Diagnosis and treatment of resistant hypertension.

Abstract Hypertension resistant to lifestyle interventions and antihypertensive medications is a common problem encountered by physicians in everyday practice. It is most often defined as a blood pressure remaining ≥ 140/90 mmHg despite the regular intake of at least three drugs lowering blood pressure by different mechanisms, one of them being a diuretic. It now appears justified to include, unless contraindicated or not tolerated, a blocker of the renin-angiotensin system and a calcium channel blocker in this drug regimen, not only to gain antihypertensive efficacy, but also to prevent or regress target organ damage and delay the development of cardiorenal complications. A non-negligible fraction of treatment-resistant hypertension have normal "out of office" blood pressures. Ambulatory blood pressure monitoring and/or home blood pressure recording should therefore be routinely performed to identify patients with true resistant hypertension, i.e. patients who are more likely to benefit from treatment intensification.

Long diagnostic delay in Crohn's disease is associated with complicated disease course and increased operation rate

Background: We have recently shown that the median diagnostic delay to establish Crohn's disease (CD) diagnosis (i.e. the period from first symptom onset to diagnosis) in the Swiss IBD Cohort (SIBDC) was 9 months. Seventy five percent of all CD patients were diagnosed within 24 months. The clinical impact of a long diagnostic delay on the natural history of CD is unknown. Aim: To compare the frequency and type of CD-related complications in the patient groups with long diagnostic delay (>24 months) vs. the ones diagnosed within 24 months. Methods: Retrospective analysis of data from the SIBDCS, comprising a large sample of CD patients followed in hospitals and private practices across Switzerland. The proportions of the following outcomes were compared between groups of patients diagnosed 1, 2-5, 6-10, 11-15, and ≥ 16 years ago and stratified according to the length of diagnostic delay: bowel stenoses, internal fistulas, perianal fistulas, CD-related surgical interventions, and extraintestinal manifestations. Results: Two hundred CD patients (121 female, mean age 44.9 ± 15.0 years, 38% smokers, 71% ever treated with immunomodulators and 35% with anti-TNF) with long diagnostic delay were compared to 697 CD patients (358 female, mean age 39.1 ± 14.9 years, 33% smokers, 74% ever treated with immunomodulators and 33% with anti-TNF) diagnosed within 24 months. No differences in the outcomes were observed between the two patient groups within year one after CD diagnosis. Among those diagnosed 2-5 years ago, CD patients with long diagnostic delay (n = 45) presented more frequently with internal fistulas (11.1% vs. 3.1%, p = 0.03) and bowel stenoses (28.9% vs. 15.7%, p = 0.05), and they more frequently underwent CD-related operations (15.6% vs. 5.0%, p = 0.02) compared to the patients diagnosed within 24 months (n = 159). Among those diagnosed 6-10 years ago, CD patients with long diagnostic delay (n = 48) presented more frequently with extraintestinal manifestations (60.4% vs. 34.6%, p = 0.001) than those diagnosed within 24 months (n = 182). For the patients diagnosed 11-15 years ago, no differences in outcomes were found between the long diagnostic delay group (n = 106) and the one diagnosed within 24 months (n = 32). Among those diagnosed ≥ 16 years ago, the group with long diagnostic delay (n = 71) more frequently underwent CD-related operations (63.4% vs. 46.5%, p = 0.01) compared to the group diagnosed with CD within 24 months (n = 241). Conclusions: A long diagnostic delay in CD patients is associated with a more complicated disease course and higher number of CD-related operations in the years following the diagnosis. Our results indicate that efforts should be undertaken to shorten the diagnostic delay in CD patients in order to reduce the risk for progression towards a complicated disease phenotype.

Invasive candidiasis as a cause of sepsis in the critically ill patient.

Invasive fungal infections are an increasingly frequent etiology of sepsis in critically ill patients causing substantial morbidity and mortality. Candida species are by far the predominant agent of fungal sepsis accounting for 10% to 15% of health-care associated infections, about 5% of all cases of severe sepsis and septic shock and are the fourth most common bloodstream isolates in the United States. One-third of all episodes of candidemia occur in the intensive care setting. Early diagnosis of invasive candidiasis is critical in order to initiate antifungal agents promptly. Delay in the administration of appropriate therapy increases mortality. Unfortunately, risk factors, clinical and radiological manifestations are quite unspecific and conventional culture methods are suboptimal. Non-culture based methods (such as mannan, anti-mannan, β-d-glucan, and polymerase chain reaction) have emerged but remain investigational or require additional testing in the ICU setting. Few prophylactic or pre-emptive studies have been performed in critically ill patients. They tended to be underpowered and their clinical usefulness remains to be established under most circumstances. The antifungal armamentarium has expanded considerably with the advent of lipid formulations of amphotericin B, the newest triazoles and the echinocandins. Clinical trials have shown that the triazoles and echinocandins are efficacious and well tolerated antifungal therapies. Clinical practice guidelines for the management of invasive candidiasis have been published by the European Society for Clinical Microbiology and Infectious Diseases and the Infectious Diseases Society of North America.

Impact of navigator timing on free-breathing submillimeter 3D coronary magnetic resonance angiography.

The purpose of this study was to investigate the impact of navigator timing on image quality in navigator-gated and real-time motion-corrected, free-breathing, three-dimensional (3D) coronary MR angiography (MRA) with submillimeter spatial image resolution. Both phantom and in vivo investigations were performed. 3D coronary MRA with real-time navigator technology was applied using variable navigator time delays (time delay between the navigator and imaging sequences) and varying spatial resolutions. Quantitative objective and subjective image quality parameters were assessed. For high-resolution imaging, reduced image quality was found as a function of increasing navigator time delay. Lower spatial resolution coronary MRA showed only minor sensitivity to navigator timing. These findings were consistent among volunteers and phantom experiments. In conclusion, for submillimeter navigator-gated and real-time motion-corrected 3D coronary MRA, shortening the time delay between the navigator and the imaging portion of the sequence becomes increasingly important for improved spatial resolution.

Delayed diagnosis of acute ischemic stroke in children - a registry-based study in Switzerland.

QUESTIONS UNDER STUDY/PRINCIPLES: After arterial ischemic stroke (AIS) an early diagnosis helps preserve treatment options that are no longer available later. Paediatric AIS is difficult to diagnose and often the time to diagnosis exceeds the time window of 6 hours defined for thrombolysis in adults. We investigated the delay from the onset of symptoms to AIS diagnosis in children and potential contributing factors. METHODS: We included children with AIS below 16 years from the population-based Swiss Neuropaediatric Stroke Registry (2000-2006). We evaluated the time between initial medical evaluation for stroke signs/symptoms and diagnosis, risk factors, co-morbidities and imaging findings. RESULTS: A total of 91 children (61 boys), with a median age of 5.3 years (range: 0.2-16.2), were included. The time to diagnosis (by neuro-imaging) was <6 hours in 32 (35%), 6-12 hours in 23 (25%), 12-24 hours in 15 (16%) and >24 hours in 21 (23%) children. Of 74 children not hospitalised when the stroke occurred, 42% had adequate outpatient management. Delays in diagnosis were attributed to: parents/caregivers (n = 20), physicians of first referral (n = 5) and tertiary care hospitals (n = 8). A co-morbidity hindered timely diagnosis in eight children. No other factors were associated with delay to diagnosis. A total of 17 children were inpatients at AIS onset. CONCLUSIONS: One-third of children with AIS were diagnosed within six hours. Diagnostic delay was predominately caused by insufficient recognition of stroke symptoms. Increased public and expert awareness and immediate access to diagnostic imaging are essential. The ability of parents/caregivers and health professionals to recognise stroke symptoms in a child needs to be improved.

Intérêt du bleu de méthylène dans la chirurgie de l'hyperparathyroïdism primaire [Methylene blue in surgery of primary hyperparathyroidism]

Is surgery for primary hyperparathyroidism easier when methylene blue (MB) is given preoperatively? This retrospective study compares the durations of interventions for primary hyperparathyroidism carried out after i.v. MB administration to those when no MB was given. Over a period of 20 years (June 1976 to December 1996), 175 consecutive patients (56 men and 119 women, with ages ranging from 16 to 92, mean 59.6) were operated upon for primary hyperparathyrodism; 55 were operated before February 1986--the period when BM was introduced routinely, and 120 after. Thirty-two other patients were excluded from the study: 14 had had a previous cervicotomy and 18 another procedure in addition to the parathyroidectomy (usually on the thyroid gland), two conditions which prolonged the time devoted to parathyroid identification and excision. Preoperative calcemia averaged 2.97 mmol/L (2.34 to 4.59) and mean preoperative PTH was equal to 2.6 times the upper normal limit (0.5 to 24.1). Both groups were similar for as age, sex, preoperative calcium and PTH, and histologies. Methylene blue was administered intravenously (5 mg/kg diluted in 500 cc of 5% glucose) over a period of time of one hour starting two hours prior to surgery. All 175 procedures were performed by two surgeons and duration of surgery was recorded from the anesthesiologist's notes. There were 149 adenomas (85%), 24 hyperplasias (14%), a combination of both in two, and unspecified in two others. Except for a case of acute lower back pain synchronous to the injection of the dye (which was immediately stopped), MB was well tolerated. Mean duration for the 55 interventions performed without MB was 68 minutes (35 to 140, median 60), compared to 49 minutes for the 120 procedures carried out after MB had been given (20 to 155, median 45). Differences in operative, times were highly significant (p < 10(-6) and represented a gain of time of 27%. Surgery for primary hyperparathyroidism was significantly shorter when it was preceded by the administration of MB, a dye which facilitates the identification of pathologic parathyroid gland(s).

Effects of a treatment gap during adjuvant chemotherapy in node-positive breast cancer: results of International Breast Cancer Study Group (IBCSG) Trials 13-93 and 14-93.

BACKGROUND: The International Breast Cancer Study Group (IBCSG) conducted two complementary randomized trials to assess whether a treatment-free gap during adjuvant chemotherapy influenced outcome. PATIENTS AND METHODS: From 1993 to 1999, IBCSG Trials 13-93 and 14-93 enrolled 2215 premenopausal and postmenopausal women with axillary node-positive, operable breast cancer. All patients received cyclophosphamide (Cytoxan, C) plus either doxorubicin (Adriamycin, A) or epirubicin (E) for four courses followed immediately (No Gap) or after a 16-week delay (Gap) by classical cyclophosphamide, methotrexate, and fluorouracil (CMF) for three courses. The median follow-up was 7.7 years. RESULTS: The Gap and No-Gap groups had similar disease-free survival (DFS) and overall survival (OS). No identified subgroup showed a statistically significant difference, but exploratory subgroup analysis noted a trend towards decreased DFS for Gap compared with No Gap for women with estrogen receptor (ER)-negative tumors not receiving tamoxifen, especially evident during the first 2 years. CONCLUSIONS: A 16-week gap between adjuvant AC/EC and CMF provided no benefit and may have increased early recurrence rates in patients with ER-negative tumors.

Effects of sex, host-plant deprivation and presence of conspecific immatures on the cannibalistic behavior of wild Ascia monuste orseis (Godart) (Lepidoptera, Pieridae)

Effects of sex, host-plant deprivation and presence of conspecific immatures on the cannibalistic behavior of wild Ascia monuste orseis (Godart) (Lepidoptera, Pieridae). The specialist cabbage caterpillar Ascia monuste orseis (Lepidoptera, Pieridae) feeds on plants of the Brassicaceae family, but may eventually ingest conspecific eggs and larvae during the larval stage. The present study examines feeding behavior of 4th and 5th instar cabbage caterpillars in relation to sex, host-plant deprivation and presence of conspecifics. We recorded number of egg ingested per larvae, developmental indices and duration of feeding, exploratory and resting behavior. Kale deprived caterpillars presented high rates of cannibalism, development delay and decreased fecundity. Cannibalism rates were not influenced by the sex of the larvae. In general, the presence of conspecific eggs did not interfere with the frequency and duration of the categorical behavioral events. We conclude that food availability is a strong factor influencing the extent to which A. monuste orseis caterpillars cannibalize.

Automated quantitative pupillometry for the prognostication of coma after cardiac arrest.

BACKGROUND: Sedation and therapeutic hypothermia (TH) delay neurological responses and might reduce the accuracy of clinical examination to predict outcome after cardiac arrest (CA). We examined the accuracy of quantitative pupillary light reactivity (PLR), using an automated infrared pupillometry, to predict outcome of post-CA coma in comparison to standard PLR, EEG, and somato-sensory evoked potentials (SSEP). METHODS: We prospectively studied over a 1-year period (June 2012-June 2013) 50 consecutive comatose CA patients treated with TH (33 °C, 24 h). Quantitative PLR (expressed as the % of pupillary response to a calibrated light stimulus) and standard PLR were measured at day 1 (TH and sedation; on average 16 h after CA) and day 2 (normothermia, off sedation: on average 46 h after CA). Neurological outcome was assessed at 90 days with Cerebral Performance Categories (CPC), dichotomized as good (CPC 1-2) versus poor (CPC 3-5). Predictive performance was analyzed using area under the ROC curves (AUC). RESULTS: Patients with good outcome [n = 23 (46 %)] had higher quantitative PLR than those with poor outcome [n = 27; 16 (range 9-23) vs. 10 (1-30) % at day 1, and 20 (13-39) vs. 11 (1-55) % at day 2, both p < 0.001]. Best cut-off for outcome prediction of quantitative PLR was <13 %. The AUC to predict poor outcome was higher for quantitative than for standard PLR at both time points (day 1, 0.79 vs. 0.56, p = 0.005; day 2, 0.81 vs. 0.64, p = 0.006). Prognostic accuracy of quantitative PLR was comparable to that of EEG and SSEP (0.81 vs. 0.80 and 0.73, respectively, both p > 0.20). CONCLUSIONS: Quantitative PLR is more accurate than standard PLR in predicting outcome of post-anoxic coma, irrespective of temperature and sedation, and has comparable prognostic accuracy than EEG and SSEP.

Prevention of age-associated dementia.

The advancement of medical sciences during the last century has resulted in a considerable increase in life expectancy. As more people live to old age, one of the most fundamental questions of the 21st century is whether the number of individuals suffering from dementia will also continue to increase. Alzheimer's disease (AD) accounts for the majority of cases of dementia in the elderly, but there is currently no curative treatment available. Several strategies have been introduced for treatment, the most recent strategy of which was the immunization of patients using antibodies against Abeta, which is a naturally occurring, even though misfolded peptide in the AD brain. Both active and passive immunization routes have been shown to reduce the pathology associated with Abeta accumulation in brains of genetically designed animal models. However, despite tremendous efforts, no unequivocal proof of therapeutic efficacy could be shown in AD patients. Particularly, the persistence of the neurofibrillary tangles in immunized brains and the issue of inducing cerebral amyloid angiopathy are major limiting factors of antibody therapy. Furthermore, physical activity, a healthy immune system and nutritional habits are suggested to protect against the onset of age-associated dementia. Thus, accumulative evidence suggests that an early integrated strategy, combining pharmacological, immunological, nutritional and life-style factors, is the most pragmatic approach to delay the onset and progression of age-associated dementia.

The timing of foreign direct investment under uncertainty: Evidence from the Spanish banking sector

This paper investigates the timing of foreign direct investment (FDI) in the banking sector. The importance of this issue would arise from the existence of differential benefits associated to be the first entrant in a foreign location. Nevertheless, when uncertainty is considered, the existence of some Ownership-Location-Internalization (OLI) advantages can make FDI less reversible and/or more delayable and therefore it may be optimal for the firm to delay the investment until the uncertainty is resolved. In this paper, the nature of OLI advantages in the banking sector has been examined in order to propose a prognostic model of the timing of foreign direct investment. The model is then tested for the Spanish case using duration analysis.

Fetal Diagnosis of Cardiac Rhabdomyoma, its Management and Outcome : P71

Objectives: This study analyses the long term cardiac and neurological outcome of patients with cardiac rhabdomyoma (CR) in order to allow comprehensive prenatal counselling. Because of the relative rarity of the disease, there is paucity of data concerning the outcome of patients with CR. Methods: A retrospective study including all cases with echocardiographic diagnosis of CR encountered between April 1986 and August 2006. Results: Of 24 CR patients identified, 7 were diagnosed in-utero at a gestational age (GA) between 28-35 weeks and 17 postnatally between 10 days and 5 years. 14 had multiple CR and 10 had one/two CR. The CRs were situated predominantly in the LV (70%), RV (52%) and IVS (48%) and to a lesser extent in the atria (13%) and pericardium (4%). Follow-up echocardiography in. 18'show\'ld complete postnatal regression of CR in 3, partial regression in 13 and no change in 2. Cardiac complications were encountered in 5 patients, 1 with WPW syndrome and SVT requiring anti-arrhythmic therapy, 1 with sub-aortic obstruction needing surgical intervention and 3 with occasional bouts of paroxysmal SVT. Long-term follow-up revealed tuberous sclerosis of Bourneville (TSB) as definite diagnosIs in 22 (92%), complicated by epilepsy in 16 (67%) and developmental delay in 14 (64%). Conclusions: CR generally regresses after birth and after the high risk perinatal period cardiac related problems are rare. The relatively poor neurodevelopmental outcome of the almost always associated TSB however should form a dominating aspect of the prenatal counselling of parents whose fetuses are diagnosed with this rare disease.

Effects of prior repeated-sprints with different recovery duration on oxygen uptake kinetics during subsequent heavy-exercise

Introduction: Prior repeated-sprints (6) has become an interesting method to resolve the debate surrounding the principal factors that limits the oxygen uptake (V'O2) kinetics at the onset of exercise [i.e., muscle O2 delivery (5) or metabolic inertia (3)]. The aim of this study was to compare the effects of two repeated-sprints sets of 6x6s separated by different recovery duration between the sprints on V'O2 and muscular de-oxygenation [HHb] kinetics during a subsequent heavy-intensity exercise. Methods: 10 male subjects performed a 6-min constant-load cycling test (T50) at intensity corresponding to half of the difference between V'O2max and the ventilatory threshold. Then, they performed two repeated-sprints sets of 6x6s all-out separated by different recovery duration between the sprints (S1:30s and S2:3min) followed, after 7-min-recovery, by the T50 (S1T50 and S2T50, respectively). V'O2, [HHb] of the vastus lateralis (VL) and surface electromyography activity [i.e., root-mean-square (RMS) and the median frequency of the power density spectrum (MDF)] from VL and vastus medialis (VM) were recorded throughout T50. Models using a bi-exponential function for the overall T50 and a mono-exponential for the first 90s of T50 were used to define V'O2 and [HHb] kinetics respectively. Results: V'O2 mean value was higher in S1 (2.9±0.3l.min-1) than in S2 (1.2±0.3l.min-1); (p<0.001). The peripheral blood flow was increased after sprints as attested by a higher basal heart rate (HRbaseline) (S1T50: +22%; S2T50: +17%; p≤0.008). Time delay [HHb] was shorter for S1T50 and S2T50 than for T50 (-22% for both; p≤0.007) whereas the mean response time of V'O2 was accelerated only after S1 (S1T50: 32.3±2.5s; S2T50: 34.4±2.6s; T50: 35.7±5.4s; p=0.031). There were no significant differences in RMS between the three conditions (p>0.05). MDF of VM was higher during the first 3-min in S1T50 than in T50 (+6%; p≤0.05). Conclusion: The study show that V'O2 kinetics was speeded by prior repeated-sprints with a short (30s) but not a long (3min) inter-sprints-recovery even though the [HHb] kinetics was accelerated and the peripheral blood flow was enhanced after both sprints. S1, inducing a greater PCr depletion (1) and change in the pattern of the fibres recruitment (increase in MDF) compared with S2, may decrease metabolic inertia (2), stimulate the oxidative phosphorylation activation (4) and accelerate V'O2 kinetics at the beginning of the subsequent high-intensity exercise.

Overview of primary monogenic dystonia.

Primary monogenic forms of dystonia manifest solely or mainly with dystonia; they have been linked to a number of genes and loci and assigned "DYT" numbers. The pure dystonia syndrome early-onset primary dystonia (DYT1) manifests with dominantly-inherited generalized dystonia, often with focal onset in a limb. DYT1 is caused by a GAG deletion in the TOR1A gene. Mutations in the THAP1 gene cause DYT6, a form of pure dystonia that primarily involves cranio-cervical and upper limb muscles. Patients with the dystonia plus syndrome DYT5 display levodopa-responsive dystonia sometimes associated with tremor or parkinsonism (DYT5a, mutations in GCH1); a more severe phenotype with psychomotor involvement can be seen in recessive forms (DYT5b with TH mutations, SPR-deficiency syndrome). Other forms of dystonia plus syndromes include myoclonic dystonia (DYT11) and rapid-onset dystonia-parkinsonism (DYT12). Finally, paroxysmal exertion-induced dystonia (DYT18, GLUT1 deficiency) is caused by mutations in the SLC2A1 gene (DYT9 and DYT18). It is part of the paroxysmal dystonia group and manifests with paroxystic movements sometimes associated with seizures and psychomotor developmental delay.

RAX and anophthalmia in humans: Evidence of brain anomalies.

PURPOSE: To report the clinical and genetic study of two families of Egyptian origin with clinical anophthalmia. To further determine the role of the retina and anterior neural fold homeobox gene (RAX) in anophthalmia and associated cerebral malformations. METHODS: Three patients with clinical anophthalmia and first-degree relatives from two consanguineous families of Egyptian origin underwent full ophthalmologic, general and neurologic examination, and blood tests. Cerebral magnetic resonance imaging (MRI) was performed in the index cases of both families. Genomic DNA was prepared from venous leukocytes, and direct sequencing of all the exons and intron-exon junctions of RAX was performed after PCR amplification. RESULTS: Clinical bilateral anophthalmia was observed in all three patients. General and neurologic examinations were normal; obesity and delay in psychomotor development were observed in the isolated case. Orbital MRI showed a hypoplastic orbit with present but rudimentary extraocular muscles and normal lacrimal glands. Cerebral MRI showed agenesis of the optic nerves, optic tracts, and optic chiasma. In the index case of family A, the absence of the frontal and sphenoidal sinuses was also noted. In the index case of family B, only the sphenoidal sinus was absent, and there was significant cortical atrophy. The three patients carried a novel homozygous c.543+3A>G mutation (IVS2+3A>G) in RAX. Parents were healthy heterozygous carriers. No mutations were detected in orthodenticle homeobox 2 (OTX2), ventral anterior homeobox 1 (VAX1), or sex determining region Y-box 2 (SOX2). CONCLUSIONS: This is the first report of a homozygous splicing RAX mutation associated with autosomal recessive bilateral anophthalmia. To our knowledge, only two isolated cases of anophthalmia, three null and one missense case affecting nuclear localization or the DNA-binding homeodomain, have been found to be caused by compound heterozygote RAX mutations. A novel missense RAX mutation was identified in three patients with bilateral anophthalmia and a distinct systemic and neurologic phenotype. The mutation potentially affects splicing of the last exon and is thought to result in a protein that has an aberrant homeodomain and no paired-tail domain. Functional consequences of this change still need to be characterized.