Peter Wellhöner

Association Between Azithromycin Therapy and Duration of Bacterial Shedding Among Patients With Shiga Toxin–Producing Enteroaggregative Escherichia coli O104:H4

CONTEXT An outbreak of Shiga toxin-producing enteroaggregative Escherichia coli (STEC O104:H4) infection with a high incidence of hemolytic uremic syndrome (HUS) occurred in Germany in May 2011. Antibiotic treatment of STEC infection is discouraged because it might increase the risk of HUS development. However, antibiotic therapy is widely used to treat enteroaggregative E coli infection. In the German outbreak, a substantial number of patients received prophylactic azithromycin treatment as part of a therapeutic regimen with the C5 antibody eculizumab. OBJECTIVE To analyze the duration of bacterial shedding in patients with STEC infection who did and did not receive oral azithromycin therapy. DESIGN, SETTING, AND PATIENTS At a single center in Lübeck, Germany, 65 patients with STEC infection, including patients with HUS as well as STEC-infected outpatients without manifestation of HUS, were investigated between May 15 and July 26, 2011, and were monitored for a mean of 39.3 days after onset of clinical symptoms. MAIN OUTCOME MEASURE Carriage of STEC after azithromycin therapy. RESULTS Twenty-two patients received oral azithromycin and 43 patients did not receive antibiotic treatment. Among antibiotic-treated patients, long-term STEC carriage (>28 days) was observed in 1 of 22 patients (4.5%; 95% CI, 0%-13.3%) compared with 35 of 43 patients (81.4%; 95% CI, 69.8%-93.0%) who were not treated with antibiotics (P < .001). All 22 patients receiving azithromycin treatment had at least 3 STEC-negative stool specimens after the completion of treatment, and no recurrence of STEC was observed in these patients. As proof of principle, 15 patients who initially were not treated with antibiotics and were long-term STEC carriers were treated with oral azithromycin given for 3 days and subsequently had negative stool specimens. CONCLUSION Treatment with azithromycin was associated with a lower frequency of long-term STEC O104:H4 carriage.

Intravascular and interstitial degradation of bradykinin in isolated perfused rat heart

1 Bradykinin (BK) has been shown to exert cardioprotective effects which are potentiated by inhibitors of angiotensin I‐converting enzyme (ACE). In order to clarify the significance of ACE within the whole spectrum of myocardial kininases we investigated BK degradation in the isolated rat heart. 2 Tritiated BK (3H‐BK) or unlabelled BK was either repeatedly perfused through the heart, or applied as an intracoronary bolus allowing determination of its elution kinetics. BK metabolites were analysed by HPLC. Kininases were identified by ramiprilat, phosphoramidon, diprotin A and 2‐mercaptoethanol or apstatin as specific inhibitors of ACE, neutral endopeptidase 24.11 (NEP), dipeptidylaminopeptidase IV and aminopeptidase P (APP), respectively. 3 In sequential perfusion passages, 3H‐BK concentrations in the perfusate decreased by 39% during each passage. Ramiprilat reduced the rate of 3H‐BK breakdown by 54% and nearly abolished [1‐5]‐BK generation. The ramiprilat‐resistant kininase activity was for the most part inhibited by the selective APP inhibitor apstatin (IC50 0.9 μM). BK cleavage by APP yielded the intermediate product [2‐9]‐BK, which was rapidly metabolized to [4‐9]‐BK by dipeptidylaminopeptidase IV. 4 After bolus injection of 3H‐BK, 10% of the applied radioactivity were protractedly eluted, indicating the distribution of this fraction into the myocardial interstitium. In samples of such interstitial perfusate fractions, 3H‐BK was extensively (by 92%) degraded, essentially by ACE and APP. The ramiprilat‐ and mercaptoethanol‐resistant fraction of interstitial kininase activity amounted to 14%, about half of which could be attributed to NEP. Only the product of NEP, [1–7]‐BK, was continuously generated during the presence of 3H‐BK in the interstitium. 5 ACE and APP are located at the endothelium and represent the predominant kininases of rat myocardium. Both enzymes form a metabolic barrier for the extravasated fraction of BK. Thus, only interstitial, but not intravascular concentrations of BK are increased by kininase inhibitors to the extent that a significant potentiation of BK effects could be explained. NEP contributes less than 5% to the total kininase activity, but is the only enzyme which is exclusively present in the interstitial space.

Effect of facial cooling and cold air inhalation on sympathetic nerve activity in men

In nine healthy subjects, cold stimuli were administered to the forehead and hand, to the oral and nasal cavities via ice cubes and to the bronchial system via inhalation of cold air (-25 degrees C). Blood pressure, heart rate and muscle sympathetic nerve activity (MSNA) from the peroneal nerve were recorded. MSNA expressed as total activity increased during cold air inhalation, cooling of the forehead (P < 0.001, ANOVA), hand and mouth (P < or = 0.05), paralleled by a rise in blood pressure during cold air inhalation and cooling of the forehead and hand (P < 0.01). Cooling of the forehead provoked a faster increase of MSNA expressed as total activity (P < 0.05) and higher levels of diastolic blood pressure (P = 0.05) compared with cooling of the hand. Bradycardia was observed only during cooling of the nasal cavity (P < 0.001) and the forehead (P < 0.05). It is concluded that cooling of the skin and mucous membranes of the tracheobronchial tract elicits sympathetically mediated hemodynamic adaptations, probably via stimulation of cold-sensitive afferents.

Cold-induced alteration of adipokine profile in humans

Adipose tissue function and sympathetic nervous system (SNS) activity are tightly interconnected. Adipose tissue is densely innervated by the SNS. Adipokines secreted by adipose tissue are implicated in maintaining energy homeostasis, the control of blood pressure, immune system function, hemostasis, and atherosclerosis. Little is known about a direct effect of SNS activation on influencing adipose tissue endocrine function in humans. In 10 lean, healthy male volunteers, SNS was activated by whole-body exposure to cold for 2 hours; a group of 10 subjects served as controls. Vital parameters were evaluated, plasma adipokine levels were measured, and adipokine gene expression in subcutaneous abdominal adipose tissue was determined. Cold exposure caused an increase in cold sensation and a drop in body temperature and heart rate. Norepinephrine, but not epinephrine, plasma levels were elevated. Adiponectin plasma concentrations were acutely and significantly decreased. There was a trend of increased monocyte chemoattractant protein-1 plasma concentrations. Interleukin-6 and leptin levels increased and decreased, respectively, in both groups. Vascular endothelial growth factor plasma levels were unaffected. Subcutaneous adipokine gene expression was unchanged. Cold exposure caused SNS activation and differentially influenced adipokine secretion. Adiponectin levels were acutely reduced, whereas monocyte chemoattractant protein-1 concentrations tended to increase. No specific changes in leptin and IL-6 concentrations were detectable. The observed alterations appeared to be posttranscriptional because adipokine gene expression was found to be unaltered.

Localizing an occult gastrointestinal bleeding by wireless PillCam SB capsule videoendoscopy in a patient with the HeartMate II left ventricular assist device.

Gastrointestinal bleeding is a known problem in patients with left ventricular assist devices (LVADs). The exact source of the bleeding is sometimes difficult to ascertain. In gastroenterology, wireless capsule videoendoscopy has become an important diagnostic tool, especially when the small intestine is involved. It is not known, however, whether an implanted LVAD would interfere with signal transmission from the capsule, nor whether the signals from the capsule would cause malfunction of the LVAD. We report the case of a patient in whom significant gastrointestinal bleeding developed after implantation of a HeartMate II LVAD (Thoratec Corporation, Pleasanton, Calif). The source of the bleeding was successfully identified by wireless PillCam SB capsule videoendoscopy (Given Imaging Ltd, Yoqneam, Israel).

Detrimental effect of high volume fluid administration in acute pancreatitis - a retrospective analysis of 391 patients.

BACKGROUND Early fluid resuscitation is recommended for the therapy of acute pancreatitis in order to prevent complications. There are, however, no convincing data supporting this approach. METHODS We reviewed 391 consecutive cases of confirmed acute pancreatitis. Admitting physicians had been advised to administer an aggressive fluid resuscitation in the early phase of disease, if possible. We tested whether disease severity according to the revised Atlanta Classification, local complications, and maximum C-reactive protein levels were predictable by the initial volume therapy in logistic and linear regression models, respectively. We also determined which parameters on admission encouraged a more aggressive fluid resuscitation. RESULTS The recorded fluid administered within the first 24 h was 5300 [3760; 7100] ml (median [1st; 3rd quartile]). More aggressive volume therapy was associated with disease severity and a higher rate of local complications. There was a linear relationship between administered volume and the maximum C-reactive protein. The amount of administered fluid was significantly attributed to age, hematocrit, and white blood cell count on admission. When adjusted for these parameters the impact of administered volume on outcome was still present but attenuated. CONCLUSIONS We found detrimental effects of fluid therapy on major outcome parameters throughout the whole range of administered volume. More volume was administered in younger patients and in patients with evidence of hemoconcentration and inflammation. The adverse effects of volume therapy persisted after elimination of these parameters. Caution should therefore be advised with regards to volume therapy in patients with acute pancreatitis.

Synthesis of kininogen and degradation of bradykinin by PC12 cells

1 In this study, the abilities of PC12 cells to synthesize and degrade kinins were investigated. Kinin formation was assessed as kinin and kininogen content of cells and supernatants in serum‐free incubations by use of a bradykinin‐specific radioimmunoassay. Expression of kininogen mRNA was demonstrated by reverse‐transcriptase PCR. Kinin degradation pathways of intact PC12 cells were characterized by identification of the kinin fragments generated from tritiated bradykinin either in the absence or presence of the angiotensin I‐converting enzyme inhibitor ramiprilat. 2 Kinin immunoreactivity in the supernatant of PC12 cell cultures accumulated in a time‐dependent fashion during incubations in serum‐free media. This effect was solely due to de novo synthesis and release of kininogen (35 pg bradykinin  h−1 mg−1 protein) since it could be suppressed by cycloheximide. Continuous synthesis of kininogen was a specific property of PC12 cells, as it was not observed in cultured macro‐ or microvascular endothelial cells. PC12 cells contained only minor amounts of stored kininogen. The rate of kininogen synthesis was not affected by ramiprilat, bacterial lipopolysaccharide, nerve growth factor or dexamethasone, but was stimulated 1.4 fold when cells were pretreated for 1 day with 1 μm desoxycorticosterone. 3 By use of cDNA probes specific for kininogen subtype mRNAs, expression of low‐molecular‐weight kininogen and T‐kininogen in PC12 cells was confirmed. Expression of high molecular weight kininogen mRNA was also shown, though only at the lowest limit of detection of the assay. 4 Degradation of tritiated bradykinin by PC12 cells occurred with a half‐life of 48 min resulting in the main fragments [1–7]‐ and [1–5]‐bradykinin. The degradation rate of bradykinin decreased to 15% in the presence of ramiprilat (250 nm). Apart from angiotensin I‐converting enzyme direct cleavage of bradykinin to [1–7]‐ and [1–5]‐bradykinin still occurred under this condition as a result of additional kininase activities. 5 Along with previous findings of B2‐receptor‐mediated catecholamine release, these results now confirm the hypothesis that a cellular kinin system is expressed in PC12 cells. The presence of such a system may reflect a role of kinins as local neuromodulatory mediators in the peripheral sympathetic system.

Prolonged blood pressure elevation following continuous infusion of angiotensin II-a baroreflex study in healthy humans.

ANG II interacts with the sympathetic nervous system at central nervous blood pressure-regulating structures, including the baroreflex. It is unknown whether prolonged BP elevation mediated by high ANG II plasma levels could induce a persistent shift of the central nervous baroreflex setpoint, lasting beyond the short ANG II plasmatic half time of a few seconds, thereby consolidating elevated BP and/or increased SNA in healthy humans. In a blinded crossover design, ANG II or placebo (saline) was infused for a 6-h period in 12 resting normotensive students (6 males, 6 females) raising BP to borderline hypertensive levels. Between 60 and 120 min after the infusion period, muscle sympathetic nerve activity (MSNA) was assessed microneurographically and correlated with oscillometric BP measurements and heart rate at supine rest (baseline) and during pharmacologic baroreceptor challenge. Infusion of ANG II increased BP to borderline-hypertensive levels, as intended, whereas heart rate remained unaltered. At baroreflex assessment (i.e., 60-120 min after end of infusion period), systolic BP was significantly higher compared with placebo (Δ8.4 ± 3.1 mmHg; P < 0.05), whereas diastolic values were nearly equal between conditions. Baseline MSNA was neither decreased nor increased, and baroreflex sensitivity to vasoactive drug challenge was not altered. Our results show that elevation of ANG II plasma levels over 6 h was able to increase systolic, but not diastolic, BP far beyond blood-mediated ANG II effects. MSNA or heart rate did not counter-regulate this BP elevation, indicating that ANG II had sustainably reset the central nervous BP threshold of sympathetic baroreflex function to accept elevated BP input signals without counter-regulatory response.