- Letzte Abfahrt Khyberpass. Afghanisch-pakistanische Ausblicke von Peter Münch, Picus Verlag Wien
- Kriminalgeschichte des Christentums, Bd 9: Mitte des 16. bis Anfang des 18. Jahrhunderts. Vom Völkermord in der Neuen Welt bis zum Beginn der Aufklärung von Karlheinz Deschner, Rowohlt
- Warum denn Gerechtigkeit. Die Logik des Kapitals. Die Politik im Widerstreit mit der Ökonomie von Günter Dux, Velbrück Wissenschaft
- Demokratie - Zumutungen und Versprechungen von Christoph Möllers, Verlag Klaus Wagenbach
- Das Deutsche Reich und der Zweite Weltkrieg. Band 10: Der Zusammenbruch des Deutschen Reiches 1945. Herausgegeben von Rolf-Dieter Müller, Deutsche Verlags-Anstalt
- Das unsterbliche Gerücht: Die Frage nach Gott und der Aberglaube der Moderne vonRobert Spaemann, Klett Cotta
- Kampfplätze der Philosophie von Durt Flasch, Klostermann
- Die Ausgeschlossenen. Das Ende vom Traum einer gerechten Gesellschaft von Heinz Bude, Hanser
- Der aufgeklärte Gott von Alexander Kissler, Pattloch
- Mohammed und die Zeichen Gottes von Nasr Hamid Abu Zaid, Herder
- Was von uns bleibt von Mathias Schreiber, Deutsche Verlagsanstalt
- Schlaglichter. Die ersten beiden islamischen Jahrhunderte von Karl-Heinz Ohlig, Verlag Hans Schiler
- Helden der Hoffnung. Die anderen Deutschen aus den Sudeten 1935-1989 von Alena Wagnerová, Aufbau Verlag
- Lieben ein Leben lang. Wie Beziehungen immer besser werden von Birgit Dechmann, Beltz
- Zeit für Berlin. Metropole für Entdecker und Genießer von Barbara Schaefer, Bruckmann Verlag
- Languedoc-Roussillon von Klaus Simon, DuMont Reiseverlag
- Paris von Sandra Kegel, Ellert&Richter
- Winterguide Südtirol von Georg Weindl, Bruckmann Verlag
Donnerstag, 30. Oktober 2008
Mittwoch, 29. Oktober 2008
Montag, 27. Oktober 2008
Sonntag, 26. Oktober 2008
In der Messehalle wie üblich dichtes Gedränge...und vor der Männertoilette eine ewig lange Schlange...Da ziehen sich tatsächlich einige auf der Toilette um???
Dann geht es los, ich schließe mich dem 5 h-Zugläufer an, bei Kilometer 20 entschwindet er immer mehr...
Vor Höchst holt mich die 5.30iger Gruppe ein, auch die zieht mir davon - wirklich nicht mein Tag!
Schießlich komme ich dann tatsächlich noch in der Festhalle an - Zeit 5.51.44!
Mehr unter http://live.frankfurt-marathon.com/2008; da werden dann in den nächsten Tagen auch die Videosequenzen bei den Zeitmessungen zu sehen sein.
Freitag, 24. Oktober 2008
Rajaraman Durai, specialist registrar1, Sumantra Kumar, consultant radiologist 2, Sha-Nawaz Ruhomauly, consultant surgeon1, Happy Hoque, consultant surgeon1
1 Department of Surgery, Queen Mary’s Hospital, Sidcup, Kent, 2 Department of Radiology Queen Mary’s Hospital, Sidcup, KentBMJ 2008;337:a1953
1 The computed tomogram
The diagnosis of acute appendicitis is often made on the basis of clinical features alone. Acute appendicitis is the commonest cause of acute abdominal pain in children and adults.1 2 In 2006-7, 42 882 patients were admitted with acute appendicitis to English NHS hospitals (www.hesonline.nhs.uk). Early appendicitis may resolve with antibiotics or it may progress to phlegmon, perforation, and abscess formation. If perforation occurs without localisation, it may present with diffuse peritonitis. The incidence of perforated appendicitis varies between 16-30%.3 4 Because very young patients may not be able to communicate, and older patients may present with non-specific signs, the risk of perforation is higher in these groups as diagnosis may be delayed.5 Appendicular perforation is more likely to occur on the third day.6 In a study on 427 patients with appendicitis,7 14 (3.25%) presented with diffuse peritonitis. In the case in question, the patient presented ten days after his abdominal pain had developed. The computed tomogram showed a thin walled gall bladder containing a few calcified gallstones without any signs of acute cholecystitis (figure 2). It also showed an 11x7 cm appendicular abscess with an air fluid level . It was adherent to the right anterior abdominal wall, medial to the caecum and the ascending colon. The terminal ileum and the ileocaecal junction seemed normal without any thickening to indicate Crohn’s disease.
The patient had a history of right iliac fossa pain with raised inflammatory markers and a high Alvarado score. The computed tomogram confirmed an appendicular (perityphlitic) abscess. No evidence was found for any other cause for the abscess.
Midline to right iliac fossa migratory pain, in conjunction with increased inflammatory markers and right iliac fossa peritonism, favours the diagnosis of appendicitis.8 The initial periumbilical pain is referred from the inflamed viscera. The pain migrates to the right iliac fossa when there is irritation of the parietal peritoneum. Several scoring systems are used for right iliac fossa pain to help in the diagnosis of appendicitis. The Alvarado score is commonly used, and when the score is maximal (10/10), the diagnostic accuracy for appendicitis may reach 100%.9 Ultrasonography10 or computed tomography11 may be useful in difficult cases. Ultrasonography is often used in women and children. Computed tomography may help to reduce the negative appendicectomy rate to 3.8%.11
Although the standard approach for appendicitis is open appendicetomy, antibiotics alone may settle appendicitis. A recent randomised controlled trial on acute appendicitis13 compared the outcomes of operative treatment (124 patients) with antibiotic treatment (128 patients). In the antibiotic group, 18 patients failed to improve and required appendicetomy. The remaining 110 patients were followed up for a year, but only 14% had recurrent symptoms.
Appendicitis has a high risk of rupture in very young and elderly patients because it may be difficult to diagnose. Escherichia coli and Bacteroides fragilis are commonly isolated organisms from appendicular abscesses.14 Abscesses larger than 3 cm can be considered serious15 16 and are unlikely to resolve with antibiotics alone.17 Open drainage or appendicectomy can lead to an infection of the wound in up to 16% of patients.18 In all cases of right iliac fossa mass, a carcinoma of the colon should be excluded.19 20 In this case the patient’s abscess was drained radiologically under the guidance of ultrasonography. The patient continued on intravenous cefuroxime and metronidazole, which had been started on admission to reduce the risk of systemic sepsis. The pus grew Enterococcus fecalis. An ultrasonography scan was repeated a week after the drain had been placed, and it showed no residual abscess. The drain was then removed.
The differential diagnosis for the aetiology of a right iliac fossa abscess includes appendicular perforation, caecal diverticular perforation, perforated caecal cancer and perforated ileum from Crohn’s disease. A computed tomogram may help in identifying the cause. Once the acute situation resolves, a colonoscopy or barium study may be required to exclude caecal malignancy.
Several options are available for an appendicular abscess. Firstly, radiological drainage and antibiotics followed by interval appendicectomy. The recent trend is to avoid interval appendicetomy. If there is no recurrence of appendicitis in the first six months, the patient may not benefit from interval appendicectomy21 because the appendix may become fibrotic and the risk of recurrence reduces (10%).22 Another option is open drainage of the abscess and attempted appendicectomy at the same time.18 This may be difficult because of the presence of adhesions and pus from the unresolved inflammatory process. The likelihood of complications such as bowel injury and wound infection is increased. Appendicular abscess is associated with a mortality of 2.9%.23Laparoscopy is useful in the diagnosis and treatment of suspected appendicitis.3 24 The operating time may be slightly longer than at open operation, but no major increase in the formation of intra-abdominal abscesses occurs in uncomplicated appendicitis.25 The laparoscopic approach reduces rates of wound infection and leads to an earlier recovery. Infection of the surgical site after laparoscopy can be reduced by stapled transection of the appendix and closure of the appendicular stump.26
- Wyer PC. Review: symptoms, signs, and lab tests have moderate accuracy for detecting appendicitis in children. Ev Based Med 2008;13:23.
- Liu CD. In: Greenfield LJ, editor. Acute abdomen and appendix. 2nd ed. Philadelphia: Lippincott-Raven, 1997:1246-61.
- Stoltzing H, Thon K. Perforated appendicitis: is laparoscopic operation advisable? Dig Surg 2000;17:610-6.[Medline]
- Humes DJ, Simpson J. Acute appendicitis. BMJ 2006;333:530-4.
[Free Full Text]
- Korner H, Sondenaa K, Soreide JA, Andersen E, Nysted A, Lende TH, et al. Incidence of acute nonperforated and perforated appendicitis: age-specific and sex-specific analysis. World J Surg 1997;21:313-7.Medline]
- Temple CL, Huchcroft SA, Temple WJ. The natural history of appendicitis in adults. A prospective study. Ann Surg 1995;221:278-81.[Medline]
- Haugen RHN. Kaiser permanente medicine 50 years ago: A study of acute appendicitis with perforation with special emphasis on sulfonamide therapy—a preliminary report. Permanente J 2001;5:19-27.
- Edmonds M. Review: inflammatory response variables, descriptors of peritoneal irritation, and migration of pain are most discriminatory of appendicitis. Ev Based Med 2004;9:120.
- Tade AO. Evaluation of Alvarado score as an admission criterion in patients with suspected diagnosis of acute appendicitis. West Afr J Med 2007;26:210-2.[Medline]
- Peng YS, Lee HC, Yeung CY, Sheu JC, Wang NL, Tsai YH. Clinical criteria for diagnosing perforated appendix in pediatric patients. Pediatr Emerg Care 2006;22:475-9.[Medline]
- Harswick C, Uyenishi AA, Kordick MF, Chan SB. Clinical guidelines, computed tomography scan, and negative appendectomies: a case series. Am J Emerg Med 2006;24:68-72.[Medline]
- Chan MY, Tan C, Chiu MT, Ng YY. Alvarado score: an admission criterion in patients with right iliac fossa pain. Surgeon 2003;1:39-41.[Medline]
- Styrud J, Eriksson S, Nilsson I, Ahlberg G, Haapaniemi S, Neovius G, et al. Appendectomy versus antibiotic treatment in acute appendicitis. a prospective multicenter randomized controlled trial. World J Surg 2006;30:1033-7.[Medline]
- Garay J, Conde J, Trallero EP, Tovar J. [Analysis of germ cultures in 57 cases of appendicular peritonitis and 16 postoperative septic complications]. Chir Pediatr 1981;22:13-6.[Medline]
- Berna-Serna JD, Madrigal M. Percutaneous management of breast abscesses. An experience of 39 cases. Ultrasound Med Biol 2004;30:1-6.[Medline]
- Siewert B, Tye G, Kruskal J, Sosna J, Opelka F, Raptopoulos V, et al. Impact of CT-guided drainage in the treatment of diverticular abscesses: size matters. Am J Roentgenol 2006;186:680-6.
[Abstract/Free Full Text]
- Zerem E, Salkic N, Imamovic G, Terzic I. Comparison of therapeutic effectiveness of percutaneous drainage with antibiotics versus antibiotics alone in the treatment of periappendiceal abscess: is appendectomy always necessary after perforation of appendix? Surg Endosc 2007;21:461-6.[Medline]
- De U, Ghosh S. Acute appendicectomy for appendicular mass: a study of 87 patients. Ceylon Med J 2002;47:117-8.[Medline]
- Fiume I, Napolitano V, Del Genio G, Allaria A, Del Genio A. Cecum cancer underlying appendicular abscess. Case report and review of literature. World J Emerg Surg 2006;1:11.[Medline]
- Rosati C, Huang SN, Ali J. Appendicular abscess presenting as neoplastic ileocecal obstruction. Can J Surg 1991;34:381-4.[Medline]
- Tekin A, Kurtoglu HC, Can I, Oztan S. Routine interval appendectomy is unnecessary after conservative treatment of appendiceal mass. Colorectal Dis 2007.
- Kumar S, Jain S. Treatment of appendiceal mass: prospective, randomized clinical trial. Indian J Gastroenterol 2004;23:165-7.[Medline]
- Aliev SA. [Debatable questions of surgical tactics in appendiceal infiltrates and periappendiceal abscess]. Khirurgiia (Mosk) 1997:48-54.
- Paya K, Rauhofer U, Rebhandl W, Deluggi S, Horcher E. Perforating appendicitis. An indication for laparoscopy? Surg Endosc 2000;14:182-4.[Medline]
- Aziz O, Athanasiou T, Tekkis PP, Purkayastha S, Haddow J, Malinovski V, et al. Laparoscopic versus open appendectomy in children: a meta-analysis. Ann Surg 2006;243:17-27.[Medline]
- Beldi G, Vorburger SA, Bruegger LE, Kocher T, Inderbitzin D, Candinas D. Analysis of stapling versus endoloops in appendiceal stump closure. Br J Surg 2006;93:1390-3.[Medline]
Donnerstag, 23. Oktober 2008
wohnlich und wärmend die schützenden Wände
gezimmert; vom Firste stolz des Richtbaumes Zier;
Herrgott, wir danken von Herzen dir
und bitten, du wolltest bewahren
vor aller Not, vor allen Gefahren
dies Haus! Und Friede soll walten
über denen, die darinnen schalten!
Wohlige Wärme in kalten Tagen
spende das Heim in trautem Behagen,
und in des Sommers erdrückender Schwüle
biete das Haus erquickende Kühle!
Noch liegt des Holzes würziger Duft
wie ein Gruß vom Walde hier in der Luft;
So herb und so frisch, so edel und rein
mög' fortan die Seele des Hauses sein!
Dem Bauherrn wünsche ich nun Glück,
dem Meister auch zum Meisterstück.
Wer mithalf hier in emsigen Streben,
Gesell' und Lehrling sollen leben!
Dann aber widme ich mit Stolz
ein Hoch dem edlen Baustoff Holz...
Spruch des Zimmermanns zum Richtfest unseres Holzhauses
Rajaraman Durai, specialist registrar1, Sumantra Kumar, consultant radiologist 2, Sha-Nawaz Ruhomauly, consultant surgeon1, Happy Hoque, consultant surgeon1
1 Department of Surgery, Queen Mary’s Hospital, Sidcup, Kent, 2 Department of Radiology Queen Mary’s Hospital, Sidcup, Kent
A 61 year old man presented with a ten day history of right sided non-colicky abdominal pain radiating to the back, and four episodes of fever with rigor, each of which lasted an hour. He had no other gastrointestinal or urinary symptoms. His only medical history was a ureteric stone. He did not take any drugs, and drunk alcohol in moderate amounts regularly.
On examination he seemed well, apyrexial but tachycardic with a pulse rate of 110 beats per minute. His blood pressure was normal. His chest was clear. Examination of his abdomen showed a tender 15x10 cm swelling in the right anterior lumbar region.Chest radiograph did not show pneumoperitoneum. His blood test showed neutrophilia (20x109/l and a raised C reactive protein of 200 mg/l. The rest of the blood tests including amylase were in the normal range. An abdominal radiograph and computed tomogram of the abdomen and pelvis were performed.
1 What can you see in the abdominal computed tomogram?
2 What is the diagnosis and why?3 How would you treat this condition?
Montag, 20. Oktober 2008
Sonntag, 19. Oktober 2008
A 47-year-old homeless man presented to the emergency department 1 week after the onset of chest pain. He was hemodynamically stable. The physical examination was unremarkable. A routine complete blood count revealed 27,000 leukocytes per cubic millimeter. A chest radiograph showed pneumopericardium (arrow) without evidence of pneumothorax or pneumomediastinum. A computed tomographic scan of the chest confirmed the diagnosis of pneumopericardium and showed circumferential wall thickening of the distal esophagus with an associated esophagopericardial fistula. Esophagoscopy revealed a deep esophageal ulcer 4.5 cm in diameter, 36 cm from the incisors; the pericardial cavity and the lining of the columnar epithelium could be directly visualized to the distal 10 cm of the esophagus. Esophageal-biopsy specimens showed intestinal metaplasia with inflammation and high-grade dysplasia. The diagnosis was Barrett's esophagus. The patient was taken to the operating room, where lavage and drainage of the pericardium were performed, a pericardial patch and an esophageal stent were placed, and jejunostomy was performed. The patient's postoperative course was uneventful, and 11 months later, the patient was well.
Karoui and Bucur NEJM 359 (14): e16, Figure 1 October 2, 2008
Samstag, 18. Oktober 2008
A 45-year-old woman with a 27-pack-year history of smoking presented for evaluation of progressive distal finger enlargement and polyarthralgias, which had developed over a period of 18 months. During the previous 3 months, she had had pain in the long bones of both legs and a nonproductive cough. Physical examination revealed symmetric, distal, bulbar swelling of the soft tissue of the fingers (Panel A, arrows), a positive Schamroth test (absence of the normal diamond-shaped window created when the dorsal surfaces of the terminal phalanges of similar fingers are opposed) (Panel B, arrow), and loss of Lovibond's angle. A chest radiograph showed a 7-cm rounded opacity in the right upper lobe (Panel C, arrow). The patient underwent a right upper lobectomy. Histopathological analysis revealed stage IB adenocarcinoma of the lung with tumor-free margins. At a 6-month follow-up visit, the patient was asymptomatic, and the clubbing and bone pain had resolved (Panels D and E, arrows). At a 30-month follow-up visit, she remained asymptomatic and without evidence of cancer.
Faller and Atkinson NEJM 359 (13): e15, Figure 1 September 25, 2008
Freitag, 17. Oktober 2008
Lange haben Gedichte in Paul Maars Schreibtischschublade geschlummert. Über 100 haben sich im Laufe der Jahrzehnte angesammelt. Und ab und an schmuggelte Paul Maar eines seiner Gedichte in die Samsbücher. Denn Lyrik, zumal Lyrik für Kinder, wollte niemand: "Wenn man mit Gedichten kommt sagen alle Verlage, oh Gott Lyrik! Das verkauft sich doch nicht", erklärt Maar.
Das hat sich mittlerweile geändert: Zu Maars 70. Geburtstag brachte der Oetinger-Verlag den Gedichtband "Jaguar und Neinguar" heraus. Es macht Spaß in dem aufwendig gestalteten Band mit den fabelhaften Illustrationen von Ute Krause zu schmökern. Mal sind die Gedichte nur zwei Zeilen lang, ein anderes Mal füllen sie mehrere Seiten. Und Paul Maar hat jetzt bei seinen Lesungen immer einige Gedichte dabei und die Kinder können die witzigen Zeilen teilweise schon auswendig.
Donnerstag, 16. Oktober 2008
How should she be further evaluated and treated?
Die Antwort gibt es nachfolgend...
Mittwoch, 15. Oktober 2008
|18.10.08||15:30||Werder Bremen||:||Borussia Dortmund|
|26.10.08||17:00||Borussia Dortmund||:||Hertha BSC|
|29.10.08||20:00||1. FC Köln||:||Borussia Dortmund|
|02.11.08||17:00||Borussia Dortmund||:||VfL Bochum 1848|
|08.11.08||15:30||Hamburger SV||:||Borussia Dortmund|
|15.11.08||15:30||Borussia Dortmund||:||Eintracht Frankfurt|
|21.11.08||20:30||Karlsruher SC||:||Borussia Dortmund|
|30.11.08||17:00||Borussia Dortmund||:||VfL Wolfsburg|
|06.12.08||15:30||Arminia Bielefeld||:||Borussia Dortmund|
|12.12.08||20:30||Borussia Dortmund||:||Bor. Mönchengladbach|
Dienstag, 14. Oktober 2008
Es gibt den Brauch, jeden Tag Uschpisin - symbolische Gäste - in die Sukka einzuladen, indem man sich an sie erinnert und von ihnen erzählt.
Donnerstag, 9. Oktober 2008
Jom Kippur ist der Abschluss der zehn Tage der Reue und Umkehr, die am Neujahrstag Rosch ha-Schanah beginnen. Zwar ist reuevolles Gebet zu allen Zeiten möglich, gilt aber an diesem Tag als besonders wirkungsvoll.
Das Morgengebet enthält zahlreiche Litaneien und Bitten um Vergebung, die auf hebräisch Selichot genannt werden.
Gemäß Maimonides „hängt alles davon ab, ob die Verdienste eines Menschen die von ihm begangenen Fehler überwiegen“. Deshalb sind zahlreiche gute Taten vor dem Urteil am Versöhnungstag angebracht. Wer von Gott als wertvoll erachtet wird, wird ins Buch des Lebens eingeschrieben, und so wird im Gebet gesagt: „Schreibe uns ins Buch des Lebens ein“. Auch begrüßt man sich mit den Worten: „Mögest du (im Buch des Lebens) für ein glückliches Jahr eingeschrieben werden.“
Mittwoch, 8. Oktober 2008
Hypothalamic IKKβ/NF-κB and ER Stress Link Overnutrition to Energy Imbalance and Obesity
IntroductionThe hypothalamus is the “headquarters” for regulating energy homeostasis ([Elmquist and Flier, 2004] and [Schwartz and Porte, 2005]). This regulation is primarily mediated in the mediobasal hypothalamus (MBH) by orexigenic AGRP neurons that coexpress two neuropeptides—NPY (neuropeptide Y) and AGRP (agouti-related protein)—and anorexigenic POMC neurons that coexpress two other neuropeptides—CART (cocaine- and amphetamine-regulated transcript) and POMC (proopiomelanocortin). Leptin and insulin work in these neurons to control these neuropeptides, leading to normal energy balance and the prevention of obesity. Research has revealed that insulin signaling and leptin signaling in the hypothalamus are integrated through at least PI-3K ([Morton et al., 2005] and [Xu et al., 2005]), FoxO1 ([Kim et al., 2006] and [Kitamura et al., 2006]), and mTOR (Cota et al., 2006). Recent studies have also identified two common inhibitors for insulin and leptin signaling, SOCS3 (Howard and Flier, 2006) and PTP1B (Bence et al., 2006), but their significance in causing disease is poorly understood.
Loss of leptin or insulin signaling in the hypothalamus is sufficient to induce or promote obesity and type 2 diabetes (T2D), as clearly demonstrated in various genetic mouse models with neuronal ablation of insulin signaling ([Bruning et al., 2000], [Burks et al., 2000] and [Obici et al., 2002]) or leptin signaling ([Balthasar et al., 2004], [Bates et al., 2003] and [Lee et al., 1996]). In obesity and T2D, along with striking hyperinsulinemia and hyperleptinemia, insulin and leptin levels in the cerebrospinal fluid are elevated, all of which indicate a chronic state of central insulin and leptin resistance. Central administration of insulin or leptin consistently compromises the ability to control food intake in animals during the development of dietary obesity, confirming that hypothalamic (or central) leptin and insulin resistance contribute to the pathophysiology of obesity and T2D. Recent research has also dissociated overnutrition from obesity, demonstrating that overnutrition directly blunts central insulin and leptin sensitivity before the onset of obesity ([Wang et al., 2001] and [Woods et al., 2004]). However, how central insulin and leptin resistance are induced by overnutrition and whether core mechanism(s) might be involved are both currently unknown.
IKKβ/NF-κB is a master switch and central regulator of innate immunity and related functions (Hayden and Ghosh, 2008). In the quiescent state, NF-κB remains inactive in the cytoplasm through binding to the inhibitory protein IκB. Activation of IKKβ by phosphorylation at S177 and S181 induces phosphorylation of its substrate IκBα at S32 and S36, ubiqitination, and subsequent proteosomal degradation. The disappearance of IκBα releases NF-κB to translocate into the nucleus where it mediates the transcription of its target genes. Research during recent decades recognized that overnutrition can induce inflammatory responses in the peripheral metabolic tissues (metabolic inflammation) and therefore cause various metabolic defects in those tissues that underlie T2D ([Hotamisligil, 2006] and [Lehrke and Lazar, 2004]). In this context, IKKβ was identified as a target for an anti-inflammatory therapy that was effective for obesity-associated T2D (Yuan et al., 2001). Subsequently, a series of discoveries revealed that IKKβ/NF-κB located in peripheral metabolic tissues affects glucose and protein metabolism in tissue-specific manners (Arkan et al., 2005 M.C. Arkan, A.L. Hevener, F.R. Greten, S. Maeda, Z.W. Li, J.M. Long, A. Wynshaw-Boris, G. Poli, J. Olefsky and M. Karin, IKK-beta links inflammation to obesity-induced insulin resistance, Nat. Med. 11 (2005), pp. 191–198. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (220)[Arkan et al., 2005], [Cai et al., 2004] and [Cai et al., 2005]). However, it still remains unexplored whether metabolic inflammation and related mediators could target the metabolic regulatory pathways in the central nervous system (CNS), thus leading to a family of diseases related to overnutrition and obesity. In this study, we explored whether IKKβ/NF-κB is the fundamental connection between overnutrition and the dysfunctions of hypothalamic signaling that cause obesity and associated problems.
Overnutrition Subverts the Innate Immune Response of Hypothalamic IKKβ/NF-κB
Obesity and its co-morbidities represent one of the greatest epidemic and public health problems facing our society. Relatively recent environmental changes, especially overnutrition, are clearly responsible for the high prevalence of these diseases. Faced with the energy abundance typical of today's developed world, our control systems have yet to evolve to readily regulate the body's energy balance. This newly emerged challenge to the control systems in our bodies has led to excessive energy stores (fat) and ultimately to disease. While the CNS control systems, like the hypothalamus, might conceivably be essential for this regulatory failure, the participating molecular program(s) remain unknown.
Our work shows that the “master switch” innate immunity regulator, IKKβ/NF-κB, while highly enriched in the hypothalamic neurons is normally not activated. Importantly, this pathway can be activated in the hypothalamic neurons by the chronic overnutrition that causes obesity. Such activation can even be mimicked without obesity by an acute but extreme oversupply of various nutrients to the CNS. Our findings indicate that persistent signals to the CNS under conditions of overnutrition can atypically stimulate an innate immunity-like response directed by IKKβ/NF-κB in the hypothalamic neurons; this process affects the neuronal regulation of energy balance (Figure 7). Overall, our findings align with the emerging view that evolution integrated some regulatory pathways that govern the body's reactions to both pathogens and nutrition (Hotamisligil, 2006). We postulate that the hypothalamus might have developed the unique property of responding to extreme environmental stimuli (previously pathogens, now overnutrition) by using IKKβ/NF-κB to affect vital systems. Thus, although the near-instantaneous signaling of hypothalamic IKKβ/NF-κB might once have been critical for survival in a pathogen-filled environment by helping innate immunity (an energy-intensive process), this signaling—as our study demonstrates—might now be very responsive and truly detrimental in today's near-constant calorie-rich environment. Hypothalamic IKKβ/NF-κB could underlie the entire family of modern diseases induced by overnutrition and obesity.
Hypothalamic IKKβ as a Potential Target to Counter Obesity and T2D
Our work also marks an initial attempt to study whether inhibiting an innate immune pathway in the hypothalamus could help to calibrate the set point of nutritional balance and therefore aid in counteracting energy imbalance and diseases induced by overnutrition. These results reveal that dietary obesity can be largely prevented by inhibiting IKKβ/NF-κB either virally or genetically, whether broadly throughout the CNS, locally in the related hypothalamic regions, or precisely in a defined subpopulation of hypothalamic neurons. Altogether, our results suggest a novel therapeutic strategy for combating the ever-increasing spread of obesity and associated diseases. We recognize that the significance of this strategy has yet to be realized in clinical practice; currently, most anti-inflammatory therapies have limited direct effects on IKKβ/NF-κB and limited capacity to be concentrated in the CNS. Nonetheless, our discoveries offer potential for treating these serious diseases. Because we also revealed that IKKβ/NF-κB normally remains inactive in the CNS, suppressing IKKβ/NF-κB in the hypothalamus is likely a safe approach. However, challenges still remain, such as finding methods to selectively suppress this pathway in the CNS, that will certainly inspire future research.
Cell Vol 135, Issue 1, 3 October 2008, Pages 61-73
Sonntag, 5. Oktober 2008
Man sollte meinen, wenn der Ball hinter der Torlinie ist, dann ist das auch ein Tor - weit gefehlt!
Wenn der Schiedsrichter den Ball nicht hinter der Torlinie sieht, dann ist das kein Tor - so ist Fußball - und der BVB gewinnt dann eben nicht...
Samstag, 4. Oktober 2008
Published 18 September 2008, doi:10.1136/bmj.a1438
Cite this as: BMJ 2008;337:a1438
Meeting the challenge of antibiotic resistance
Otto Cars, professor1, Liselotte Diaz Högberg, researcher2, Mary Murray, freelance consultant; member of the WHO expert panel on national drug policy; visiting research fellow and freelance consultant on rational use of medicines3, Olle Nordberg, former executive director4, Satya Sivaraman, journalist5, Cecilia Stålsby Lundborg, associate professor and professor6,7, Anthony D So, director8, Göran Tomson, professor international health system research and director of doctoral programme6,9
1 Infectious Diseases, Department of Medical Sciences, Uppsala University, Uppsala, Sweden, 2 Department of Medical Sciences, Uppsala University, 3 Wee Jasper, University of South Australia School of Pharmacy and Medical Sciences, Adelaide, Australia , 4 Dag Hammarskjöld Foundation, Uppsala, 5 New Delhi, India, 6 Division of International Health (IHCAR), Department of Public Health Sciences, Karolinska Institutet, Stockholm , 7 Nordic School of Public Health, Göteborg, Sweden, 8 Program on Global Health and Technology Access, Terry Sanford Institute of Public Policy, Duke University, Durham, NC, USA, 9 Medical Management Centre (MMC), Karolinska Institutet, Stockholm
Correspondence to: O Cars firstname.lastname@example.org
A concerted global response is needed to tackle rising rates of antibiotic resistance, say Otto Cars and colleagues
Antibiotics changed the world. Since their discovery almost eight decades ago, they have revolutionised the treatment of infections, transforming once deadly diseases into manageable health problems. The growing phenomenon of bacterial resistance, caused by the use and abuse of antibiotics and the simultaneous decline in research and development of new medicines, is now threatening to take us back to a pre-antibiotic era. Without effective treatment and prevention of bacterial infections, we also risk rolling back important achievements of modern medicine such as major surgery, organ transplantation, and cancer chemotherapy.
Data from low income and middle income countries indicate that, because of the development of resistance to first line antibiotics, 70% of hospital acquired neonatal infections could not be successfully treated by using WHO’s recommended regimen.1 A recently published study of Tanzanian children confirmed that ineffective treatment of bloodstream infections due to antibiotic resistance predicts fatal outcome independently of underlying diseases.2 In that hospital based study, mortality from bloodstream infections caused by Gram negative bacteria was more than double the mortality from malaria.Antibiotic resistance is becoming important in high income countries. In England and Wales, for example, the number of registered deaths in which meticillin resistant Staphylococcus aureus (MRSA) is mentioned increased from less than 50 in 1993 to more than 1600 in 2006. In 2007 there was a slight decrease.3 The European Centre for Disease Prevention and Control, in its first epidemiological report on communicable diseases in Europe, states that the most important disease threat in Europe is from micro-organisms that have become resistant to antibiotics.4 5
The emergence of antibiotic resistance is further complicated by the fact that bacteria and their resistance genes are travelling faster and further.6 7 We are facing not only epidemics but pandemics of antibiotic resistance.8 Airlines now carry more than two billion passengers annually, vastly increasing the opportunities for rapid spread of infectious agents, including antibiotic resistant bacteria, internationally. 9 The spread of resistance is also facilitated by worldwide distribution of food.10 Another important factor is poor hygiene in hospitals as well as in the community, augmenting the rapid spread of antibiotic resistant bacteria in vulnerable populations.
Unblocking collective action
Although the essential components of control of antibiotic resistance have long been well known, success has been limited in changing policies and efficiently responding to the problem.11 12 The relative lack of data on the morbidity and mortality attributable to antibiotic resistance, including the economic impact on individuals as well as on health care and societies, may explain the weak reaction from politicians, public health workers, and consumers to this threat to public health.
Individual stakeholders might well recognise the problem, but because it is complex, antibiotic resistance often becomes no one’s responsibility, which blocks collective action. Action is urgently needed in three key areas: leadership on international and national levels, change in the behaviour of consumers and providers, and the development of antibacterial agents to match current public health needs.
International and national leadership
In 1998, the World Health Assembly adopted a resolution urging member states to take action on the problem of antimicrobial resistance.13 In 2000, the World Health Organization requested a massive effort to prevent the "health care catastrophe of tomorrow,"7 and shortly thereafter presented a global strategy for the containment of antimicrobial resistance, calling for a multidisciplinary and coordinated approach.14 However, sufficient financial and human resources to implement the strategy were never provided. Member states recognised this lack of leadership and initiated a new resolution, adopted by the World Health Assembly in 2005, requesting the director general to strengthen WHO’s leadership role in containing antimicrobial resistance and to provide more technical support.15
Little has taken place to implement the resolution. The difficulties of enforcing these recommendations on a global level are evident, and the links between the well formulated strategies at the level of global society and the acceptance level by national policymakers are weak. WHO, international professional organisations, and other international stakeholders must provide coordination and resources for generating up to date information on the burden and the magnitude of antibiotic resistance at regional and subregional levels. Evidence is needed on effective interventions for prevention and control of antibiotic resistance at national and local levels, and more emphasis on prevention of infectious diseases is needed. Solving basic problems such as lack of safe drinking water, poor nutrition, and dysfunctional sanitation will go a long way toward curbing the needless use of antibiotics as quick-fix solutions to avoidable diseases.7
At national level
Strategies for containing antibiotic resistance in low income countries are still blocked by patients’ poverty and weak health systems,16 and many high income countries with well developed regulations and policies lack coordinated strategies against antibiotic resistance. Although the European Union has responded to the resistance problem, antibiotics are still sold over the counter without a prescription in some EU countries, violating existing laws and regulations, and in all countries self medication with leftover medicines occurs.17 The root causes of certain behaviours need to be tackled, and the ultimate responsibility for coordinating the work lies with the government.
National mandated multidisciplinary programmes can move from recommendations to implementation and audits.18 For example, in Sweden the government is funding Strama, a nationwide multidisciplinary and multifaceted action programme against antibiotic resistance. Antibiotic sales have been reduced without measurable negative consequences, and resistance remains low.19 In Chile, after a mass media campaign, regulatory measures were implemented to make antibiotics available by prescription only, resulting in an initial decrease of 35% in antibiotic sales.20
Social constraints and cultural views of infectious conditions influence the use of antibiotics.21 Although the public’s demand for antibiotics often is perceived as high even for conditions without a clinical indication for antibiotic treatment,22 23 studies have shown that this demand is overestimated by the prescriber,24 and antibiotics could therefore successfully be replaced by better information and follow-up.
The role of the patients as consumers is growing stronger. They need access to information and knowledge to reduce their expectations of antibiotics in self limiting infections, and doctors need new tools to help them justify their treatment decisions.25 It could be unrealistic to expect people to restrict their antibiotic use in favour of a common good to prevent resistance—but if the arguments for restricting the use of antibiotics can be made sufficiently convincing, reduced demand from the consumer may be the strongest force driving change. Studies increasingly emphasise the risk for the individual when taking an antibiotic, including the risks of becoming a long term carrier of antibiotic resistant bacteria,26 27 which might confer a greater risk in a subsequent severe infection. Reliable information on the adverse effects of antibiotics on the microbiological flora might provide a stronger incentive for not using antibiotics unnecessarily than would more general messages about risks for society through the development of resistance. For prescribers and other drug providers, multifaceted interventions including so called academic detailing are effective to increase adherence to recommendations in both high income settings and low income settings.28 29
Developing new antibacterials
For many years, needs for antibacterial drugs were met by the pharmaceutical industry, and the apparent symbiosis between the interests of the community and those of the industry prevailed. Today we see a different scenario. Existing antibiotics are losing their effect at an alarming pace, but development of new antibiotics is declining. More than a dozen new classes of antibiotics were developed in the 1930s through the 1960s, but only two new classes have been developed since then.30 Nor does the trend of declining innovation seem to be reversing. In a study of the top 15 pharmaceutical companies, only 1.6% of drugs in development were antibiotics, none of which were from novel classes and leaving need unmet for multiresistant Gram negative infections.31
With existing incentives, current levels of innovation are clearly inadequate.32 Proposals on how to break this trend have been put forward. Some have suggested arrangements that would increase the anticipated revenue by lengthening the period of patent protection or exclusivity over data submitted for drug registration. However, antibiotics already have small markets and emergence of resistance may further reduce the expected return of investment, so these incentives are likely to do little to stimulate greater innovation for antibacterials.33 There are also scientific challenges for development of new antibiotics.34
If today’s market cannot deliver what the public needs, we must envisage other approaches that better engage both public and private sector resources.35 One model is product development partnerships (PDPs), arrangements between public organisations and private companies to develop drugs when markets otherwise fail to meet public health priorities. This approach is now used for some drug projects targeting other neglected infectious diseases, such as malaria and tuberculosis.36 Mechanisms creating supplements or replacing revenues in small and resource poor markets are another approach. Advanced market commitments (AMCs) create a fund that guarantees a certain price for drugs that meet therapeutic targets where there is a demand for the drug. A recent example is the pneumococcal vaccine AMC.37
A gap analysis of drugs currently under development in light of current resistance patterns and trends would give priority to the most urgently needed antibiotics and give incentives for developing antibacterials with new mechanisms of action. But no matter how innovation is accelerated, any public investment must be matched by public health accountability. The use of new antibiotics must be safeguarded by regulations and practices that ensure rational use, to avoid repeating the mistakes we have made by overusing the old ones.
Another lack is efficient and affordable diagnostics with high sensitivity and specificity to distinguish bacterial from viral diseases, and to identify resistance patterns in bacteria. Such diagnostics would reduce inappropriate use of antibiotics and minimise the delays of treatment, thereby saving lives.
Moving to concerted action
A fundamentally changed view of antibiotics is needed. They must be looked on as a common good, where individuals must be aware that their choice to use an antibiotic will affect the possibility of effectively treating bacterial infections in other people. All antibiotic use, appropriate or not, "uses up" some of the effectiveness of that antibiotic, diminishing our ability to use it in the future.38 ReAct—Action on Antibiotic Resistance believes that for current and future generations to have access to effective prevention and treatment of bacterial infections as part of their right to health, all of us need to act now. The window of opportunity is rapidly closing.
Cite this as: BMJ 2008;337:a1438
Contributors and sources: OC, LDH, MM, SS, CSL, and ADS are members of the international secretariat and all authors are active members of ReAct – Action on Antibiotic Resistance (www.reactgroup.org), a growing global network of individuals and organisations working towards the mission that current and future generations should have access to antibiotic treatment as a part of their right to health. ReAct was initiated in 2004 by Strama, the Swedish strategic programme against antibiotic resistance (www.strama.se); the Dag Hammarskjöld Foundation (www.dhf.uu.se), and the Division of International Health (IHCAR) at Karolinska Institutet, Stockholm, Sweden. Supported by the Swedish Development Cooperation Agency (Sida), ReAct is working towards five objectives: identify and facilitate removal of critical evidence gaps that block action to contain antibiotic resistance; develop strategic options to remove barriers to innovation of new antibiotics and diagnostics; advocate for better access to and use of effective and affordable antibiotics for those in need; promote global consensus for a new paradigm on the use of antibiotics; increase awareness of antibiotic resistance as a threat to global public health and engage key stake holders in action.
- Zaidi AK, Huskins WC, Thaver D, Bhutta ZA, Abbas Z, Goldmann DA. Hospital-acquired neonatal infections in developing countries. Lancet 2005;365:1175-88.
- Blomberg B, Manji KP, Urassa WK, Tamim BS, Mwakagile DS, Jureen R, et al. Antimicrobial resistance predicts death in Tanzanian children with bloodstream infections: a prospective cohort study. BMC Infect Dis 2007;7:43.
- National Statistics. MRSA deaths decrease in 2007, www.statistics.gov.uk/cci/nugget.asp?id=1067
- European Centre for Disease Prevention and Control. Annual epidemiological report on communicable diseases in Europe. December 2007. http://ecdc.europa.eu/pdf/ECDC_epi_report_2007.pdf
- ReAct—Action on Antibiotic Resistance. Burden of resistance to multi-resistant gram-negative bacilli (MRGN). 1 March 2007. http://soapimg.icecube.snowfall.se/stopresistance/ReAct_Burden%20of%20resistance%20to%20Multi%20resist%20and%20Gram%20negative%20Bacilli%20MRGN.pdf
- Grundmann H, Aires-de-Sousa M, Boyce J, Tiemersma E. Emergence and resurgence of meticillin-resistant Staphylococcus aureus as a public-health threat. Lancet 2006;368:874-85.
- World Health Organization. Report on infectious diseases 2000: overcoming antimicrobial resistance. 2000. www.who.int/infectious-disease-report/2000/index.html
- Cantón R, Coque TM. The CTX-M β-lactamase pandemic. Current Opinion in Microbiology 2006;9:466-75.
- World Health Organization. World health report 2007: a safer future: global public health security in the 21st century. 2007. www.who.int/whr/2007/whr07_en.pdf
- Butaye P, Michael G B, Schwarz S, Barrett TJ, Brisabois A, White DG. The clonal spread of multidrug-resistant non-typhi Salmonellaserotypes. Microb Infect 2006;8:1891-7.
- Huovinen P, Cars O. Control of antimicrobial resistance: time for action. BMJ 1998;317:613-4.
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- World Health Assembly. Emerging and other communicable diseases: antimicrobial resistance. May 1998. http://mednet3.who.int/prioritymeds/report/append/microb_wha5117.pdf
- World Health Organization. Global strategy for containment of antimicrobial resistance. 2001. www.who.int/drugresistance/WHO_Global_Strategy_English.pdf
- World Health Assembly. Improving the containment of antimicrobial resistance. May 2005. www.tufts.edu/med/apua/Chapters/WHA58_27-en.pdf
- Okeke IN, Aboderin OA, Byarugaba DK, Ojo KK, Opintan JA. Growing problem of multidrug-resistant enteric pathogens in Africa. Emerg Infect Dis 2007;13(11). www.cdc.gov/EID/content/13/11/1640.htm
- Grigoryan L, Haaijer-Ruskamp FM, Johannes Burgerhof GM, Mechtler R, Deschepper R, Tambic-Andrasevic A, et al. Self-medication with antibiotics in the general population: a survey in nineteen European countries. Emerg Infect Dis 2006;12(3). www.cdc.gov/ncidod/EID/vol12no03/05-0992.htm
- Carbon C, Cars O, Christiansen K. Moving from recommendation to implementation and audit: part 1. Current recommendations and programs: a critical commentary. Clin Microbiol Infect 2002;8(suppl 2):92-106.
- Mölstad S, Erntell M, Hanberger H, Melander E, Norman C, Skoog G, et al. Sustained reduction of antibiotic use and low bacterial resistance: 10-year follow-up of the Swedish Strama programme. Lancet Infect Dis 2008;8:125-32.
- Bavestrello FL, Cabello MA, Casanova Z, Dunny. Impact of regulatory measures on antibiotic sales in Chile. Rev Méd Chile 2002;130:1265-72.
- Harbarth S, Samore MH. Antimicrobial resistance determinants and future control. Emerg Infect Dis 2005;11(6). www.cdc.gov/ncidod/EID/vol11no06/05-0167.htm
- Chen C, Chen YM, Hwang KL, Lin SJ, Yang CC, Tsay RW, et al. Behavior, attitudes, and knowledge about antibiotic usage among residents of Changhua, Taiwan. J Microbiol Immunol Infect 2005;38:53-9.
- Trepka M, Belongia E, Chyou P-H, Davis J, Schwartz B. The effect of a community intervention trial on parental knowledge and awareness of antibiotic resistance and appropriate antibiotic use in children. Pediatrics 2001;107:6.
- Macfarlane J, Holmes W, Macfarlane R, Britten N. Influence of patients’ expectations on antibiotic management of acute lower respiratory tract illness in general practice: questionnaire study. BMJ 1997;315:1211-4.
- Del Mar C. Prescribing antibiotics in primary care. BMJ 2007;335:407-8.
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- Nasrin D, Collignon PJ, Roberts L, Wilson EJ, Pilotto LS, Douglas RM. Effect of beta lactam antibiotic use in children on pneumococcal resistance to penicillin: prospective cohort study. BMJ 2002;324:28-30.
- Dollman WB, LeBlanc VT, Stevens L, O’Connor PJ, Turnidge JD. A community-based intervention to reduce antibiotic use for upper respiratory tract infections in regional South Australia. Med J Aust 2005;182:617-20.
- Awad AI, Eltayeb IB, Baraka OZ. Changing antibiotics prescribing practices in health centers of Khartoum State, Sudan. Eur J Clin Pharmacol 2006;62:135-42.
- Infectious Diseases Society of America. Bad bugs, no drugs: as antibiotic discovery stagnate and a public health crisis brews. July 2004. www.idsociety.org/badbugsnodrugs.html
- Spellberg B, Powers JH, Brass EP, Miller LG, Edwards JE Jr. Trends in antimicrobial drug development: implications for the future. Clin Infect Dis 2004;38:1279-86.
- Projan SJ. Why is big pharma getting out of antibacterial drug discovery? Curr Opin Microbiol 2003;6:427-30.
- Outterson K, Samora JB, Keller-Cuda K. Will longer antimicrobial patents improve global public health? Lancet Infect Dis 2007;7:559-66.
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- Moran M. A breakthrough in R&D for neglected diseases: new ways to get the drugs we need. PLoS Med 2005;2:e302.
- Document prepared by the World Band and GAVI under the guidance of Governments of Italy, Canada, and the United Kingdom. AMC Pilot Proposal. 7 September 2006. www.vaccineamc.org/files/AMCPilotProposal.pdf
- Laxminarayan R, Malani A, Howard D, Smith DL. Extending the cure: policy responses to the growing threat of antibiotic resistance. Alexandria: Resources for the Future, 2007. www.extendingthecure.org/research_and_downloads.html