bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiovascular Fitness, Insulin Resistance and Metabolic Syndrome in Severely Obese Prepubertal Italian Children
Authors: Brufani Claudia , Grossi Armando , Fintini Danilo , Fiori Rossana , Ubertini Graziamaria , Colabianchi Diego , Ciampalini Paolo , Tozzi Alberto , Barbetti Fabrizio , Cappa Marco
Published: October 2008

Aim: To evaluate if insulin resistance (IR) and metabolic syndrome (MS) were associated with poor cardiovascular fitness in very obese prepubertal Italian subjects. Methods: Children referred to the Endocrinology and Diabetes Unit of Bambino Gesù Children’s Hospital underwent an OGTT with glucose and insulin assays. QUICKI, ISI and HOMA-IR were calculated. Total and HDL cholesterol, triglycerides and percentage of body fat (DEXA) were determined. Cardiovascular fitness (maximal treadmill time) was evaluated using a treadmill protocol. The MS was defined as having 3 or more of following risk factors: obesity, impaired glucose tolerance, high blood pressure, low HDL-cholesterol, high triglycerides. Results: Fifty-five very obese prepubertal Italian children were enrolled in the study. Unadjusted correlation revealed maximal treadmill time negatively related to fasting insulin (r = –0.53, p < 0.0001) and HOMA-IR (r = –0.57, p < 0.0001) and positively to QUICKI (r = 0.51, p < 0.0001) and ISI (r = 0.46, p = 0.0035). These relationships remained significant when in multivariate analysis age, gender, BMI SD and body composition were accounted for (all p < 0.01). The presence of the MS was independently associated with maximal treadmill time. Conclusion:Poorcardiovascular fitness, IR and MS were independently related, suggesting that the relationship between fitness and insulin action develops early in life.
Late-Onset Triple A Syndrome: A Risk of Overlooked or Delayed Diagnosis and Management
Authors: Salmaggi Andrea , Zirilli Lucia , Pantaleoni Chiara , De Joanna Gabriella , Del Sorbo Francesca , Koehler Katrin , Krumbholz Manuela , Huebner Angela , Rochira Vincenzo
Published: October 2008

Background/Aims: A 33-year-old man was referred for the first time to the Division of Neurology because of the presence and progression of neurological symptoms. Dysphagia, weakness, reduced tear production, and nasal speech were present. In order to point the attention of late-onset triple A syndrome we describe this case and review the literature. Methods: Hormonal and biochemical evaluation, Schirmer test, tilt test and genetic testing for AAAS gene mutations. Results: Late-onset triple A syndrome caused by a novel homozygous missense mutation in the AAAS gene (A167V in exon 6) was diagnosed at least 17 years after symptom onset. Conclusions: The association between typical signs and symptoms of triple A syndrome should suggest the diagnosis even if they manifest in adulthood. The diagnosis should be confirmed by Schirmer test, endocrine testing (both basal and dynamic), genetic analysis, and detailed gastroenterological and neurological evaluations. Awareness of the possible late onset of the disease and of diagnosis in adulthood is still poor among clinicians, the acquaintance with the disease is more common among pediatricians. The importance of an adequate multidisciplinary clinical approach, dynamic testing for early diagnosis of adrenal insufficiency and periodical reassessment of adrenal function are emphasized.
Patient Dependence and Longitudinal Changes in Costs of Care in Alzheimer’s Disease
Authors: Zhu Carolyn W. , Leibman Christopher , McLaughlin Trent , Zbrozek Arthur S. , Scarmeas Nikolaos , Albert Marilyn , Brandt Jason , Blacker Deborah , Sano Mary , Stern Yaakov
Published: October 2008

Background/Aims: To examine the incremental effect of patients’ dependence on others, on cost of medical and nonmedical care, and on informal caregiving hours over time. Methods: Data are obtained from 172 patients from the Predictors Study, a large, multicenter cohort of patients with probable Alzheimer disease (AD) followed annually for 4 years in 3 University-based AD centers in the USA. Enrollment required a modified Mini-Mental State Examination score ≧30. We examined the effects of patient dependence (measured by the Dependence Scale, DS) and function (measured by the Blessed Dementia Rating Scale, BDRS) on medical care cost, nonmedical care cost, and informal caregiving time using random effects regression models. Results: A one-point increase in DS score was associated with a 5.7% increase in medical cost, a 10.5% increase in nonmedical cost, and a 4.1% increase in caregiving time. A one-point increase in BDRS score was associated with a 7.6% increase in medical cost, a 3.9% increase in nonmedical cost and an 8.7% increase in caregiving time. Conclusions: Both functional impairment and patient dependence were associated with higher costs of care and caregiving time. Measures of functional impairment and patient dependence provide unique and incremental information on the overall impact of AD on patients and their caregivers.
Mineralocorticoids Restore Quiescent Morphology and Reduce VEGF Receptor Expression in Inflamed Choroidal Endothelial Cells in vitro
Authors: Fitzgerald Melinda , Evill Lauren , Banz Kelly , Carroll Simon , Rodger Jennifer
Published: October 2008

Background/Aims: While the glucocorticoid triamcinolone acetonide (9α-fluoro-16α-hydroxyprednisolone, TA) has been widely administered as a treatment of ocular inflammation, mineralocorticoids have not been tested for their efficacy. Methods: We assessed cellular morphology and actin distribution by immunomicroscopy and light microscopy, membrane permeability with transendothelial resistance and cell surface vascular endothelial growth factor receptor-1 (VEGF-R1) expression by flow cytometry. Results: Fludrocortisone acetate was more effective than TA in restoring quiescent morphology and reducing membrane permeability in phorbol-12-myristate-acetate (PMA)-stimulated choroidal endothelial cells (CECs). Each of the corticosteroids inhibited VEGF-R1 cell surface expression in PMA-responsive CECs. Conclusion: Mineralocorticoids may be of potential use in reducing vascular permeability in ocular disease.
Ambulatory Blood Pressure, Proteinuria and Uric Acid in Children with IgA Nephropathy and Their Correlation with Histopathological Findings
Authors: Seeman Tomáš , Pohl Michael , John Ulrike , Dušek Jiří , Vondrák Karel , Janda Jan , Stejskal Josef , Groene Hermann-Josef , Misselwitz Joachim
Published: October 2008

Background/Aims: In adults, nighttime hypertension and hyperuricemia are new risk factors for progression of IgA nephropathy (IgAN). In children, nighttime blood pressure (BP) and serum uric acid have never been investigated. The aim of the study was to investigate nighttime BP and uric acid in children with IgAN. Methods: Data on children with IgAN from two pediatric nephrology centers were retrospectively reviewed (renal biopsy – subclasses according Hass I–V, ambulatory blood pressure monitoring ABPM, serum uric acid, proteinuria). Results: Twenty-eight untreated children with IgAN were included. Hypertension was diagnosed on the basis of ABPM in 54% of children, 50% were nondippers and 25% have isolated nighttime hypertension. The mean ambulatory BP was higher at nighttime than during daytime (systolic nighttime BP 1.11 ± 0.79 SDS vs. daytime 0.59 ± 0.79, diastolic nighttime BP 1.16 ± 0.95 vs. daytime 0.52 ± 1.10, p < 0.01 for systolic and p = 0.01 for diastolic). Children with severe histological subclasses (III–IV) tended to have higher prevalence of hypertension than children with mild subclasses (I–II), 67% vs. 38%, p = 0.13. Hyperuricemia was diagnosed in 14% of children. A significant correlation was found between proteinuria and histopathological subclasses (r = 0.44, p < 0.05). Conclusion: Children with IgAN have often nighttime hypertension. Hypertension and proteinuria are associated with severe histopathological findings. Hyperuricemia is a rare finding in children.
Cortical Cyto- and Chemoarchitecture in Three Small Australian Marsupial Carnivores: Sminthopsis macroura, Antechinus stuartii and Phascogale calura
Authors: Ashwell K.W.S. , McAllan B.M. , Mai J.K. , Paxinos G.
Published: October 2008

The cyto- and chemoarchitecture of the cerebral cortex has been examined in three small (mouse-sized) polyprotodont marsupial carnivores from Australia (the stripe-faced dunnart, Sminthopsis macroura; the brown antechinus, Antechinus stuartii; and the red-tailed phascogale, Phascogale calura) in order to compare the cortical topography of these marsupials with that of diprotodontids, didelphids and eutherians. All three species studied had similar cortical cytoarchitecture. The isocortical surface was dominated by primary somatosensory (S1) and visual (V1) areas. Putative secondary sensory areas (S2, V2M, V2L) were also identified. The primary somatosensory cortex demonstrated clumps of granule cells in the presumptive mystacial field, whereas the primary visual area showed a distinctive chemical signature of intense calbindin immunoreactivity in layer IV. On the other hand, the primary auditory area was small and indistinct, but flanked by a temporal association area (TeA). A cytoarchitecturally distinct primary motor cortex (M1) with prominent pyramidal neurons in layer V and poor layer IV was identified medially to S1, and at rostral levels a putative secondary motor area was identified medial to M1. Transitional areas between isocortex and allocortical regions showed many cyto- and chemoarchitectural similarities to those reported for eutherian (and in particular rodent) cortex. Medially, two cingulate regions were found at rostral levels, with dysgranular and granular ‘retrosplenial’ areas identified caudally. Laterally, granular and agranular areas surrounded the rostral rhinal fissure, to be replaced by ectorhinal and perirhinal areas caudally. The findings indicate that the cyto- and chemoarchitectural features which characterize the iso- and allocortex in these small marsupial carnivores are similar to those reported in didelphids and eutherians and our findings suggest the existence of putative dedicated motor areas medial to the S1 field.
Baseline NIH Stroke Scale Responses Estimate the Probability of Each Particular Stroke Subtype
Authors: Leira E.C. , Adams Jr. H.P. , Rosenthal G.E. , Torner J.C.
Published: October 2008

Background: Emergency treatment of ischemic stroke should ideally be mechanism specific, but acute subtype diagnosis is problematic. Since different subtypes often are associated with specific patterns of neurological deficits, we hypothesize that scores on baseline NIH stroke scale (NIHSS) items may help emergently stratify patients by their probability of having a particular stroke subtype. Methods: We performed multivariate polytomous logistic regression analyses on 1,281 patients enrolled in the Trial of ORG 10172 in Acute Stroke Treatment (TOAST). We tested the predictive value of individual items to the baseline NIHSS exam, and syndromic combinations of those items, in anticipating the TOAST stroke subtype at 3 months adjusting for atrial fibrillation. We then used the most significant NIHSS items to construct a predictive model. Results: The NIHSS items that discriminate between stroke subtypes are language, neglect, visual field and brachial predominance of weakness. Among patients without atrial fibrillation, a normal score for these 4 variables conveys a 46% chance of lacunar stroke, 12% of atherothrombotic stroke and 10% of cardioembolism. This pattern gradually reverses with increased numbers of abnormal responses. Those with abnormalities in all 4 items have a 0.1% chance of lacunar stroke, 50% of atherothrombotic stroke and 39% of cardioembolism. Conclusions: Language, neglect, visual fields and brachial predominance of weakness in the baseline NIHSS help discriminate between subtypes, particularly between lacunar and nonlacunar strokes. Clinical trials testing interventions aimed to particular stroke mechanisms may use these NIHSS items to emergently stratify patients based on their probability of having a particular stroke subtype.
Nonuniform Weakness in the Paretic Knee and Compensatory Strength Gains in the Nonparetic Knee Occurs after Stroke
Authors: Lomaglio Melanie J. , Eng Janice J.
Published: October 2008

Background: This study was designed to quantify torque production at different joint angles in the paretic and nonparetic knee joints of individuals with stroke. Methods: Extension and flexion torques were measured at 6 angles of the knee joint and normalized to peak torque in 19 subjects with stroke and 19 controls. Results: Paretic knee extension torque was lower than controls when the knee was positioned near extension. In contrast, nonparetic knee extension and flexion torques were higher than controls when the knee was positioned near full flexion. Conclusions: The paretic knee extensors demonstrated exaggerated weakness at short muscle lengths and the nonparetic knee extensors and flexors demonstrated selective strength gains. Clinicians should therefore consider paretic knee extensor strengthening near full extension and promote symmetrical use of the legs to prevent compensatory overuse of the nonparetic leg.
Comparison of the New PRC Software with the Established Algorithm of the FMF UK for the Detection of Trisomy 21 and 18/13
Authors: Lüthgens K.
Published: October 2008

Objective: The aim of this study was to compare the newly developed Prenatal Risk Calculation (PRC) software and the established Fetal Medicine Foundation (FMF) UK algorithm for their detection and false-positive rates in prenatal screening of trisomy 21 or 18/13. Methods: Nuchal translucency was measured by FMF-certified sonographers in 39,004 pregnancies. Risks for trisomy 21 and 18/13 were calculated together with serum PAPPA and free beta-hCG in all cases. Overall, 109 cases of trisomy 21 and 39 cases of trisomy 18 or 13 occurred. The detection rates were calculated for all 109 trisomy 21 cases using both PRC and ASTRAIA, software based on the official algorithm of the FMF UK. The false-positive rate was calculated on the basis of all 39,004 cases for ASTRAIA and on the basis of 3,620 additional cases for PRC. The comparison of the algorithms was performed by the calculation of receiver-operating characteristic (ROC) curves. Results: The detection rates for trisomy 21 for a 5% false-positive rate were 91% (99/109) for PRC and 90% (98/109) for ASTRAIA. The difference was not significant. ROC curve analysis showed an area under the curve (AUC) of 0.976 for PRC and 0.975 for ASTRAIA (p = 0.80). At a cutoff of 1:300, PRC showed a slightly (nonsignificantly) higher, but nonsignificant false-positive rate (3.8% for ASTRAIA, version since 2005, 5.1% for PRC) associated with a slightly (nonsignificantly) higher, but nonsignificant detection rate of 91% (PRC) versus 88% (ASTRAIA). The false-positive rate of the biochemical risk (without NT) in PRC was significantly higher (17.7%) than with the FMF UK algorithm (9.0%) at a common risk cutoff of 1:300. A reason for the higher false-positive rates in PRC may be the missing correction for maternal weight, smoking status, and ethnicity. The detection rates for trisomy 18/13 at a risk cutoff of 1:150 were 79% for PRC and 77% for ASTRAIA. False-positive rates for trisomy 18/13 at a cutoff of 1:150 were 1.5% for PRC and 0.6% for ASTRAIA (differences were nonsignificant). Conclusion: For a 5% false-positive rate, the new PRC software detects as many trisomy 21 and trisomy 18/13 cases as the established algorithms of the FMF UK. In order to reduce the false-positive rate for the biochemical risk, the algorithm of the PRC software should be redesigned to include the maternal weight, smoking status of the mother, and the ethnicity.
Perineural Invasion in Aggressive Skin Carcinomas of the Head and Neck
Authors: Cernea Claudio R. , Ferraz Alberto R. , de Castro Inês V. , Sotto Miriam N. , Logullo SPACEngela F. , Bacchi Carlos E. , Plopper Caio , Wanderlei Felipe , de Carlucci, Jr. Dorival , Hojaij Flávio C.
Published: October 2008

Introduction: Perineural invasion is a well-recognized form of cancer dissemination. However, it has been reported only in few papers concerning cutaneous carcinomas (basal cell, BCC, and squamous cell, SCC). Moreover, the incidence is considered to be very low. Niazi and Lambert [Br J Plast Surg 1993;46:156–157] reported only 0.18% of perineural invasion among 3,355 BCCs. It is associated with high-risk subtypes, as morphea-like, as well as with an increased risk of local recurrence. No paper was found in the literature looking for perineural invasion in very aggressive skin cancers with skull base extension, with immunohistochemical analysis. Methods: This is a retrospective review, including 35 very advanced skin carcinomas with skull base invasion (24 BCCs and 11 SCCs, operated on at a single institution from 1982 to 2000). Representative slides were immunohistochemically evaluated with antiprotein S-100, in order to enhance nerve fibers and to detect perineural invasion. The results were compared to 34 controls with tumors with a good outcome, treated in the same time frame at the same Institution. Results: Twelve (50.0%) of the BCCs with skull base invasion had proven perineural invasion, as opposed to only 1 (4.6%) of the controls, and this difference was statistically significant (p < 0.001). Regarding SCCs, 7 aggressive tumors (63.6%) showed perineural invasion compared to only 1 (10.0%) of the controls, but this difference did not reach significance (p = 0.08), due to the small number of cases. Conclusions: In this series, it was demonstrated that immunohistochemically detected perineural invasion was very prevalent in advanced skin carcinomas. In addition, it was statistically associated with extremely aggressive BCCs with skull base invasion.
Rett Syndrome: From the Gene to the Disease
Authors: Matijevic Tanja , Knezevic Jelena , Slavica Marko , Pavelic Jasminka
Published: October 2008

Rett syndrome (RTT, MIM No. 312750) is a progressive neurodevelopmental disorder and one of the most common causes of mental retardation. It is transmitted as an X-linked dominant trait, therefore almost exclusively affecting females. About 80% of RTT cases are sporadic caused by mutations in the MECP2 gene located on Xq28. The gene codes for two isoforms of the methyl-CpG-binding protein (MeCP2, MeCP2B) which are involved in transcriptional silencing through DNA methylation. The gene has 4 exons. The fourth one is the largest. Almost all mutations in MECP2 occur de novo. Although mutations are dispersed throughout the gene, about 67% of all MECP2 mutations, caused by C>T transitions at 8 CpG dinucleotides, are located in the third and fourth exon. The most common mutation is R168X. So far, there is no clear evidence on genotype-phenotype correlations. There are also reports claiming that the same mutation can provoke different phenotypes. It was shown that MeCP2 can silence certain genes. One of them, brain-derived neurotrophic factor, is essential for neural plasticity, learning and memory. This discovery revealed the role of MeCP2 in the control of neuronal activity-dependent gene regulation and suggested that the pathology of RTT may result from deregulation of this process.
Possible Precipitation of Migraine Attacks with Prophylactic Treatment
Authors: Donnet A. , Vuillaume De Diego E. , Lanteri-Minet M.
Published: October 2008

The initiation of a prophylactic treatment in a migraine sufferer depends upon the stratification of the patient’s frequency of attacks and the disability they cause, as well as the patient’s acute consumption and comorbid diseases. We report on 14 patients who were among a group of 618 migraine sufferers who received a new preventative treatment. These 14 patients developed an increase in the frequency of their migraine attacks that was possibly induced by this new prophylactic treatment. The clinical description of the migraine attacks remained the same but the frequency of the attacks of migraine without aura was dramatically increased. This is, to our knowledge, the first description of a possible precipitation of attacks of migraine without aura with a prophylactic treatment. There is no link with a specific class of prophylactic treatment. We hypothesize that the migraine sufferers who experienced aggravation after the new prophylactic drug had been introduced had a paradoxical decrease in the induction threshold for cortical spreading depression (CSD). Mechanisms of such a decrease are unknown and are probably multifactorial, but changes in serotonin neurotransmission have been experimentally demonstrated to modify cortical excitability and favour CSD. The aggravation was described only for attacks without aura. However, with only 14 patients, it is not possible to predict whether suffering from that the type of migraine is a factor that predisposes a patient to aggravation. While additional cases are necessary, physicians should be aware of the possibility that prophylactic treatment may exacerbate migraine attacks.
Mitoxantrone Does Not Restore the Impaired Suppressive Function of Natural Regulatory T Cells in Patients Suffering from Multiple Sclerosis
Authors: Putzki Norman , Kumar Manoj , Kreuzfelder Ernst , Grosse-Wilde Hans , Diener H.C. , Limmroth Volker
Published: October 2008

CD4+CD25+ regulatory T (Treg) cells play a major role in controlling autoimmunity by suppressing self-reactive T cells. Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system, where T cells are of major importance. Treg cell frequency and function are potential therapeutic targets of MS treatment. Mitoxantrone (MX) is a potent immunosuppressant for the treatment of active MS. We investigated the long-term effects of MX on the suppressive function of Treg after mitogen and myelin basic protein (MBP) stimulation in 20 MX-treated patients. MX therapy did not restore the reduced suppressive activity of a mixture of CD25intermediate or CD25high expressing Treg (healthy controls, MBP: 37.3%; MS patients, MBP: –1.9 vs. 6.6% suppression after MX treatment for 6 months, p > 0.2). The frequency of Treg cells was not affected by MX. A single infusion of MX (10 mg/m2 body surface) induced a selective and persistent reduction of approximately 30% of absolute and relative counts of B lymphocytes (p < 0.05). MX therapy does not influence Treg cell frequency or function. MX seems to exhibit its efficacy in MS mainly by a suppression of humoral immunity.
Brucella: A Cause of Peripheral Neuropathy
Authors: Kutlu Gulnihal , Ertem Gunay Tuncer , Coskun Ozlem , Ergun Ufuk , Gomceli Yasemin B. , Tulek Necla , Inan Levent Ertugrul
Published: October 2008

Brucellosis is a common infectious disease in Mediterranean countries. We evaluated the peripheral nerve involvement in patients with brucellosis. Thirty-eight patients with brucellosis were examined. Four of them were excluded because of B12 deficiency and diabetes mellitus. Thirty-four patients were included. The average age was 43.08 ± 15.3 years. Patients were divided into two groups according to the abnormality in their peripheral nervous system (PNS) examination. All patients underwent nerve conduction and needle electromyography EMG studies. Twenty normal healthy subjects were used as a control group. Axonal sensorimotor neuropathy was determined in 12 patients who also had abnormality in PNS examination. After 6 months of treatment, nerve conduction studies were nearly normal in these patients. The EMG findings of the remaining 22 patients were normal, as well as the clinical examination. However, the motor conduction velocities of median (p < 0.001), peroneal (p < 0.001), and ulnar (p < 0.05) nerves were decreased, F wave latencies were prolonged in the posterior tibial and peroneal nerve, and distal latency was also prolonged in the posterior tibial nerve (p < 0.05) when compared to healthy subjects. Sensory conduction velocities of the median (p < 0.001), ulnar and sural (p < 0.05) nerve were also decreased. Brucellosis may be considered as a cause of clinical or subclinical peripheral neuropathy and should be evaluated especially in endemic areas.
Polycystic Ovary Syndrome and Migraine Headache, Is There Any Correlation?
Authors: Pourabolghasem S. , Najmi S. , Arami M.A.
Published: October 2008

Background: To evaluate the role of some sex hormones in migraine headaches, the aim of this study was to assess the prevalence and characteristics of headache, especially migraine, in patients with polycystic ovary syndrome (PCO) compared with women without this disease. Methods: One hundred and thirty-three women with PCO and 107 controls were interviewed by 2 neurologists experienced in headache diagnosis. The headache disorders were classified according to the International Headache Society criteria. The statistical significance was determined using the χ2 test, and a p value of <0.05 was considered significant. Results: Forty-five women (33.8%) of the 133 cases without PCO complained of headache. Of the PCO patients, 48 women (44.9%) suffered from headache. The prevalence of headache was not significantly higher among women with PCO (p = 0.85). The same results were found for migraine headache (p = 0.13). Conclusion: Migraine is not more frequent in women with PCO. It was concluded that male sex hormones and especially testosterone do not play an important role in the exacerbation of migraine headache.
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucoencephalopathy and Right-to-Left Shunt: Lack of Evidence for an Association in a Prevalence Study
Authors: Mazzucco S. , Anzola G.P. , Ferrarini M. , Taioli F. , Olivato S. , Burlina A.P. , Fabrizi G.M. , Rizzuto N.
Published: October 2008

Background /Aims: Up to more than 50% of cryptogenetic stroke patients and patients with migraine with aura (MA) are found to have a right-to-left shunt (RLS), which is usually due to a patent foramen ovale. Moreover, both MA and stroke are cardinal features of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). Notch3 mutations have been suggested to induce an abnormally high incidence of atrial septal defects in a family harbouring an Arg141Cys pathogenetic mutation. We sought to determine the prevalence of RLS in CADASIL patients with different Notch3 mutations, both with and without migraine as a clinical feature. Methods: Subjects with a molecular diagnosis of CADASIL were tested for the presence of an RLS by means of contrast-enhanced transcranial Doppler (TCD). The diagnosis of migraine was made according to the 2004 International Headache Classification. Results: Sixteen CADASIL patients were tested; 6 had MA. Four patients displayed an RLS on contrast-enhanced TCD examination. Three of these patients had MA. Both patients with Arg141Cys displayed a large RLS. Conclusion: We conclude that RLS is not necessarily linked to CADASIL as a comorbidity factor. Nevertheless, there could be a relation between RLS and specific Notch3 mutations, such as Arg141Cys.
Prokinetics Influence the Pharmacokinetics of Rabeprazole
Authors: Arai Katsuhito , Takeuchi Yoshiaki , Watanabe Hideki , Tsukurimichi Atsushi , Uchida Naoki , Imawari Michio
Published: October 2008

Background: Proton pump inhibitors (PPIs) are unstable at a low PH. Accelerated transfer of PPIs to the upper small intestine may influence the pharmacokinetics of PPIs. Aim: To see if concomitant use of mosapride citrate with rabeprazole sodium influences the pharmacokinetics of the PPI. Methods: Two-way crossover pharmacokinetic studies were conducted in 9 healthy subjects. 20 mg of rabeprazole was given orally and plasma was obtained before and 1, 2, 3, 4, 5, 6 and 8 h after the dosing. Two weeks later, 5 mg of mosapride was given concomitantly with rabeprazole and plasma was collected as above. The plasma concentrations of rabeprazole were determined by high-performance liquid chromatography. The maximum plasma concentrations (Cmax) and the area under the time-plasma concentration curve (AUC) of rabeprazole, and the time to maximum plasma concentration (tmax) were compared in the presence or absence of mosapride. Results: Concomitant use of mosapride resulted in significant increases of mean Cmax and mean AUC with ratios of 1.57 and 1.47, respectively. The median tmax changed from 4 to 3 h, although the change was not significant. Conclusions: Mosapride significantly influenced pharmacokinetics of rabeprazole. Co-administration of mosapride could have some favorable effect in PPIs-based therapy.
Correlation of Gut Hormones with Irritable Bowel Syndrome
Authors: Zhang Hongjie , Yan Yan , Shi Ruihua , Lin Zheng , Wang Meifeng , Lin Lin
Published: October 2008

Background: Irritable bowel syndrome (IBS) is a functional bowel disorder which is characterized by abdominal pain and disturbed bowel habits. The pathophysiological mechanism is complex and still remains incompletely clear. Alterations at both the central and the peripheral level are thought to contribute to the symptoms of IBS, including psychosocial factors, visceral hypersensitivity and abnormal gastrointestinal motility and secretion. Several gut peptides contribute to the regulation of gastrointestinal function, but little is known about gut hormone secretion in IBS. Methods: We evaluated the concentrations of cholecystokinin (CCK), vasoactive intestinal peptide (VIP), somatostatin, substance P, neuropeptide Y (NPY) in plasma and in sigmoid tissue in 40 patients with IBS and 15 age- and gender-matched controls by using radioimmunoassay. Results: IBS patients had higher plasma level of CCK (p < 0.01), and the level of CCK in the sigmoid was also increased compared with controls (p < 0.05). The levels of somatostatin and substance P in fasting plasma and in the sigmoid were not different between IBS patients and control subjects (p > 0.05), but the levels of VIP in sigmoid tissue or in plasma were higher in IBS patients than in control group (p < 0.01). The NPY levels in both plasma and the sigmoid were significantly lower in IBS patients than in controls (p < 0.05). Plasma NPY level in patients with IBS with diarrhea as a predominant bowel pattern was lower than in patients with IBS with constipation as a predominant bowel pattern. Conclusion: IBS patients have increased levels of CCK and VIP and decreased NPY levels in fasting plasma and sigmoid tissue. These alterations of VIP, CCK and NPY may play a role in the pathogenesis of IBS.
White Matter Lesion Subtypes and Cognitive Deficits in Patients with Memory Impairment
Authors: Stenset Vidar , Hofoss Dag , Berstad Audun Elnaes , Negaard Anne , Gjerstad Leif , Fladby Tormod
Published: October 2008

Aim: To analyze the relationship between periventricular (PV) and subcortical (SC) white matter lesions (WML) and cognitive function in patients with memory impairment. Methods: In total, 253 patients with Global Deterioration Scale scores ≧3 who had been referred to a university-based memory unit due to memory complaints were included (mean age 69.7 years, 124 females). Cognitive function was assessed with the Mini-Mental State Examination (MMSE) and the Neurobehavioral Cognitive Status Examination (Cognistat), and full test results were available for 217 patients. PV and SC WML loads (semi-quantitative rating on axial T2-weighted MRI scans) were used in linear regression as predictors of cognition. Results: MMSE was significantly correlated with SC WML (p = 0.005), but not with PV WML (p = 0.19). Cognistat tests for orientation, comprehension, visuoconstruction, calculation, similarities, and judgment were negatively correlated with SC WML (p < 0.01), as was verbal memory with parieto-occipital SC WML (p < 0.05). Visuoconstruction and calculation were negatively correlated with PV WML (p < 0.05). Parieto-occipital WML were more strongly related to cognition than fronto-temporal WML. Only SC WML were significantly correlated with cognition when PV and SC WML were entered simultaneously in the regression model. Conclusion: In patients with cognitive impairment, SC WML, in particular in parieto-occipital regions, were associated with reduced cognitive function.
Neonatal Stress or Morphine Treatment Alters Adult Mouse Conditioned Place Preference
Authors: Boasen Jared F. , McPherson Ronald J. , Hays Sarah L. , Juul Sandra E. , Gleason Christine A.
Published: October 2008

Background: Hospitalized preterm infants may experience pain and stress, and narcotics are often administered to lessen their suffering. However, prolonged narcotic therapy may be detrimental during neonatal brain development. Using a rat model combining neonatal stress and morphine, we found that neonatal morphine impaired adult learning. Here we describe a new mouse model examining lasting effects of neonatal stress and morphine. Objective: We tested whether repeated neonatal stress and/or morphine exposure affects early neurodevelopmental or adult behaviors. Methods: Five groups of C57/BL6 mice (1: untreated; 2: morphine (2 mg/kg s.c., b.i.d.); 3: saline, 4: stress + morphine; 5: stress + saline) were treated from postnatal day (P) 5 to P9. Stress consisted of daily maternal separation/isolation (08:00–15:00 h) with gavage feedings and twice daily exposure to brief hypoxia/hyperoxia. Developmental behaviors included righting (P5) and negative geotaxis (P9). Adult behaviors included elevated plus maze, morphine place-preference conditioning, and forced-swimming. Plasma con- centrations of morphine (P7) and corticosterone (P9 and adult) were measured. Results: Neonatal stress or neonatal morphine alone impaired adult place-preference conditioning, but the combination did not (interaction p < 0.01). Adult basal corticosterones were reduced by neonatal morphine treatment. There were no substantial differences in elevated plus maze or forced-swimming times. Conclusions: Neonatal stress and morphine treatment produced long-lasting behavioral and hormonal effects which suggest that neonatal morphine reduces adult arousal and neonatal stress exaggerates adult arousal, each to a degree sufficient to alter learning, while the combined impact of these neonatal treatments does not alter adult learning.
Change in Cardiovascular Risk Factors with Progression of Kidney Disease
Authors: Fried Linda F. , Katz Ronit , Cushman Mary , Sarnak Mark , Shlipak Michael G. , Kuller Lewis , Newman Anne B.
Published: October 2008

Background: Prior studies evaluating the relationship of kidney disease with cardiovascular risk factors have been limited by their cross-sectional design. We evaluated the change in lipids, inflammatory and procoagulant biomarkers with decline in kidney function in a nested case-cohort study in the Cardiovascular Health Study, a community-based study of adults aged >65 years. Methods: Individuals with an increase in serum creatinine ≥0.3 mg/dl (baseline to 3 years later, n = 207) were matched to controls of similar age, race, gender, diabetes and baseline serum creatinine, but whose change in creatinine was <0.3 mg/dl. Baseline and change in risk factors were analyzed with conditional logistic regression. Results: Changes in C-reactive protein were similar. In contrast, cases had larger increases in fibrinogen (OR 1.38 per standard deviation, 95% confidence interval 1.08–1.76) and factor VIII [1.38 (1.10–1.72)] and larger decreases in HDL [OR 0.80 (0.64, 1.00)]. Change in interleukin-6 was greater in cases than controls, but this did not persist after multivariate adjustment. However, in linear regression, change in interleukin-6 was correlated with change in creatinine. Conclusion: Cardiovascular risk factors and kidney function may change concurrently. This could lead to an increased risk of cardiovascular disease as kidney function worsens.
Rapamycin Attenuates the Severity of Murine Adriamycin Nephropathy
Authors: Lui Sing Leung , Tsang Ryan , Chan Kwok Wah , Zhang Florence , Tam Sidney , Yung Susan , Chan Tak Mao
Published: October 2008

Background: Rapamycin is an immunosuppressive drug with potent antifibrotic activity. We evaluated the effect of rapamycin on murine adriamycin nephropathy, a model of progressive glomerulosclerosis and tubulointerstitial fibrosis. Methods: Adriamycin nephropathy was induced in Balb/c mice by a single intravenous injection of adriamycin. The mice were treated orally with either saline or rapamycin, beginning at the time of adriamycin injection or rapamycin starting 1 week after adriamycin injection. The mice were sacrificed 6 weeks after adriamycin injection. Results: Saline-treated mice developed massive proteinuria and impaired renal function. Kidney sections from saline-treated mice showed marked focal segmental glomerulosclerosis, tubular dilation with protein cast deposition, interstitial fibrosis, and numerous infiltrating macrophages and T lymphocytes. The intrarenal expression of Collagen I and RANTES was also increased. In contrast, both groups of rapamycin-treated mice had markedly reduced proteinuria and preserved renal function, with only mild histological abnormalities. The intrarenal expression of Collagen I and RANTES was reduced, concomitant with a significant reduction in interstitial inflammatory cell infiltration. Conclusions: Rapamycin is effective in attenuating the glomerular and tubulointerstitial abnormalities in adriamycin nephropathy. The beneficial effects of rapamycin are mediated, at least in part, through reduced RANTES expression and inflammatory cell infiltration.
The prostacyclin analogue iloprost increases circulating endothelial progenitor cells in patients with critical limb ischemia
Authors: Di Stefano Rossella , Barsotti Maria , Melillo Elio , Iorio Mariacarla , Santoni Tatiana , Armani Chiara , Dell’Omodarme Matteo , Ristori Chiara , Balbarini Alberto , De Caterina Raffaele
Published: October 2008

Patients with critical limb ischemia (CLI) have low levels of endothelial progenitor cells (EPC). Iloprost has been demonstrated to stimulate vascular endothelial growth factor (VEGF) and promote angiogenesis. We investigated the effects of iloprost on EPC levels in vivo in CLI patients. Twenty-three patients with stage III and IV CLI were treated with iloprost for four weeks, improving clinical and instrumental parameters. Mononuclear cells isolated from peripheral blood were cultured to obtain “early” EPC, evaluated counting adherent cells with double positivity for acetylated low-density lipoprotein uptake and Ulex Europaeus lectin at flow cytometry. These cells also co-expressed the monocyte markers CD14 and CD45.Iloprost increased EPC number in the whole patient population: pre-treatment median: 13,812/ml; range: 1,263–83,648/ml; post-treatment median: 23,739/ml; range: 3,385–99,251/ml; p=0.035, irrespective of age, sex, disease stage or atherosclerosis risk factors. In conclusion, iloprost increases EPC number in peripheral blood in vivo. Such an effect may have therapeutic relevance.
Glutathione regulates integrin αIIbβ3-mediated cell adhesion under flow conditions
Authors: Ball Chalmette , Vijayan K. Vinod , Nguyen Trung , Anthony Kim , Bray Paul F. , Essex David W. , Dong Jing-fei
Published: October 2008

The platelet integrin αIIbβ3 mediates the final step of platelet aggregation that requires pre-activation through an inside-out signal initiated by agonists. Experiments conducted under static conditions using platelet-rich plasma show that platelet activation and adhesion activity of αIIbβ3 are regulated by glutathione (GSH-GSSG) redox potential.However,it remains unclear as to whether GSH-GSSG exerts its regulatory role in platelets by direct targeting of αIIbβ3 or intracellular signals that activate the integrin. A role of fluid shear stress is also not known. We examined the effects of GSH-GSSG on the adhesion of CHO cells expressing two HPA variants of human αIIbβ3 to the immobilized fibrinogen and von Willebrand factor (VWF) under flow conditions. GSH-GSSG dose-dependently reduced the number of adherent cells to fibrinogen and VWF under 2.5 dyn/cm2 of shear stress, a physical force calculated to be 110 dyne on platelets. GSH treatment also abolished the hyperadhesion activity of cells expressing the Pro33 variant of αIIbβ3.The inhibition was also observed with washed platelets. The data differ from the early observation that GSH enhanced platelet aggregation induced by sub-threshold concentrations of platelet agonists. The results suggest that GSH may have distinct effects on agonist-induced αIIbβ3 activation and on the αIIbβ3-fibrinogen or αIIbβ3-VWF bonds when exposed to fluid shear stress. They further suggest that the HPA phenotype may be redox-regulated.
Modelling and expression studies of two novel mutations causing factor V deficiency
Authors: Pavlova Anna , Heinz Stefan , Blaise Mathias , Chandra Tamir , Poetsch Bernd , Seifried Erhard , Oldenburg Johannes , Delev Daniel
Published: October 2008

Human coagulation factor V (FV), a non-enzymatic cofactor of the prothrombinase complex, is required for the rapid generation of thrombin. FV deficiency is a rare autosomal recessive bleeding disorder. We describe two novel mutations,Tyr91Asn and Asp2098Tyr,found in two probands with a residual FV activity of 51% and 4%, respectively. Modelling and structural analysis of these mutations were performed following short-duration molecular dynamics (MD) simulation.Asp2098Tyr lead to abolishment of the highly conserved salt bridge Asp2098-Arg2171 presumably required for structural integrity of the C2 domain. MD studies suggest that additional conformational changes resulting from this mutation involve local rearrangements at Tyr2063 and Tyr2064 and so affect the phospholipid-membrane binding. MD modelling of the Try91Asn mutant revealed a conformational change nearby the Cu2+ binding site that could affect overall stabilization of the heavy and light chains. These findings suggest that both mutations influence the structural integrity of FV protein. Transient expression data of wild-type and mutant FV variants in 293T human embryonic kidney cells showed FV-specific activity reduced to 26% for Asp2098Tyr and 56% for Tyr91Asn compared to that of wild-type. Thus, both the data from the short duration molecular dynamic simulation and from expression analysis indicate alterations of the FV protein variants that explain the clinical phenotype.
Venous thromboembolism in the elderly
Authors: Gore Joel M. , Lessard Darleen , Emery Cathy , Pacifico Luigi , Reed George , Gurwitz Jerry H. , Goldberg Robert J. , Spencer Frederick A.
Published: October 2008

While the magnitude of venous thromboembolism (VTE) increases dramatically with advancing age,relatively little is known about the contemporary management of VTE in the elderly and the impact of age on associated short- and long-term outcomes. The objectives of this population-based study were to compare the clinical characteristics,treatment practices,and outcomes of subjects ≥65 years with VTE to those of younger patients.The medical records of residents of the Worcester (MA, USA) metropolitan area with ICD-9 codes consistent with VTE during 1999, 2001, and 2003 were independently validated and reviewed by trained data abstractors. Information about patients’ demographic and clinical characteristics, hospital management practices, and hospital and long-term outcomes was collected. There were a total of 1,897 validated events of VTE – 1,048 (55%) occurred in patients ≥65 years of age. Patients ≥65 years were less likely to have “unprovoked” VTE than younger patients.They were less likely to receive parenteral anticoagulation or warfarin as acute treatment. Rates of recurrent VTE did not differ significantly between patients 65 years of age or older compared to younger patients but the adjusted rates of major bleeding were increased approximately two-fold in older patients. In conclusion, advancing age is not a predictor of recurrent VTE but is associated with a significant increase in major bleeding episodes. Physicians treating elderly patients with VTE should continue to base their decisions on clinical characteristics previously shown to impact the risk of recurrent VTE. These decisions must be tempered by our observation that major bleeding occurs frequently in these patients.
Common polymorphisms of cyclooxygenase-2 and prostaglandin E2 receptor and increased risk for acute coronary syndrome in coronary artery disease
Authors: Szczeklik Wojciech , Sanak Marek , Rostoff Pawel , Piwowarska Wieslawa , Jakiela Bogdan , Szczeklik Andrew
Published: October 2008

The arachidonic acid metabolites participate in development of coronary artery disease (CAD) and the plaque’s instability.We assessed two common genetic polymorphisms: of cyclooxyge-nase-2 (COX-2) (COX 2.8473, rs5275) and prostaglandin EP2 receptor gene (uS5, rs708494) in patients with CAD. Out of 1,368 patients screened by coronary arteriography, two groups fulfilled the entry criteria and were studied: stable coronary disease (sCAD, n=125) and acute coronary syndromes (ACS, n=63).They did not differ in the main characteristics.All patients were on aspirin at least seven days prior to the study.In 70 control subjects, the same genotypes were ascertained, expression of cyclooxygenases in peripheral blood monocytes was assessed by flow cytometry, and in-vitro biosynthesis of PGE2 was measured by mass spectrometry. COX-2 CC homozygotes (variant allele), were more common, while EP2 GG homozygotes (wild-type) were less common in ACS (p=0.03 and p=0.017) than in the sCAD group.A combined genotype characterized by the presence of the wild-type COX2.8743T allele and the wild type homozygous EP2uS5 genotype (TT or CT | GG) decreased risk ratio of ACS in CAD patients (relative risk 0.41;95% confidence interval 0.21–0.81).COX-2 polymorphism in control subjects did not affect the enzyme expression or PGE2 production by peripheral blood monocytes, but production of PGE2 increased by 40.1% in the subjects homozygous for EP2 receptor allele uS5A following lipopolysaccharide stimulation. In conclusion, the combined COX-2 (COX 2.8473) and the EP2 receptor (uS5) genotypes seem to influence CAD stability, but in peripheral blood monocytes only EP2 receptor modulates PGE2 production.
Elevated white blood cell count and outcome in cancer patients with venous thromboembolism
Authors: Trujillo-Santos Javier , Micco Pierpaolo , Iannuzzo Mariateresa , Lecumberri Ramón , Guijarro Ricardo , Madridano Olga , Monreal Manuel ,   for the RIETE Investigators
Published: October 2008

A significant association between elevated white blood cell (WBC) count and mortality in patients with cancer has been reported,but the predictive value of elevatedWBC on mortality in cancer patients with acute venous thromboembolism (VTE) has not been explored. RIETE is an ongoing registry of consecutive patients with acute VTE. We compared the three-month outcome of cancer patients with acuteVTE according to theirWBC count at baseline. As of May 2007, 3805 patients with active cancer and acuteVTE had been enrolled in RIETE. Of them, 215 (5.7%) had low- (<4,000 cells/µl), 2,403 (63%) normal- (4,000–11,000 cells/µl), 1,187 (31%) elevated (>11,000 cells/µl) WBC count. During the study period 190 patients (5.0%) had recurrent VTE, 156 (4.1%) major bleeding, 889 (23%) died (399 of disseminated cancer, 113 of PE, 46 of bleeding. Patients with elevated WBC count at baseline had an increased incidence of recurrent VTE (odds ratio [OR]: 1.6; 95% confidence interval [CI]:1.2–2.2),major bleeding (OR:1.5;95% CI:1.1–2.1) or death (OR:2.7;95% CI:2.3–3.2).Most of the reported causes of death were significantly more frequent in patients with elevated BC count.Multivariate analysis confirmed that elevated WBC count was independently associated with an increased incidence of all three complications. In conclusion, cancer patients with acute VTE and elevated WBC count had an increased incidence of VTE recurrences,major bleeding or death. This worse outcome was consistent among all subgroups and persisted after multivariate adjustment.