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BACKGROUND: Concurrent chemotherapy and thoracic radiotherapy followed by prophylactic cranial irradiation (PCI) is the standard treatment in limited-disease small-cell lung cancer (LD-SCLC), with 5-year overall survival (OS) of only 25% to 33%. PATIENTS AND METHODS: STIMULI is a 1:1 randomised phase II trial aiming to demonstrate superiority of consolidation combination immunotherapy versus observation after chemo-radiotherapy plus PCI (protocol amendment-1). Consolidation immunotherapy consisted of four cycles of nivolumab [1 mg/kg, every three weeks (Q3W)] plus ipilimumab (3 mg/kg, Q3W), followed by nivolumab monotherapy (240 mg, Q2W) for up to 12 months. Patient recruitment closed prematurely due to slow accrual and the statistical analyses plan was updated to address progression-free survival (PFS) as the only primary endpoint. RESULTS: Of the 222 patients enrolled, 153 were randomised (78: experimental; 75: observation). Among the randomised patients, median age was 62 years, 60% males, 34%/65% current/former smokers, 31%/66% performance status (PS) 0/1. Up to 25 May 2020 (median follow-up 22.4 months), 40 PFS events were observed in the experimental arm, with median PFS 10.7 months [95% confidence interval (CI) 7.0-not estimable (NE)] versus 42 events and median 14.5 months (8.2-NE) in the observation, hazard ratio (HR)= 1.02 (0.66-1.58), two-sided P= 0.93. With updated follow-up (03 June 2021; median: 35 months), median OS was not reached in the experimental arm, while it was 32.1 months (26.1-NE) in observation, with HR= 0.95 (0.59-1.52), P= 0.82. In the experimental arm, median time-to-treatment-discontinuation was only 1.7 months. CTCAE v4 grade =3 adverse events were experienced by 62% of patients in the experimental and 25% in the observation arm, with 4 and 1 fatal, respectively. CONCLUSIONS: The STIMULI trial did not meet its primary endpoint of improving PFS with nivolumab-ipilimumab consolidation after chemo-radiotherapy in LD-SCLC. A short period on active treatment related to toxicity and treatment discontinuation likely affected the efficacy results.

Eine 34-jahrige Patientin wurde nach erfolgreicher kardiopulmonaler Reanimation im kardiogenen Schock vorstellig. Fremdanamnestisch wurde eine Migrane angegeben. Die Notfallechokardiographie zeigte eine eingeschrankte linksventrikulare Pumpfunktion mit basomittventrikularer Hypokinesie und apikaler Hyperkontraktilitat. Die kraniale Computertomographie ergab den Hinweis auf eine stattgefundene massive Subarachnoidalblutung (SAB), sodass unter Berucksichtigung der Fremdanamnese (starkste Kopfschmerzen) die Diagnose einer SAB-assoziierten umgekehrten Takotsubo-Kardiomyopathie gestellt werden konnte. Im Rahmen einer SAB sollte stets an die Assoziation von extrazerebralen Organdysfunktionen, wie das Auftreten einer invertierten Takotsubo-Kardiomyopathie, gedacht werden.

Essential hypertension (EH) is a widespread disease and might be prevalent in apnea divers and master athletes. Little is known about the influence of EH and the antihypertensive drugs (AHD) on cardiovascular reactions to combined breath hold (BH) and exercise. In this pilot study, healthy divers (HCON) were compared with treated hypertensive divers with regard to heart rate (HR) and mean blood-pressure (MAP) responses to BH, exercise and the combination of both. Ten subjects with EH and ten healthy divers were tested. 3 different 20 s stimuli were applied: BH combined with 30 W or 150 W and 150 W without BH. The time-charts during the stress intervals and during recovery were compared. Subjects treated with an angiotensin-converting enzyme (ACE) inhibitor showed higher changes for MAP values if breath hold was performed. HR responses were obviously changed if a β-blocker was part of the medication. One subject showed extreme MAP responses to all stimuli and conspicuous HR if BH was involved. The modulation of HR-/MAP-response in EH subjects depends on the mechanisms of antihypertensive agents. The combination of an ACE inhibitor and a β-blocker may give the best protection. It is recommended to include short apnea tests in the fitness-to-dive examination to individually predict potential endangerment.

Die Lungensonographie beschrankte sich bisher auf den Ausschluss oder Nachweis von Pleuraergussen und die sonographisch-gesteuerte Pleurapunktion. In den letzten Jahren hat die Bedeutung der Lungensonographie als Diagnostikum in der Notfall- und Intensivmedizin zugenommen. Einfachheit und bettseitige Anwendbarkeit machen die Lungensonographie zu einem bedeutenden Verfahren fur alle Akutsituationen bei Dyspnoe oder bei Oxygenierungsproblemen. Verschiedene Lungenerkrankungen, wie der Pleuraerguss, die pulmonalvenose Stauung und das Lungenodem, die Pneumonie und der Pneumothorax, konnen unter Notfallbedingungen mittels Lungensonographie sehr schnell erfasst werden.

Resume Introduction La sante neonatale demeure une preoccupation majeure dans nos pays aux conditions d’accueil du nouveau-ne tres difficiles. Ce travail vise a analyser les facteurs de risque de deces des nouveau-nes de faible poids de naissance dans des structures sanitaires urbaines au sud du Sahara. Patients et methodes Il s’agit d’une etude retrospective de type descriptif du 1er janvier 2006 au 31 decembre 2010, portant sur les antecedents gestationnels et les parametres epidemiologiques cliniques de nouveau-nes de faible poids de naissance ( Resultats Le taux de prematurite etait de 60,8 %. Les nouveau-nes de faible poids de naissance ont constitue 64,8 % des hospitalisations avec un sex-ratio de 1,1. Trente-trois pour cent des meres etaient âgees de moins de 20 ans et 77,6 % des parturientes etaient des femmes au foyer. L’hypertension arterielle etait retrouvee dans 4,8. Le poids etait compris entre 1500 et 2000 g pour 33,2 %. Parmi les nouveau-nes, 25,7 % ont ete reanimes. La mortalite etait de 30,6 % et 50,8 % des deces survenaient dans les 48 premieres heures d’hospitalisation. Le score d’APGAR etait inferieur a 7 a une minute, l’accouchement par voie basse, le faible poids de naissance, la grossesse monofœtale, la duree d’hospitalisation inferieure ou egale a sept jours, la structure sanitaire de Saint-Camille ont ete les facteurs de risque significativement associes a la mortalite. Conclusion La mortalite neonatale precoce lors de faible poids de naissance demeure une preoccupation au Burkina Faso. Il est donc imperatif d’entreprendre des actions plus soutenues dans le sens d’une meilleure prevention et d’une prise en charge adequate des nouveau-nes (adoption de la methode kangourou, renforcer les moyens de reanimation du nouveau-ne…)

Anamnese und klinischer Befund: Eine 70-jahrige Patientin klagte nach einem heftigen Streit mit einem Hundebesitzer uber persistierende Angina pectoris und Belastungsdyspnoe, so dass sie sich 5 Tage nach dem Ereignis in unserer Klinik vorstellte. Untersuchungen: Das EKG zeigte T-Inversionen in den inferioren und anterioren Ableitungen sowie eine verlangerte QTc-Zeit (490 ms). Das NTproBNP war mit 6733 ng/l erhoht bei normalem Troponin T. Die anschliesende Echokardiographie und Herzkatheteruntersuchung konnte eine eingeschrankte linksventrikulare Pumpfunktion (EF 55 %) mit apikaler Akinesie nachweisen. Koronarangiographisch wurde eine koronare Makroangiopathie ausgeschlossen. In Zusammenschau aller Befunde wurde die Diagnose einer Stress-Kardiomyopathie, das sogenannte Tako-Tsubo-Syndrom, gestellt. Therapie und klinischer Verlauf: Eine Therapie der linksventrikularen Dysfunktion wurde leitliniengerecht eingeleitet. Im Rahmen der Nachkontrolle konnte einerseits eine Verbesserung der linksventrikularen Pumpfunktion jedoch andererseits ein neu aufgetretener linksventrikularer apikaler Thrombus nachgewiesen werden, so dass zusatzlich eine Antikoagulationstherapie begonnen wurde. Folgerung: Bei apikaler Akinesie im Rahmen eines Tako-Tsubo-Syndroms sollte stets an die Moglichkeit der Entstehung eines linksventrikularen Thrombus in nur wenigen Tagen gedacht werden.

Diabetes mellitus und Herzinsuffizienz zeigen eine hohe Koexistenz und begunstigen sich gegenseitig in der Entstehung. Die Koexistenz der beiden Erkrankungen ist mit einer sehr ungunstigen Prognose assoziiert. Es existiert praktisch keine Evidenz fur Behandlungsempfehlungen zur Pravention der Herzinsuffizienz bei Diabetes und zur antihyperglykamischen Therapie bei manifester Herzinsuffizienz. Die allgemein empfohlene Herzinsuffizienztherapie scheint hingegen bei Diabetikern genauso effektiv zu sein wie bei Nichtdiabetikern und sollte konsequent durchgefuhrt werden.

Nach einem vergleichsweise trivialen Verkehrsunfall stieg der 65-jahrige Unfallfahrer aus dem Fahrzeug und kollabierte kurz darauf. Zufallig vor Ort befindliche Polizeibeamte leiteten unverzuglich eine kardiopulmonale Reanimation ein. Ein Passant entnahm aus einem benachbarten Firmenfoyer den dort stationierten, frei zuganglichen Defibrillator. Nach Anbringen der Elektroden und Analyse des Defibrillators wurde ein Schock (200 Joule, biphasisch) ausgelost. Das zugrunde liegende Kammerflimmern wurde dadurch terminiert. In der Klinik ergab die Akutherzkatheteruntersuchung eine hochgradige, filiforme Stenose der proximalen rechten Koronararterie, die durch einen Stent versorgt wurde. Aufgrund der optimalen Basismasnahmen, der sofortigen notfallmedizinischen Versorgung und der erfolgreichen Revaskularisation war der Verlauf sehr gunstig; der Patient konnte ohne jegliche neurologische Defizite nach Hause entlassen werden. Der Fall zeigt beispielhaft, dass automatisierte externe Defibrillatoren im Rahmen der kardiopulmonalen Reanimation auch von Laien problemlos und sicher angewandt werden konnen.

It is necessary to know the specific pathobiology of a persistent epithelial defect to determine the strategy to be employed to assist in its repair. Lid position and function must be normal and any deficiency in the quantity and quality of the tears enhanced by tear preparations and closure of the lacrimal canaliculi. Adverse drug effects must be eliminated. Multiple corneal punctures and excision of reduplicated basal lamina have virtually eliminated the problem of recurrent corneal erosions. Control of any inflammatory process also speeds healing. Vitamin supplements, especially A, reverse defects associated with xerophthalmia. In any of these diseases, mechanical treatments consisting of soft contact lenses for persistent epithelial defects and collagen shields for the delivery of antibiotics or steroids to the eye may be employed. Tarsorrhaphy relieves the problem of persistent epithelial defects in neurotrophic keratitis and a variety of other conditions characterized by persistent surface breakdown. Preliminary data from open label studies of epidermal growth factors and fibronectin are encouraging but not yet conclusive.

Background: The objective of this study was to assess the frequency of varicose recurrence 14 years after flush ligation of the saphenofemoral (SFJ) or saphenopopliteal (SPJ) junction with additional stripping of the incompetent saphenous vein. Patients and methods: Our study group comprised 245 extremities of 210 patients operated upon in 1990 for either great saphenous vein (GSV) or small saphenous vein (SSV) incompetence. Limbs were assessed with Duplex ultrasound by a practitioner other than the original surgeon and relevant patient data was recorded. Results: In 68.5% of re-examined limbs Duplex imaging provided no evidence for recurrent varicose veins at the former SFJ or SPJ. This included 15 legs (= 6.1%) where reflux immediately proximal to the junction but originating from adjacent veins (i.e. pudendal vein, epigastrical vein) was detected. In 31.5%, reflux from the operated SFJ or SPJ (junctional recurrence) was detected but only a minor percentage of legs (6.9%) had actually developed a clinically relevant recurrent varicosity (> 3 mm in diameter) branching out from the former junction and requiring treatment. Patients with a BMI < 30 were less likely to suffer recurrent varicose veins (no recurrence in 72.7%) than patients with a BMI ≥ 30 (no recurrence in 54.5%). Conclusions: 14 years after flush ligation of the SFJ or SPJ with stripping of the incompetent saphenous vein, junctional recurrences were found in less than one-third of re-examined extremities. In the absence of surgical errors, we must assume neovascularisation as cause for these recurrences. Duplex US determined a clinically relevant recurrence (> 3 mm in diameter) in only 7% of limbs. Post-operative varices seem to develop less often after SPJ surgery than after SFJ surgery and according to our data, obesity (BMI ≥ 30) constitutes a significant risk factor.

A growing body of literature describes diagnostic and prognostic value of B-type natriuretic peptides (BNP) in cardiac diseases since it was first described in 1988. As BNP is mainly secreted in the left ventricular (LV) myocardium, BNP was found to reflect LV function much better than any other neurohumoral factor. Thus, BNP is recommended as the first noninvasive blood test for determination of cardiac function by some authors. The introduction of fully automated, rapid bioassays for measurement of BNP and the aminoterminal part of its pro-hormone (NT-pro-BNP) made it possible to use the test even in emergency care settings. Here we review the literature with special focus on assessment of BNP and NT-pro-BNP in the following clinical settings: community screening for LV dysfunction, primary diagnosis of heart failure in general practice and emergency department (ED) and risk stratification in cardiac dysfunction and acute coronary syndromes. In addition, we discuss which applications can be recommended for daily clinical use from the cardiologist's point of view.

Knowledge is sparse about the extent of potential dehydration due to prolonged strenuous cycling and its haematological acute effects on the haematocrit (Hct) in study populations credibly not taking any kind of doping. With increasing training load levels of Hct and haemoglobin (Hb) decrease in both amateurs and professionals as a long-term consequence due to expanded plasma volume (PV). On a short-term basis, however, counteracting dehydration potentially brought about by endurance exercise may cause a rise in Hct bringing competitive cyclists into conflict with the current condition regulations and Hct cut-off of 50 % set by the International Cycling Union (UCI) in its fight against erythropoietin (rhEPO) doping. On the other hand adequate and sufficient fluid substitution being substantial for a successful endurance performance should prevent any pronounced Hct rises. To study the haematological acute effects of prolonged strenuous cycling we measured Hct, Hb, red blood cell (RBC) count and plasma protein in a reliably 'clean' population of 38 well-trained male amateur cyclists before, immediately after and one day after an extraordinary ultramarathon. The pre-race levels of Hct, Hb and RBC count were placed in the lower range of normal distribution and well below the Hct cut-off limit of the UCI. Immediately post-exercise the mean levels of Hct, Hb, RBC count and protein remained unchanged. One day after race, however, all four parameters significantly dropped by 3 %, 6.7 %, 6.5 %, 9.9 % respectively (p0.001), indicating marked post-exercise PV expansion. The calculated percentage increase in PV was 11.9 %. No evidence for coexisting exercise-induced haemolysis was found. Our study shows that in "clean, rhEPO-free" amateur cyclists who involve in strenuous marathon cycling the haematological short-term effects of extraordinary marathon cycling consist in considerable PV expansion making Hct values fall on the following day. The findings - gained from amateurs though - suggest that despite all its disadvantages the UCI Hct cut-off represents an appropriate means to discourage from excessive rhEPO doping at least as long as the available direct methods for detecting this kind of misuse are not yet applied by the international sports federations.

ZusammenfassungDie Kniekehle und die Variationen der Parvavarikosis stellen in der Diagnostik des Krampfaderleidens häufig ein größeres Problem dar. So ist allein die reine V.s.p.-Mündung in Bezug auf die Mündungshöhe in die Vena poplitea bzw. in die distale Vena femoralis superficialis äußerst variantenreich. Daneben gilt es, eine Kniekehlenperforansvene von insuffizienten Gastrocnemiusvenen bzw. anderen Perforansvenen zu unterscheiden. Als eine weitere Variante zieht die so genannte Ischiadicusvarize subfaszial, längs durch das Gebiet der Kniekehle. Die Diagnose einer wahrscheinlich von der Vena glutaea inferior ausgehenden Varikosis der Vena ischiadica ist nur zulässig, wenn vorher atypische Mündungsareale am distalen und proximalen Oberschenkel zur Vena femoralis superficialis, zur Vena femoralis profunda oder zu Ästen der Vena saphena magna ausgeschlossen wurden. Unsere Untersuchungen zeigen, dass die als Ischiadicusvarize bezeichnete Vene topographisch nicht unbedingt direkt mit dem N. ischiadicus zusammenhängen muss.

Background: The demonstration of ϵ germline gene (Cϵ) transcripts and mature mRNA for the ϵ heavy chain gene (Iϵ) in the nasal mucosa suggested that IgE synthesis may occur in allergic rhinitis. Objective: In view of our previous demonstration of increases in IL-4 mRNA + cells in asthmatic subjects, we assessed whether local IgE synthesis may also be a feature of bronchial asthma. Methods: Fiberoptic bronchoscopic mucosa biopsy specimens were obtained from 9 atopic asthmatic subjects and 10 nonatopic normal (intrinsic) control subjects. To control for atopy, we also studied 9 nonatopic asthmatic subjects and 10 atopic nonasthmatic control subjects. Tissue was processed for immunohistochemistry for B cells (CD20) and in situ hybridization for Iϵ and Cϵ RNA + cells and IL-4 mRNA + cells. Results: B-cell numbers in the bronchial mucosa were similar for asthmatic subjects compared with control subjects, whereas significantly higher numbers of Iϵ RNA + ( P = .02 and P = .04, respectively), Cϵ RNA + ( P = .01 and P = .03, respectively), and IL-4 mRNA + ( P = .001 and P = .001, respectively) cells were observed in atopic asthmatic subjects and nonatopic asthmatic subjects, respectively, but not in atopic control subjects compared with nonatopic control subjects. In asthmatic subjects there were significant correlations between Iϵ RNA + cells ( r = 0.54, P = .02) and Cϵ RNA + cells ( r = 0.48, P = .05) when compared with the number of IL-4 mRNA + cells. Conclusion: Increases in Iϵ and Cϵ RNA + cells, but not B-cell numbers, in the bronchial mucosa provide evidence for local IgE synthesis in both atopic and nonatopic asthma. These changes appear to relate to asthma rather than atopy per se and, at least in part, may be under the regulation of IL-4. (J Allergy Clin Immunol 2001;107:686-92.)

In multiple myeloma, the polymerase chain reaction (PCR) of the Ig heavy chain with allele-specific oligonucleotide (ASO) primers is a common and well-described method of identifying the tumor clone in peripheral blood (PB), bone marrow (BM) or leukapheresis products (LA). A factor which is crucial to the detection of clonal Ig rearrangements lies in the 'purity' of the tumor tissue used for the consensus PCR. We describe the application of a method to enrich CD138 positive myeloma cells derived from weakly infiltrated PB-, BM- and LA-samples. These are subjected to immunomagnetic enrichment with the MACS system, using an CD138 antibody directly conjugated to magnetic beads to obtain an enriched tumor cell population and the subsequent amplification of tumor specific IgH rearrangements. We investigated 29 samples (ten PB, ten BM, nine LA) with a median myeloma cell content of 0.5%. The approach led to a median enrichment factor of 118. Tumor-specific rearrangements could be amplified reproducibly from samples containing less than 0.1% myeloma cells.

Als Hashimoto-Enzephalopathie wird eine steroid-sensitive, schubformig oder stetig progrediente Enzephalopathie bezeichnet, welche mit einer Hashimoto-Thyreoiditis assoziiert ist. Charakteristische klinische Befunde sind Verwirrtheit, epileptische Anfalle, Vigilanzminderung, schlaganfallahnliche Episoden, Myoklonien und Tremor. Die Liquordiagnostik zeigt meist eine Proteinerhohung ohne Pleozytose, das EEG generalisierte und umschriebene Verlangsamungen, seltener triphasische Wellen und epilepsietypische Potentiale; die zerebrale Bildgebung mittels CT oder MRT sowie die zerebrale Angiographie sind in der Regel normal. Wir stellen 2 Patientinnen im Alter von 55 und 77 Jahren vor, bei denen die Symptome einer Hashimoto-Enzephalopathie gut auf eine Behandlung mit Steroiden ansprachen, und geben einen Uberblick uber die Literatur.

Recent studies have provided evidence for increased IL-4 expression in the airways of atopic and nonatopic asthmatic subjects. IL-4 is believed to perform important regulatory roles in asthma; however, the expression of the IL-4 receptor has not been investigated. In this study we examined the mRNA and protein expression of the specific alpha-subunit of the IL-4 receptor (alphaIL-4R) in bronchial biopsy specimens obtained from atopic and nonatopic asthmatic subjects.Asthmatic subjects and nonasthmatic control subjects were recruited, and lung function measurements were performed before bronchoscopy. Endobronchial biopsy specimens were examined for the presence of alphaIL-4R mRNA and immunoreactivity by using in situ hybridization and immunocytochemistry, respectively.alphaIL-4R mRNA-positive and immunoreactive cells were detected in the epithelium and subepithelium in biopsy specimens from all subjects. Expression of alphaIL-4R mRNA and protein was significantly increased in the epithelium and subepithelium of biopsy specimens from atopic asthmatic subjects compared with atopic control subjects (P.05 and P.001, respectively). Epithelial alphaIL-4R mRNA expression and immunoreactivity did not differ significantly between nonatopic asthmatic subjects and nonatopic control subjects. Although the numbers of alphaIL-4R mRNA-positive cells were augmented in the submucosa of intrinsic asthmatic subjects compared with nonatopic control subjects (P.05), alphaIL-4R immunoreactivity did not differ significantly between these groups. Increased alphaIL-4R immunoreactive signals were also detected in the endothelial cell layer in both atopic and intrinsic asthmatic subjects compared with atopic and nonatopic control subjects, respectively (P.05). Combined in situ hybridization immunocytochemistry performed on biopsy sections from asthmatic and control subjects demonstrated alphaIL-4R mRNA expression in CD3-positive T cells and tryptasepositive mast cells, with T cells comprising the larger proportion of alphaIL-4R mRNA-positive cells. Numbers of alphaIL-4R mRNA-positive or immunoreactive cells did not correlate with CD3-positive cell numbers, numbers of IL-4 mRNA-positive cells, or indices of pulmonary function.These results demonstrate constitutive alphaIL-4R expression in normal airways and enhanced expression in airway tissue from asthmatic individuals.

Atopic and nonatopic (intrinsic) asthmatics were characterized by a broadly conserved bronchial mucosal proeosinophilic cytokine network in which IL-5 appears to play a key role. Inappropriate IgE-mediated mechanisms may occur in asthma, irrespective of its atopic status, as suggested by elevated serum IgE concentrations and bronchial mucosal expression of FcepsilonRI, IL-4, IL-13, Iepsilon, and Cepsilon. In general, these observations support the concept that these subtypes of asthma, despite showing distinct clinical and biologic features, share many common immunopathologic mechanisms. The most promising future directions of research regarding intrinsic asthma concern the possible identification of novel allergens or antigens, the detailed description of local bronchial mucosal IgE production, and the understanding of a possible macrophage dysfunction. Furthermore, a role for infectious (viral?) or autoimmune processes has yet to be firmly identified in intrinsic asthma. Animal models may also help us to understand the role of IgE and atopy in asthma. Although these are largely IgE-mediated mechanisms, allergen-induced bronchial hyperresponsiveness and eosinophilic inflammation can also occur in the absence of IgE (null mutation of the Cepsilon locus), as shown in a mouse model of hypersensitivity to Aspergillus fumigatus (57). Thus, despite the absence of atopy, IgE-mediated mechanisms may operate in intrinsic asthma (Fig. 1).

Novel arylpiperazines were identified as alpha 1-adrenoceptor (AR) subtype-selective antagonists by functional in vitro screening. 3-[4-(ortho-Substituted phenyl)piperazin-1-yl]propylamines were derivatized with N,N-dimethyl anthranilamides, nicotinamides, as well as carboxamides of quinoline, 1,8-naphthyridine, pyrazolo[3,4-b]pyridine, isoxazolo[3,4-b]pyridine, imidazo[4,5-b]pyridine, and pyrazolo[1,5-a]pyrimidines. Strips of rabbit bladder neck were employed as a predictive assay for antagonism in the human lower tract. Rings of rat aorta were used as a "negative screen" for the test antagonists. Binding to alpha 1-ARs was relatively sensitive to size and electronic features of the arylpiperazine portion of the antagonists and permissive to these features on the heteroaryl carboxamide side. These structure-affinity findings were exploited to produce nicotinamides (e.g. 13ii and 25x) and pyrazolo[3,4-b]pyridines (e.g. 37f and 37y) ligands with nanomolar affinity at the alpha 1-AR subtype prevalent in the human lower urinary tract(pA2 values: 8.8, 10.7, 9.3, and 9.9, respectively) and displaying 2-3 orders of magnitude selectivity over the alpha 1D-AR.

Intrinsic asthma is characterized by an increased number of activated eosinophils and macrophages and an increased expression of the hematopoietic growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF) in the bronchial mucosa.This study was carried out to investigate the expression of alpha GM-CSF receptor (alpha GM-CSFr) messenger RNA and protein in the bronchial mucosa of patients with intrinsic or atopic asthma and of control subjects and to correlate the expression of alpha GM-CSFr to the number of EG2+ cells (eosinophils) and CD68+ cells (macrophages) and pulmonary function.Nineteen patients with stable asthma (9 with atopic and 10 with intrinsic asthma) and 22 normal control subjects (12 atopic and 10 nonatopic subjects) were recruited, and FEV1 (percent predicted) and PC20 were measured before bronchoscopy. Endobronchial biopsy specimens were obtained and examined for membrane-bound alpha GM-CSFr by using in situ hybridization and immunocytochemistry.alpha GM-CSFr mRNA- and protein-positive cells were identified in biopsy specimens from all four groups studied. There was no significant difference in the number of cells expressing alpha GM-CSFr mRNA and protein in patients with atopic asthma compared with atopic and nonatopic control subjects. However, the numbers of alpha GM-CSFr mRNA- and protein-positive cells were significantly higher in nonatopic patients with asthma compared with atopic patients with asthma and atopic and nonatopic control subjects (p0.001). In the patients with intrinsic asthma, the number of alpha GM-CSFr mRNA-positive cells per millimeter of basement membrane correlated with numbers of CD68+ cells (r2 = 0.87, p0.001) but not with EG2+ cells, and colocalization studies demonstrated that 80% of the cells expressing alpha GMCSFr mRNA were CD68+. The expression of GM-CSF was also significantly increased in patients with intrinsic asthma compared with those with atopic asthma and control subjects (p0.05). In addition, in intrinsic asthma, there was a correlation between alpha GM-CSFr mRNA and FEV1 (r2 = 0.61, p0.05).These results demonstrate that elevated numbers of cells expressing alpha GM-CSFr can be detected in nonatopic asthma but not in atopic asthma and suggest that this increased expression is predominantly macrophage-associated and may play an important pathophysiologic role in intrinsic asthma.

Eosinophilic inflammation and interleukin-5 (IL-5) expression are characteristic features of the bronchial mucosa in asthma. We have investigated the differential expression of membrane and soluble isoforms of alpha IL-5 receptor (alpha IL-5Rm and alpha IL-5Rs) mRNA in asthmatics and in normal control subjects and examined the correlation between alpha IL-5Rm and alpha IL-5Rs expression and the FEV1 and airway hyperresponsiveness. Nineteen subjects with stable asthma (atopic = 9; intrinsic = 10) and 22 control subjects (atopic = 12; nonatopic = 10) were recruited. Endobronchial biopsies were obtained and processed for in situ hybridization and double-staining techniques. There was a significant increase in the number of cells per millimeter basement membrane expressing mRNA for total, membrane-bound, and soluble alpha IL-5R in asthmatics when compared with that in nonasthmatic control subjects (p0.001); 93% of the cells positive for alpha IL-5R mRNA were EG2+ve eosinophils. There was no significant difference in the expression of alpha IL-5Rm and alpha IL-5Rs between the atopic and nonatopic asthmatics. The expression of alpha IL-5Rm and alpha IL-5Rs was also nonsignificantly different between the atopic and nonatopic control subjects. However, in the asthmatic subjects, the number of positive cells expressing mRNA for alpha IL-5Rm inversely correlated with FEV1(r2 = 0.89, p0.001), whereas the expression of alpha IL-5Rs mRNA directly correlated with FEV1 (r2 = 0.52, p0.001). There were no significant correlations between alpha IL-5R isoforms and the methacholine PC20. These results suggest that alpha IL-5R upregulation and differential regulation of alternatively spliced alpha IL-5R mRNA transcripts may influence the eosinophil response and the accompanying changes in airflow limitation in both atopic and nonatopic variants of chronic asthma.

Das Restless-legs-Syndrom (RLS) ist eine der haufigsten neurologischen Erkrankungen. Kardinalsymptom ist der Bewegungsdrang, v. a. in den Beinen. Perioperativ kann ein RLS neu auftreten, oder die Symptome eines vorhandenen RLS konnen exazerbieren. Schwerer Schlafentzug, forcierte Immobilisation und akuter Eisenmangel sind haufige Ausloser. Eine medikamentose Therapie kann einen wichtigen auslosenden und exazerbierenden Faktor darstellen. Arzneimittel, die dopaminantagonistische, serotonerge oder opioidantagonistische Wirkungen besitzen, sollten vermieden werden. Die medikamentose Dauertherapie des RLS sollte so kurz wie moglich unterbrochen und falls notig nicht oral uberbruckt werden. Bei Krankheiten, die mit einem sekundaren RLS assoziiert sein konnen, ist besonders an die mogliche Provokation oder Exazerbation eines RLS zu denken. Dies gilt speziell fur M. Parkinson, Diabetes mellitus, terminale Niereninsuffizienz, Ruckenmarkschaden oder bei Schwangeren. Bisher gibt es keine ausreichende Evidenz, dass irgendeine Anasthesieform das RLS negativ beeinflusst.

Our purpose was to determine whether chelation of Ca2+ and Mg2+ is the mechanism by which sodium citrate inhibits corneal ulceration in the alkali-injured rabbit eye. The right eyes of 60 albino rabbits (2-2.5 kg) were alkali-injured by filling a 12-mm-diameter plastic well placed on the corneal surface with 0.4 ml of 1 N NaOH. After 35 s the alkali was aspirated, and the well was rinsed with physiological saline. Animals were randomly distributed to three treatment groups of equal size. Two drops of the following topical medications were administered on the hour (14 times per day) for 35 days: physiological saline, 10% citrate in saline, and 346 mM Ca2+, 346 mM Mg2+, and 10% citrate in saline. During the experiment, significantly fewer ulcerations occurred in the citrate-treated eyes (five of 20, 25%) than in the saline-treated eyes (13 of 20, 65%) or in the calcium-magnesium-citrate-treated eyes (15 of 20, 75%). When ulcerations did develop in the citrate group, they occurred significantly later and were less severe than those in the saline and calcium-magnesium-citrate groups. There was a significant increase in the number of eyes with signs of band keratopathy and translucent areas in the calcium-magnesium-citrate group when compared with the other two groups. As in previous studies, sodium citrate significantly inhibited the development of corneal ulcers after alkali injury. The annullment of the favorable effect of citrate on ulceration in the alkali-injured eye by the addition of calcium and magnesium shows that the mechanism of action of citrate is the chelation of these divalent cations.

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor signs in Parkinson’s disease. However, clinical studies suggest that DBS of the STN may also affect cognitive and emotional functions. Objective: To study the impact of STN stimulation in Parkinson’s disease on perception of facial expressions. Results: There was a selective reduction in recognition of angry faces, but not other expressions, during STN stimulation. Conclusions: The findings may have important implications for social adjustment in these patients.

Alkali treatment of whole cornea produces a high molecular weight polypeptide causing a respiratory burst in neutrophils. The current study was conducted to determine if this stimulant could be elicited from cultured or scraped corneal cells (epithelium, keratocytes, or endothelium). Fresh or previously frozen epithelium, endothelium, and stroma were isolated from bovine eyes, alkali treated, and tested for the presence of the respiratory burst stimulant. The same procedure was performed on cultured bovine epithelium, keratocytes, and endothelium. To determine if the stimulant is specific to corneal cells, the component parts of human blood (cellular and extracellular) were separated, treated with alkali, and tested individually. Activation of the respiratory burst of polymorphonuclear leukocytes (PMNs) was used as a marker for the presence of the stimulant. All alkali-degraded cell samples, except red blood cells, produced a respiratory burst when added to viable PMNs. Alkali-treated plasma induced weak stimulation. Bovine corneal epithelium was alkali-treated and separated by high-performance liquid chromatography (HPLC) according to molecular size. The stimulant was shown to have a high molecular weight by its recovery in HPLC fraction number 7. These results demonstrate that the PMN stimulant originates from cells. This PMN stimulant is proposed as an inflammatory mediator in the alkali-injured cornea.

There is debate about increased mortality risk associated with low levels of glycaemia. To address this issue, we examined the shape of the risk relationship between glycated haemoglobin and mortality in a UK population. In 17,196 men and women aged 39–82 years participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study in Norfolk without known diabetes or cardiovascular disease, we estimated HRs for total and cause-specific mortality comparing categories of glycated haemoglobin (

The purpose of the study was to identify epithelial and stromal proteins that exhibit up- or down-regulation in keratoconus (KC) vs. normal human corneas. Because previous proteomic studies utilized whole human corneas or epithelium alone, thereby diluted the specificity of the proteome of each tissue, we selectively analyzed the epithelium and stromal proteins. Individual preparations of epithelial and stromal proteins from KC and age-matched normal corneas were analyzed by two independent methods, i.e., a shotgun proteomic using a Nano-Electrospray Ionization Liquid Chromatography Tandem Mass Spectrometry [Nano-ESI-LC-MS (MS)(2)] and two-dimensional-difference gel electrophoresis (2D-DIGE) coupled with mass spectrometric methods. The label-free Nano-ESI-LC-MS (MS)(2) method identified 104 epithelial and 44 stromal proteins from both normal and KC corneas, and also quantified relative changes in levels of selected proteins, in both the tissues using spectral counts in a proteomic dataset. Relative to normal corneal epithelial proteins, six KC epithelial proteins (lamin-A/C, keratin type I cytoskeletal 14, tubulin beta chain, heat shock cognate 71 kDa protein, keratin type I cytoskeletal 16 and protein S100-A4) exhibited up-regulation and five proteins (transketolase, pyruvate kinase, 14-3-3 sigma isoform, phosphoglycerate kinase 1, and NADPH dehydrogenase (quinone) 1) showed down-regulation. A similar relative analysis showed that three KC stromal proteins (decorin, vimentin and keratocan) were up-regulated and five stromal proteins (TGF-betaig h3 (Bigh3), serotransferrin, MAM domain-containing protein 2 and isoforms 2C2A of collagen alpha-2[VI] chain) were down-regulated. The 2D-DIGE-mass spectrometry followed by Decyder software analysis showed that relative to normal corneas, the KC corneal epithelium exhibited up-regulation of four proteins (serum albumin, keratin 5, L-lactate dehydrogenase and annexin A8) and down-regulation of four proteins (FTH1 [Ferritin heavy chain protein 1], calpain small subunit 1, heat shock protein beta 1 and annexin A2). A similar relative analysis of stroma by this method also showed up-regulation of aldehyde dehydrogenase 3A1 (ALDH3A1), keratin 12, apolipoprotein A-IV precursor, haptoglobin precursor, prolipoprotein and lipoprotein Gln in KC corneas. Together, the results suggested that the Nano-ESI-LC-MS(MS)(2) method was superior than the 2D-DIGE method as it identified a greater number of proteins with altered levels in KC corneas. Further, the epithelial and stromal structural proteins of KC corneas exhibited altered levels compared to normal corneas, suggesting that they are affected due to structural remodeling during KC development and progression. Additionally, because several epithelial and stromal enzymes exhibited up- or down-regulation in the KC corneas relative to normal corneas, the two layers of KC corneas were under metabolic stress to adjust their remodeling.

OBJECTIVES. Nationwide, human immunodeficiency virus type 1 (HIV-1) seroprevalence surveys using dried neonatal blood specimens are critical to estimating HIV-1 seroprevalence among childbearing women. However, the noninclusion of blood specimens deemed "quantity not sufficient" (QNS) for HIV-1 antibody testing potentially introduces bias. In Wisconsin beginning in 1990, we modified the survey protocol to reduce QNS rates and assess bias introduced by QNS specimens. METHODS. The HIV-1 antibody assay was modified to use four 1/8-in blood spots when a single 1/4-in blood spot could not be obtained. Both methods obtain identical blood volumes for testing. RESULTS. During a 27-month period, 7396 (4.8%) of 154,683 specimens were deemed QNS using 1/4-in blood spots. Of these, 6590 (89%) were of sufficient quantity to be tested using four 1/8-in blood spots; 6 (0.09%) specimens tested with 1/8-in blood spots were HIV-1 Western blot assay positive compared with 44 (0.03%) of 147,287 1/4-in specimens (odds ratio = 3.0; 95% confidence interval = 1.2, 7.4). CONCLUSIONS. Because noninclusion of QNS specimens potentially introduces bias, incorporating the results of HIV-1 antibody testing of QNS specimens using four 1/8-in blood spots can improve the accuracy of HIV-1 seroprevalence estimates in these serologic surveys.

The cockroaches Blatella germanica and Supella longipalpa can act as intermediate hosts of Trichospirura leptostoma as demonstrated by experimental infestation. The parasite developed from the embryonated egg into the infective larval stage (L3) in cockroaches within 5-6 weeks. After experimental infection of marmosets (Callithrix jacchus), eggs were first found in faecal samples (prepatency) at 8-9 weeks post-infection. Patency lasts about 2 years. Despite the presence of living adult worms in the marmosets' pancreas, no additional eggs were observed in their faeces after the patent period.

The chemotactic behavior of polymorphonuclear leukocytes (PMNs) suspended in a three-dimensional gel of native collagen fibers was analyzed using a new visual assay aided by computer assisted tracking. Cell behavior was observed in a 7 microliters chamber closed at either end with capillary tubes tipped with dialysis membrane. The chemoattractant, LTB4, was placed in one capillary tube and the control substance in the opposite tube. Under microscopic observation neutrophils were videotaped, their images digitized, and the x and y coordinates of the cell centroids captured at 30 s intervals for 15 min and subsequently analyzed. The data generate a global perspective of neutrophil behavior in a medium simulating a collagenous tissue. The results show that when leukotriene B4 was substituted for HBSS the PMN population underwent chemotactic displacement. PMN chemotaxis was increased greatly when the concentration of LTB4 was increased from 10 nM to 1 microM in separate experiments. This result was partly achieved by movement of an increasing percentage of the PMN population, less frequent stops, and longer durations of motility for individual cells. The most dramatic effect of LTB4 on neutrophil behavior was a large increase in directional movement toward the chemotactic source. The effects of LTB4 fell dramatically when the gradient source concentration was increased to 10 microM. The visual assay described here provides clear evidence that LTB4 induces true neutrophil chemotaxis in a collagenous matrix.

Currently available topical antifungals are often not satisfactory for the treatment of nail infections, because of the inability to penetrate the nail plate. Terbinafine HCl nail solution is a novel antifungal formulation containing a nail penetration enhancer dodecyl-2-N,N-dimethylaminopropionate hydrochloride (DDAIP HCl, trade name NexACT-88). In this study, we used a guinea pig model of Trichophyton mentagrophytes dermatophytosis and evaluated the clinical and mycological efficacy of different terbinafine HCl nail solutions (TNS) formulated with or without DDAIP HCl. Ciclopirox (8%) nail lacquer (Penlac), the only Food and Drug Administration approved topical treatment for onychomycosis, was used as a comparator. Following the IACUC Guidelines, the skin of male albino guinea pigs was abraded under anaesthesia. Each animal was infected with T. mentagrophytes ATCC 24953 (cell suspension containing 1 x 10(7) conidia). The experimental animals were divided into 11 groups (five animals per group) and tested with the following formulations: vehicle control, 0.5% DDAIP HCl, 1%, 5% and 10% TNS (without DDAIP HCl), 1% TNS with 0.5%, 2.5% and 5.0% DDAIP HCl, 5% and 10% TNS with 0.5% DDAIP HCl, 8% ciclopirox nail lacquer and an untreated control group. Evaluation of clinical and mycological efficacy was performed 72 h after completion of a 7-day treatment regimen. Skin biopsy samples were processed for histopathological examination. The infected untreated control guinea pigs showed patches of hair loss and ulcerated or scaly skin and fungal invasion of hair roots. The vehicle and 0.5% DDAIP HCl treated groups showed minimal clinical efficacy (only 11% and 5%, respectively). In contrast, all three concentrations of TNS (1%, 5% and 10% terbinafine HCl) formulated with or without 0.5% DDAIP HCl showed 100% mycological efficacy by the hair root invasion test. Clinical efficacy of the 5% and 10% TNS improved with addition of 0.5% DDAIP HCl (47.4% and 73.8% vs. 68.4% and 89.5%, respectively). In addition, no fungal elements were detected in the treated guinea pig skin. All formulations of TNS resulted in a higher clinical and mycological efficacy compared with the 8% ciclopirox nail lacquer (P = 0.0444). In conclusion, TNS containing 1%, 5% and 10% terbinafine HCl formulated with and without DDAIP HCl demonstrated high antifungal efficacy in experimental dermatophytosis. Addition of 0.5% DDAIP HCl to 5% and 10% TNS significantly enhanced the clinical and mycological efficacy of these formulations which were superior compared with the 8% ciclopirox nail lacquer. Evaluation of the 1%, 5% and 10% TNS in clinical trials for the treatment of dermatophytosis and onychomycosis is warranted.

This report presents the four main themes that emerged from a seminar organized by the International Peace Academy (now the International Peace Institute) and the Geneva Centre for Security Policy in Geneva on 29/30 November 2007. First, it addresses the question of the conceptual relationship between organised crime and peace operations, outlining a framework for functional analysis focusing on the complex environments in which international interventions take place and the functions that organised crime and peace operations play in those environments. Second, it looks at the causal relationship between peace operations and organised crime. Third, it turns to the strategic conclusions flowing from this analysis, investigating a number of trade-offs involved when peace operations confront organised crime. Last, it presents some of the most salient operational considerations and lessons learnt from the Seminar and the discussion papers prepared for it.

Proline-glycine-proline (PGP) peptides have been identified as inflammatory mediators initiating neutrophil invasion into alkali-injured cornea. The complementary peptide, arginine-threonine-arginine (RTR), has been shown to bind to the PGP sequence and impede neutrophil infiltration. A prior study showed that L-RTR tetramer and D-RTR tetramer, used alternately (14 times a day), resulted in significantly reduced incidences of corneal ulceration and severity. The purpose of this experiment is to determine the effectiveness of both tetramers, used separately, compared with control.Rabbit corneas were exposed to 1 N NaOH for 35 seconds. Sixteen animals were randomly assigned to each of 3 groups: 1) phosphate-buffered saline (PBS), 2) 1.5 mM L-RTR, or 3) 800 microM D-RTR. One drop of each was administered hourly (14 times a day) for 36 days. Additional studies were done to assess neutrophil infiltration into corneas with and without RTR treatment.The severity of corneal ulceration in both RTR groups was statistically significantly different from the 21st day of the experiment to the end. As a result of ulcers healing in the L-RTR group, there was a statistically significant reduction in the number of ulcers beginning on day 22 versus control. Although there was healing in the D-RTR group, the incidence of ulcers was not significantly different from control or L-RTR. Morphometric analysis revealed decreased neutrophil (PMN) invasion with RTR treatment compared with PBS control.Binding of the PGP molecules by RTR tetramer seems to deprive the cornea of this neutrophilic chemotactic stimulus, leading to a reduction in the severity and incidence of corneal ulceration.

Ectopic splenic tissue simulating renal, pancreatic, hepatic and even pelvic malignant tumours have been reported previously [1-4]. Autopsy studies have demonstrated that the pathological entities that affect the spleen also affect the accessory spleen [5]. To our knowledge this is the first reported case of an accessory spleen, markedly enlarged by portal hypertension, presenting as a splenic pseudotumour. The patient had a TIPS (transjugular intrahepatic portosystemic shunt) procedure prior to its operative removal and the role of pre-resectional TIPS is also discussed.

Interleukin 18 (IL-18) is an important pro-inflammatory cytokine in the early phase of human immune response to microbial infections. The influence of strenuous exercise on the intrinsic balance of IL-18 and its endogenous antagonist IL-18 binding protein (IL-18 BP) is unknown, but could be of major relevance for the athlete's immune function empirically and epidemiologically proven to be altered after exhaustive exertion. To study the effect of strenuous marathon cycling on the interaction of IL-18 and IL-18 BP we investigated 37 male, healthy, and well-trained amateur cyclists participating in the Otztaler Radmarathon in Tyrol (distance: 230 km; cumulative altitude difference: 5500 m). IL-18 was measured by a commercially available ELISA-Kit and IL-18 BP by a novel IL-18 BP ELISA method. Free, unbound IL-18 was calculated according to a standard equation. The mean plasma level of IL-18 was 142.27 +/- 21.85 pg/ml pre-race, remained nearly unchanged (124.35 +/- 13.16 pg/ml; p = 1.0) immediately after competition (mean race time 9 h 38 min), but declined significantly 24 h afterward (62.92 +/- 6.80 pg/ml; p = 0.002). The plasma levels of IL-18 BP increased considerably immediately after and kept on rising for the following 24 h (pre-race: 1.51 +/- 0.20 ng/ml; immediately post-race: 3.84 +/- 0.26 ng/ml, p < 0.001; 24 h post-race: 4.33 +/- 0.42 ng/ml, p < 0.001). Therefore, the calculated free IL-18 was 122.06 +/- 16.79 pg/ml pre-race, declined to 82.86 +/- 8.59 (p = 0.05) immediately post-race and to 39.17 +/- 3.76 pg/ml 24 h post-race (p < 0.001). The respective percentages of this post-exercise reduction in free IL-18 plasma levels were 32 % and 68 %. The present study reveals an exercise-induced significant decline in free IL-18 accompanied by an immediate up-regulation of IL-18 BP and decreased IL-18 in marathon cyclists. This down-regulation of free IL-18 may (i) limit the magnitude and duration of a too excessive inflammatory response to the exercise-induced tissue damage and (ii) on the other hand contribute to the elevated susceptibility to infection in athletes undergoing exhaustive exercise.

Purpose: To determine if transplanted corneal epithelial stem cells are safely and efficiently attached to the deficient limbal niche with use of fibrin sealant. The primary outcome is measured with respect to the stability of the transplant, with secondary qualitative evaluations of inflammation, patient comfort, speed of operation, and incidence of complications. Methods: This retrospective case study examined a total of 114 corneal stem cell reconstructions performed in 95 patients from 1996 to 2004 using corneal stem cells primarily, with a minority of amnion alone, or both. Fibrin sealant was used as the only technique of stem cell adhesion for limbal reconstruction for primary or recurrent pterygia and various stem cell-deficient diseases from 2000 to 2004. Results: The fibrin sealant group showed 1 small recurrence of pterygium but no complications. With sutures, there were 3 recurrences in the pterygia group. After completion of all surgical procedures, all patients were free of pterygia. Miscellaneous stem cell deficiencies were included to demonstrate that corneal stem cell transplants can be used in other corneal procedures in addition to pterygia. Conclusions: Fibrin sealant alone effectively and safely attached corneal stem cell transplants to the limbal niche. The additional qualitative observations of a reduction in operation time, postoperative pain, and inflammation augurs for more extensive use of fibrin sealants in ophthalmology.

In recreational cyclists marathon cycling influences renal function only on a minimal scale. Respective information on extreme ultramarathon cycling in better trained athletes is not available. The objective was to evaluate the renal and haematological effects of ultraendurance cycling in the world's best ultramarathon cyclists. Creatinine (CR), urea, haemoglobin (Hb), haematocrit (Hct) and plasma volume (PV) were investigated in 16 male ultramarathon cyclists during the 1st Race Across the Alps in 2001 (distance: 525 km; cumulative altitude difference: 12,600 m). All renal functional parameters were normal pre-exercise. During the race serum CR, urea and uric acid rose significantly by 33, 97 % and 18 % (p0.001 respectively) and nearly normalised again on the following day. The decline in calculated CR clearance was 25 %. There was a negative correlation (r=- 0.575, p=0.02) between the rise in serum CR and the athlete's training kilometers. The serum urea/CR ratio rose above 40 in 12 athletes (75 %). Mean fractional sodium excretion and fractional uric acid excretion fell below 0.5 % (p0.001) and 7 %, indicating reduced renal perfusion. The deflection of the renal functional parameters was temporary and nearly gone after 24 hours of recovery. Hct declined during the race from 0.44 to 0.42, and continued falling on the next day (0.42 --0.40; p0.001). The corresponding rises in calculated PV were + 8 % and + 22 %. The study affirms that in world class cyclists the enormous strains of ultramarathon cycling influence renal function only on a minimal scale. The impact on the PV, however, is pronounced leading to marked haemodilution post-exercise. This very temporary "impairment of renal function" seems to be the physiological response to ultramarathon cycling and may be attenuated to some extent by preceding high-volume training.

Purpose: To manage the complication of stress fractures in foldable acrylic intraocular lenses. Methods: During an implantation of a foldable acrylic intraocular lens (AcrySof, Alcon Laboratories, Fort Worth, Texas), the optic was noted to have developed paracentral stress fractures along the fold approximately 50% deep. Results: The lens was explanted and replaced without difficulty. Conclusions: The observed complication can be avoided by recognizing that it might occur, wetting the lens before slowly folding it, and inspecting it carefully before insertion.

A 39-year-old man underwent phototherapeutic keratectomy via excimer laser for recurrent corneal erosions secondary to basement membrane dystrophy with the subsequent development of irregular astigmatism and central stromal opacity. The cornea was scraped and treated with 0.02% mitomycin C using a total of 14 drops over a period of 6 days. Corneal edema developed as a consequence of low endothelial cell count with dysfunctional cells. A corneal transplant restored acuity of 20/20 with binocular vision. It is believed that the underlying endothelium was exposed to toxic doses of mitomycin C sufficient to damage and destroy vital cells. The author reports this case not to criticize the use of mitomycin C in visually disabling post-phototherapeutic keratectomy or photorefractive keratectomy haze but to apprize colleagues of a potential pitfall. The author believes that the use of mitomycin C as a 1-time application at the end of surgery is a safe and valuable adjunct to recover vision when no other is known. However, continued topical application of mitomycin C to the central cornea, in the face of an epithelial defect or an epithelium with inadequate barrier function, increases the risk of endothelial damage.

Objectives: To analyse the heart rate (HR) response and estimate the ultraendurance threshold—the optimum maintainable exercise intensity of ultraendurance cycling—in ultraendurance elite cyclists competing in the Race across the Alps. Methods: HR monitoring was performed in 10 male elite cyclists during the first Race across the Alps in 2001 (distance: 525 km; cumulative altitude difference: 12 600 m) to investigate the exercise intensity of a cycle ultramarathon and the cardiopulmonary strains involved. Four different exercise intensities were defined as percentages of maximal HR (HR max ) as follows: recovery HR (HR re ), max ; moderate aerobic HR (HR ma ), 70–80%; intense aerobic HR (HR ia ), 80–90%; and high intensity HR (HR hi ), >90%. Results: All athletes investigated finished the competition. The mean racing time was 27 hours and 25 minutes, and the average speed was 18.6 km/h. The mean HR max was 186 beats/min, and the average value of measured HRs (HR average ) was 126 beats/min resulting in a mean HR average /HR max ratio of 0.68, which probably corresponds to the ultraendurance threshold. The athletes spent 53% (14 hours 32 minutes) of total race time within HR re , 25% (6 hours 51 minutes) within HR ma , 19% (5 hours 13 minutes) within HR ia , and only 3% (49 minutes) within HR hi , which shows the exercise intensity to be predominantly moderate (HR re + HR ma = 78% or 21 hours 23 minutes). The HR response was influenced by the course profile as well as the duration. In all subjects, exercise intensity declined significantly during the race, as indicated by a decrease in HR average /HR max of 23% from 0.86 at the start to 0.66 at the end. Conclusions: A substantial decrease (10% every 10 hours) in the HR response is a general cardiovascular feature of ultramarathon cycling, suggesting that the ultraendurance threshold lies at about 70% of HR max in elite ultramarathon cyclists.

The stress of strenuous long-term exercise may alter renal function. Whether this is also true for marathon cycling is unknown so far. The purpose of this study was to evaluate renal function following competitive marathon cycling. We investigated 38-male, well-trained recreational cyclists credibly not taking any kind of doping who participated in the Otztal Radmarathon. Blood and urine specimens were taken the day before, immediately after and one day after competition. Baseline renal functional parameters--normal before competition--increased significantly afterwards and remained elevated during 24 hours of recovery. The rises in serum creatinine, urea and uric acid were 20, 54 and 42 % (p < 0.001 respectively). The corresponding decline in estimated creatinine clearance was 18 %. In all athletes the serum urea/creatinine ratio rose above 40, fractional sodium excretion and fractional uric acid excretion fell below 0.4 % and 15 %, indicating reduced renal perfusion. The observed effects lasted for at least 24 h despite a stable fluid balance during the race and an expanding plasma volume (PV) in the recovery period. Levels of haematocrit remained unchanged immediately post-race but significantly declined from 0.44 to 0.41 on the following day (p < 0.001). The calculated rise in PV was + 10.8 %. Electrolyte homeostasis was preserved throughout the observation period. Post-exercise proteinuria was small and of the mixed glomerular-tubular type. There was neither evidence for exercise-induced haemolysis, nor for significant skeletal muscle damage. The finding obtained from well-hydrated recreational athletes reveals that the extraordinary strains of marathon cycling influence renal function only on a minimal scale. Though minor, the physiological effects were long-lasting. The results obtained suggest that a reduced renal perfusion is the mechanism responsible for the slight impairment of renal function following exhaustive marathon cycling.

The combination of electrical deep brain stimulation (DBS) with functional imaging offers a unique model for tracing brain circuitry and for testing the modulatory potential of electrical stimulation on a neuronal network in vivo. We therefore applied parametric positron emission tomography (PET) analyses that allow characterization of rCBF responses as linear and nonlinear functions of the experimentally modulated stimulus (variable stimulator setting). In patients with electrodes in the thalamic ventrointermediate nucleus (VIM) for the treatment of essential tremor (ET) here we show that variations in voltage and frequency of thalamic stimulation have differential effects in a thalamo-cortical circuitry. Increasing stimulation amplitude was associated with a linear raise in rCBF at the thalamic stimulation site, but with a nonlinear rCBF response in the primary sensorimotor cortex (M1/S1). The reverse pattern in rCBF changes was observed with increasing stimulation frequency. These results indicate close connectivity between the stimulated nucleus (VIM) and primary sensorimotor cortex. Likewise, stimulation parameter-specific modulation occurs at this simple interface between an electrical and a cerebral system and suggests that the scope of DBS extends beyond an ablation-like on-off effect: DBS could rather allow a gradual tuning of activity within a neuronal circuit.

This paper recommends design considerations in order to prepare the Assault Variant for urban warfare. The future battlefield will be the urban arena. Underdeveloped countries are producing vast urban slums at an alarming rate. Suspended in underprivileged conditions such as poverty, starvation, and disease, this class will seek change through radical means creating regional crisis. With the United States politically and economically engaged throughout the globe, such a crisis may threaten U.S. interests requiring a military response. Additionally, our adversaries realize the futility in challenging the U.S. military on open, unrestricted ground; therefore, they will seek to degrade U.S. abilities in the restrictive terrain of cities. Though designed for long range, direct fire engagements, history has shown that tanks have excellent utility in urban fighting. This has been proven again during recent experiments designed to create effective urban tactics. The MEEEV Program's Assault Variant will replace the premier capabilities of the M1A1 Main Battle Tank in the year 2020. The Assault Variant's design supports the concepts within Expeditionary Maneuver Warfare - Seabasing, Ship to Objective Maneuver, and Sustained Operations Ashore - creating a smaller, lighter, and more logistically efficient design. Of concern is that this design is not appropriate for fighting in urban areas. Conclusion: in order to prepare the Assault Variant for likely urban warfare, this paper offers sensible urban-minded recommendations to the Assault Variant's firepower, protection, mobility, and command and control systems, as well as its training regimen.

The aim of the study was to analyze the exercise intensity of recreational cyclists participating in a cycling-touring event. In 14 male healthy recreational cyclists heart rate (HR) monitoring was performed during the Otztal Radmarathon 1999 (distance: 230 km; altitude difference: 5500 m) in order to evaluate the HR response and to estimate the cardiopulmonary strains for the less-trained athlete confronted with such a marathon. Four different exercise intensities were defined as percentages of maximal HR (HR(max)) as follows: recovery HR (HR(re))70 % of HR max; moderate aerobic HR (HR(ma)) = 70 - 80 %; intense aerobic HR (HR(ia)) = 80 - 90 %; and anaerobic HR (HR(an))90 %. All athletes finished the competition successfully. The mean racing time was 10 h 14 min, the average speed 22.5 km/h. The mean HR(max) was 188 bpm, the average value of the measured HRs (HR(average)) was 145 bpm resulting in a mean HR(average)/HR(max) ratio of 0.77. Athletes spent 18.5 % (1 h 54 min) of total race time within HR(re), 28 % (2 h 52 min) within HR(ma), 39.5 % (4 h 02 min) within HR(ia), and 14 % (1 h 26 min) within HR(an). The vast majority of exercise was done under "aerobic conditions" (HR(re) + HR(ma) + HR(ia) = 86 % or 8 h 48 min) - confirming the knowledge that the aerobic energy supply is crucial for the performance of long-term exercise. The large amount of high exercise intensities (HR(ia) + HR(an) = 53.5 % or 5 h 30 min), however, features the intense cardiopulmonary strains evoked by such competitions. The HR response was related to the course profile with HRs significantly declining in all subjects to an extent of 10 % during the course of race. Our findings show that the exercise intensity borne by recreational cyclists during a cycle-touring event is high and very similar to that of professionals. With respect to the high cardiovascular strains a thorough medical screening is advisable for any participant of such an event combining both high volume and high intensity loads.