESULTS: HbA1c and glucose levels were similar in patients with high and intermediate beta cell area, but were significantly higher in those with the lowest beta cell area (p < 0.0001). Insulin secretion was reduced only in patients with the lowest beta cell area (p < 0.001). The relative beta cell deficits at the onset of diabetes and impaired glucose tolerance were 64% and 21%, respectively, based on 2 h glucose levels. Deteriorating insulin sensitivity was associated with a small increase in the incidence of diabetes. CONCLUSIONS/INTERPRETATION: In conclusion, pancreatic diabetes probably develops after a reduction in beta cell area of ~65%. Post-challenge glucose excursions are much more closely related to pancreatic beta cell area than to fasting glycaemia, thereby underlining the usefulness of the OGTT in patients with pancreatic disorders.

Determinants of glucose control in patients with chronic pancreatitis.

AIMS/HYPOTHESIS: Diabetes frequently develops in patients with chronic pancreatitis (CP). Partial pancreatectomy has emerged as a treatment option for such patients. We addressed whether the development of diabetes in CP patients is related to pancreatic beta cell area or clinical variables, and which factors predict the diabetes risk after partial pancreatectomy. METHODS: Fractional beta cell area was determined in pancreatic tissue samples obtained from 114 CP patients undergoing pancreatic surgery and related to measures of glucose control, as well as clinical and anthropometric data. Seventy-four patients without diabetes at the time of surgery were contacted again 2.5 +/- 1.0 years after partial pancreatectomy in order to obtain information about the post-operative development of diabetes. RESULTS: In the surgical samples in the whole cohort, pancreatic beta cell area was 0.40 +/- 0.06% in patients with and 0.64 +/- 0.06% in those without previously known diabetes (p = 0.039). There was an inverse non-linear relationship between pancreatic beta cell area and fasting glucose concentrations (r = 0.29) as well as HbA(1c) levels (r = 0.36). Nineteen out of 74 previously normoglycaemic patients (26%) developed diabetes over an average period of 2.5 years of follow-up. Pre-operative fasting glucose levels, HbA(1c) and BMI were identified as predictors of diabetes after partial pancreatectomy. However, pancreatic beta cell area did not differ in those who subsequently developed diabetes (0.66 +/- 0.15%) and those who did not (0.62 +/- 0.08%, p = 0.45). CONCLUSIONS/INTERPRETATION: Hyperglycaemia in CP patients is associated with reduced beta cell area. However, reduced beta cell area does not predict the development of diabetes, suggesting that other factors are more important determinants of alterations in glucose metabolism in patients with CP.

Metabolic consequences of a 50% partial pancreatectomy in humans.

AIMS/HYPOTHESIS: Partial pancreatectomy is frequently performed in patients with pancreatic tumours or chronic pancreatitis, but little is known about the metabolic impact of this intervention. We examined the effects of approximately 50% partial pancreatectomy on glucose homeostasis and insulin secretion. METHODS: Fourteen patients with chronic pancreatitis, ten patients with pancreatic carcinoma and 13 patients with benign pancreatic tumours or extra-pancreatic masses (control group) underwent 240 min oral glucose tolerance tests before and after pancreatic tail-resection (n = 12), duodenopancreatectomy (n = 19) or duodenum-preserving pancreatic-head resection (n = 6). RESULTS: Partial pancreatectomy led to a reduction in post-challenge insulin excursions by 49% in chronic pancreatitis patients, 52% in carcinoma patients and 55% in controls (p < 0.05). Nevertheless, post-challenge glucose concentrations were transiently ameliorated after surgery (p < 0.001). In the control participants, pancreatic-head resection caused a transient reduction of post-challenge glycaemia, whereas pancreatic-tail resection increased both fasting and post-challenge glycaemia (p < 0.05). Insulin sensitivity was highest in chronic pancreatitis patients before surgery (p < 0.01), but remained unchanged by the partial pancreatectomy. High pre-operative body weight and elevated fasting glucose levels were associated with poor glycaemic control after surgery. CONCLUSIONS/INTERPRETATION: Insulin secretion is diminished after pancreatic-head and -tail resection, but post-challenge glucose concentrations can be ameliorated after pancreatic-head resection. These data highlight the unequal impact of different surgical procedures on glucose control and suggest that obesity and high pre-operative glucose levels should be considered as risk factors for the development of hyperglycaemia after pancreatic surgery.

Excess glycaemic excursions after an oral glucose tolerance test compared with a mixed meal challenge and self-measured home glucose profiles: is the OGTT a valid predictor of postprandial hyperglycaemia and vice versa?

INTRODUCTION: Postprandial hyperglycaemia is often assumed in individuals with high glucose excursions during an oral glucose tolerance test (OGTT), but the relationship between glucose levels during the OGTT and after a mixed meal is yet unclear. We addressed whether (i) glucose concentrations after an oral glucose load are similar to those after a test meal or under daily life conditions and (ii) impaired glucose tolerance (IGT) predicts postprandial hyperglycaemia. PATIENTS AND METHODS: A total of 60 subjects with normal (NGT), IGT or diabetic (DM) glucose tolerance were examined with an OGTT, a mixed meal challenge (3433 kJ) and a self-determined 10-point home glucose profile. RESULTS: There was a significant correlation between the 120-min OGTT glucose levels and the glycaemic excursions after the test meal and during everyday conditions. However, glucose excursions during the OGTT exceeded those after the test meal and during everyday conditions by approximately 20 and approximately 30% respectively. Likewise, insulin and C-peptide levels rose to higher levels after oral glucose compared with mixed meal ingestion. The mean self-determined diurnal glucose levels were already 10% higher in subjects with IGT compared with NGT subjects (p < 0.0001). CONCLUSIONS: Glucose levels reached after an oral glucose challenge and during real life are correlated to some extent, but the absolute levels of glycaemia greatly differ between both conditions. Therefore, 'postchallenge' glucose levels measured during an OGTT might be used as a predictor of 'postprandial hyperglycaemia', but caution should be taken when both terms are used synonymously. Furthermore, subjects with IGT during an OGTT already exhibit increased postprandial glucose levels under real-life conditions. This suggests that IGT should already be considered an overt disease condition rather than merely a high-risk situation.

Autonomic dysfunction of gastric motility in major depression.

BACKGROUND: Patients suffering from major depressive disorder (MDD) often complain about somatic symptoms. Cardiac complaints have been examined predominantly. However, gastrointestinal complaints are also reported frequently and are associated with worse outcomes. The research concerning changes in gastric motility of these patients is rather sparse. The aim of our study was to determine dysfunction of gastric motility and gastrointestinal symptoms in MDD. The duration and severity of MDD were examined regarding its influence over gastric emptying. METHODS: Gastric emptying was determined by a 13C-acetate breath test in patients with MDD (n = 29) and healthy control subjects (n = 51). Prior to this, depressive illness was operationalized using external and self-assessment scales (HAMD-21, MADRS, BDI, CGI). Whether the severity or duration of MDD influenced the gastric emptying parameters was examined using Spearman's correlation. In addition, autonomic complaints were recorded by means of an ANS score. Each ANS score item was determined using a Mann-Whitney U or Kruskal-Wallis test concerning the gastric emptying parameters. RESULTS: There was a significant difference in the parameters of the maximum gastric emptying rate (Tmax) and gastric half emptying time T1/2b between patients with MDD and healthy control subjects (Tmax 66.21min vs 53.35min, p < 0.006, T1/2b 207.59min vs 133.27min, p < 0.005). There was a significant negative correlation between Tmax and the severity of MDD determined with the depression rating scales BDI (Spearman's rank - 0.521, p = 0.013) and HAMD-21 (r - 0.384, p = 0.048). No correlation was found between the duration of MDD and the maximum gastric emptying rate (r - 0.125, p = 0.519) and gastric half emptying time (r - 0.62, p = 0.749). CONCLUSION: Gastrointestinal motility is significantly impaired in patients with MDD compared to healthy control subjects. Autonomic complaints were indicated frequently in MDD patients. The duration of MDD had no influence over the time of gastric emptying. There was a significant negative correlation between the severity of MDD and Tmax, indicating that the Tmax was reached earlier with the progression of MDD. The slowing of gastric motility in MDD patients is likely a result of a dysfunction of the autonomic nervous system.

Persistent spatial structuring of coastal ocean acidification in the California Current System.

The near-term progression of ocean acidification (OA) is projected to bring about sharp changes in the chemistry of coastal upwelling ecosystems. The distribution of OA exposure across these early-impact systems, however, is highly uncertain and limits our understanding of whether and how spatial management actions can be deployed to ameliorate future impacts. Through a novel coastal OA observing network, we have uncovered a remarkably persistent spatial mosaic in the penetration of acidified waters into ecologically-important nearshore habitats across 1,000 km of the California Current Large Marine Ecosystem. In the most severe exposure hotspots, suboptimal conditions for calcifying organisms encompassed up to 56% of the summer season, and were accompanied by some of the lowest and most variable pH environments known for the surface ocean. Persistent refuge areas were also found, highlighting new opportunities for local adaptation to address the global challenge of OA in productive coastal systems.

Estimation of time as a measure of pain magnitude.

A new method of measuring pain is presented where the patient's estimation of time is used as a pain-related parameter. Pain patients experience a certain time period as increased when compared with pain free control subjects. The increase in time estimation correlates roughly with the clinical estimate of pain severity in different diagnostic groups. Successfully treated patients change their time estimation towards normal. It is considered that this method could be used to evaluate a certain patient's pain and the effectiveness of treatment in relation to the mean time estimate of other patients with the same diagnosis.

Signs of adaptation to local pH conditions across an environmental mosaic in the California Current Ecosystem.

Little is known about the potential for rapid evolution in natural populations in response to the high rate of contemporary climatic change. Organisms that have evolved in environments that experience high variability across space and time are of particular interest as they may harbor genetic variation that can facilitate evolutionary response to changing conditions. Here we review what is known about genetic capacity for adaptation in the purple sea urchin, Strongylocentrotus purpuratus, a species that has evolved in the upwelling ecosystem of the Northeast Pacific Ocean. We also present new results testing for adaptation to local pH conditions in six populations from Oregon to southern California. We integrate data on 19,493 genetic polymorphisms with data on local pH conditions. We find correlations between allele frequency and rank average time spent at pH <7.8 in 318 single-nucleotide polymorphisms in 275 genes. Two of the genes most correlated with local pH are a protein associated with the cytoskeleton and a proton pump, with functional roles in maintenance of cell volume and with internal regulation of pH, respectively. Across all loci tested, high correlations with local pH were concentrated in genes related to transport of ions, biomineralization, lipid metabolism, and cell-cell adhesion, functional pathways important for maintaining homeostasis at low pH. We identify a set of seven genes as top candidates for rapid evolutionary response to acidification of the ocean. In these genes, the putative low-pH-adapted allele, based on allele frequencies in natural populations, rapidly increases in frequency in purple sea urchin larvae raised at low pH. We also found that populations from localities with high pH show a greater change in allele frequency toward putative low-pH-adapted alleles under experimental acidification, compared with low-pH populations, suggesting that both natural and artificial selection favor the same alleles for response to low pH. These results illustrate that purple sea urchins may be adapted to local pH and suggest that this species may possess the genetic capacity for rapid evolution in response to acidification. This adaptive capacity likely comes from standing genetic variation maintained in nature by balancing selection across the spatial and temporal environmental mosaic that characterizes the California Current Ecosystem.

Emergence of anoxia in the California current large marine ecosystem.

Eastern boundary current systems are among the world's most productive large marine ecosystems. Because upwelling currents transport nutrient-rich but oxygen-depleted water onto shallow seas, large expanses of productive continental shelves can be vulnerable to the risk of extreme low-oxygen events. Here, we report the novel rise of water-column shelf anoxia in the northern California Current system, a large marine ecosystem with no previous record of such extreme oxygen deficits. The expansion of anoxia highlights the potential for rapid and discontinuous ecosystem change in productive coastal systems that sustain a major portion of the world's fisheries.

Detection of direct versus indirect effects: were experiments long enough?

To evaluate the hypothesis that indirect effects generally take much longer to become evident in manipulative studies of community regulation than do direct effects and thus may often be missed, I studied the effect of experiment duration in a survey of marine intertidal interaction webs. Contrary to expectation, indirect effects appeared either simultaneously with direct effects or shortly after direct effects were evident. While experiment durations varied greatly, on average most direct and indirect effects became statistically significant within the first 20%-40% of the total experiment duration. Further, the duration of most experiments appeared sufficient so that most indirect effects that would be generated by the manipulation could be observed. On average, a period of "constancy" (i.e., of no further change) lasting roughly 20%-60% of the total experiment duration occurred after the last indirect effect was observed. Experiment duration did not vary with web species richness, which suggests no tendency to perform manipulations for more (or less) time in more complex webs. The number of indirect effects per species did not increase with increasing experiment duration, nor did the number of longer interaction chains (four species vs. three species), which suggests no trends for increased complexity of indirect effects with longer experiments. Ecological theory states that, in interaction webs whose dynamics are imperfectly known, indirect effects may compromise the predictability of species manipulations. However, empirical results suggest that, despite incomplete knowledge of indirect effects, community dynamics may be more predictable than expected.

Role of scale and environmental factors in regulation of community structure.

Pattern in ecological communities - the distribution, abundance and diversity of species - depends on a complex interplay between large - and local-scale processes. Large-scale variation in factors such as environmental stress, dispersal or productivity sets the stage for local-scale ecological processes such as predation or competition. Until recently, most research focused on local-scale explanations of community pattern. Current models attempt to integrate the role of individual large-scale factors with local-scale processes. This trend will continue, with increased effort to understand the specific means by which large-scale factors cause variation among communities.

[Effect of furosemide on the hemodynamics of the kidney medulla during salt depletion]. / Die Wirkung von Furosemid auf die Hämodynamik des Nierenmarks bei Salzverarmung.

UNLABELLED: In sodium depleted rats cortical and medullary blood flow was studied before and after 4-chloro-N-(2-furylmethyl)-5-sulfamoyl-anthranilic acid (furosemide). 86Rb was used as an indicator of renal hemodynamics. Its activity was assessed in systemic blood and in tissue slices of the kidney. At the beginning of the experiments the animals were loaded p.o. with 1.3 ml/100 g b.w. of isotonic saline. 3 h later a rapid i.v. injection of 50 muCi (=5.6 MBq) 86Rb was given to 12 control and 9 furosemide treated animals. RESULTS: After 0.7 mg/100 g b.w. of furosemide the sodium and water excretion rises to 820% and 860% resp. (p less than 0.0005). Systemic body hematocrit increases from 47 to 49%. The renal cortical blood flow is not influenced by furosemide. Compared with controls there is a decrease in blood flow through the outer medulla from 1.57 +/- 0.65 to 1.00 +/- 0.37 ml/g.min, through the inner medulla from 0.75 +/- 0.30 to 0.59 +/- 0.23 ml/g.min, and through the papillary tips from 0.85 +/- 0.40 to 0.46 +/- 0.18 ml/g.min. However, these hemodynamics changes are not significant. It is concluded that the decrease in renal medullary hemodynamics of furosemide-treated rats is due to a stimulation of the renin-angiotensin system.

[Differentiation of the effect of diuretic urine extracts on the renal medullary blood flow (author's transl)]. / Differenzierung der Wirkung von diuretischen Harnextrakten auf die Nierenmarkdurchblutung

In sodium depleted rats urine extracts of hydrated healthy human volunteer cause an increase in water excretion of 52% (p less than 0.005) and in sodium excretion of 45% (p less than 0.005). Cardiac output of the volumen loaded rats increases from 465 +/- 104 ml to 528 +/- 128 ml/kg-min (p=n.s.). Rb86 is used as an indicator for renal hemodynamics. Compared with controls there is an increase in blood flow through the outer medulla from 1.57 +/- 0.65 to 2.28 +/- 0.61 ml/g-min, through the inner medulla from 0.75 +/- 0.30 to 1.01 +/- 0.30 ml/g-min, and through the papillary tips from 0.85 +/- 0.04 ml to 1.21 +/- 0.25 ml/g-min. The experiments show that the diuretic/natriuretic urine extracts influence the hemodynamics of the renal medulla.However, since the significance level of the enhanced medullary blood flow is only low (p less than 0.1) it is impossible to find out the direct site of action of the urine extracts.

Studies on the fine structure of corynebacterium diphtheriae-granules.

The seemingly homogeneous metachromatic and electron-scattering granules of Corynebacterium diphtheriae have two structural components as revealed under conditions of low beam load and by use of ribonuclease. They contain high percentages of P and Ca. Findings point to participation of ribosomes and intracytoplasmic membranes in the formation of the granules.

Electron microscopy of frozen-hydrated bacteria.

Amorphous, unstained, frozen-hydrated sections of bacteria provide a faithful high-resolution image of procaryotic cells. Conventional preparation artifacts due to fixation, staining, and dehydration are nonexistent. Freezing damage is avoided by using glucose as a cryoprotectant. Cutting damage on frozen material is severe, but sectioning artifacts, being always related to the cutting direction, can be systematically recognized and thus taken into consideration. Geometry and density distribution of the bacterial envelope can be resolved to about 3 nm. The following main features have been observed. In Escherichia coli the inner and outer membranes have an approximately uniform density profile. The distance between the two membranes is constant, ca. 33 nm. In Staphylococcus aureus the cell wall is ca. 40 nm wide. It is bordered on the cytoplasmic side by an asymmetric 5.5-nm-wide bilayer. The bacterial nucleoid, clearly visible with conventional preparation methods, appears in exponentially growing bacteria as an ill-defined central region with approximately the same density as the rest of the cytoplasm. It becomes more clearly visible when bacteria are in the stationary phase, plasmolysed, fixed, or stained. We confirm that "mesosomes," hitherto quite often considered to be essential organelles in all procaryotes, are artifacts. They appear in large numbers during osmium fixation.

Benthic-pelagic links and rocky intertidal communities: bottom-up effects on top-down control?

Insight into the dependence of benthic communities on biological and physical processes in nearshore pelagic environments, long considered a "black box," has eluded ecologists. In rocky intertidal communities at Oregon coastal sites 80 km apart, differences in abundance of sessile invertebrates, herbivores, carnivores, and macrophytes in the low zone were not readily explained by local scale differences in hydrodynamic or physical conditions (wave forces, surge flow, or air temperature during low tide). Field experiments employing predator and herbivore manipulations and prey transplants suggested top-down (predation, grazing) processes varied positively with bottom-up processes (growth of filter-feeders, prey recruitment), but the basis for these differences was unknown. Shore-based sampling revealed that between-site differences were associated with nearshore oceanographic conditions, including phytoplankton concentration and productivity, particulates, and water temperature during upwelling. Further, samples taken at 19 sites along 380 km of coastline suggested that the differences documented between two sites reflect broader scale gradients of phytoplankton concentration. Among several alternative explanations, a coastal hydrodynamics hypothesis, reflecting mesoscale (tens to hundreds of kilometers) variation in the interaction between offshore currents and winds and continental shelf bathymetry, was inferred to be the primary underlying cause. Satellite imagery and offshore chlorophyll-a samples are consistent with the postulated mechanism. Our results suggest that benthic community dynamics can be coupled to pelagic ecosystems by both trophic and transport linkages.

Coastal oceanography sets the pace of rocky intertidal community dynamics.

The structure of ecological communities reflects a tension among forces that alter populations. Marine ecologists previously emphasized control by locally operating forces (predation, competition, and disturbance), but newer studies suggest that inputs from large-scale oceanographically modulated subsidies (nutrients, particulates, and propagules) can strongly influence community structure and dynamics. On New Zealand rocky shores, the magnitude of such subsidies differs profoundly between contrasting oceanographic regimes. Community structure, and particularly the pace of community dynamics, differ dramatically between intermittent upwelling regimes compared with relatively persistent down-welling regimes. We suggest that subsidy rates are a key determinant of the intensity of species interactions, and thus of structure in marine systems, and perhaps also nonmarine communities.