bluuebunny/crossref_metadata_2025 huggingface dataset:
Migrating Partial Seizures in Infancy: Expanding the Phenotype of a Rare Seizure Syndrome
Authors: Marsh Eric , Melamed Susan E. , Barron Todd , Clancy Robert R.
Published: March 2005

Summary:  Purpose: The constellation of early‐onset, unprovoked, alternating electroclinical seizures and neurodevelopmental devastation was first described by Coppola et al. We report six new patients and the prospect of a more optimistic developmental outcome.

Methods: Retrospective chart reviews were performed on six infants evaluated at the Children's Hospital of Philadelphia (five patients) and at Hershey Medical Center (one patient) who had electroclinically alternating seizures before age 6 months of age. Electroclinical characteristics and long‐term follow‐up were recorded.

Results: All had unprovoked, early‐onset (range, 1 day to 3 months; mean, 25 days) intractable electroclinical seizures that alternated between the two hemispheres. Each patient underwent comprehensive brain imaging and neurometabolic workups, which were unrevealing. In all patients, subsequently intractable partial seizures developed and often a progressive decline of head circumference percentile occurred with age. Three demonstrated severe developmental delay and hypotonia. All survived, and 7‐year follow‐up on one patient was quite favorable.

Conclusions: Our patients satisfied the seven major diagnostic criteria first described by Coppola et al. The prognosis of this rare neonatal‐onset epilepsy syndrome from the original description and subsequent case reports was very poor, with 28% mortality, and the majority of survivors were profoundly retarded and nonambulatory. Our patient data validate the diagnostic criteria of this syndrome and further quantify a previously described observation of progressive decline of head circumference percentiles with age. Our data also suggest that the prognosis of this syndrome, although poor, is not as uniformly grim as the cases reported previously in the literature.
Effects of Status Epilepticus Early in Life on Susceptibility to Ischemic Injury in Adulthood
Authors: Giorgi Filippo S. , Malhotra Samit , Hasson Henry , Velíšková Jana , Rosenbaum Daniel M. , Moshé Solomon L.
Published: March 2005

Summary:  Purpose: Status epilepticus (SE) commonly occurs in children, whereas ischemic stroke is the most frequent neurologic insult in adults. The purpose of this study was to determine the effect of SE induced in immature (15 days old; PN15) male rats, on susceptibility to subsequent transient focal cerebral ischemia induced in adulthood.

Methods: SE was induced by flurothyl ether (FE) or kainic acid (KA). Rats that did not develop seizures after FE or KA served as controls. Five weeks later, the now‐adult rats were subjected to middle cerebral artery occlusion (MCAo) for 1 or 2 h by using the intraluminal filament technique. The extent of the infarct volume was evaluated 24 h later.

Results: In rats submitted to 1‐h‐long FE‐SE, the volume of infarction was significantly reduced compared with that in rats exposed to FE without SE. Longer duration of FE‐SE was acutely lethal. KA‐SE induced prolonged behavioral SE (156 ± 17.5 min). In these rats, the volume of infarction was significantly larger compared with that in rats that did not show any electrographic seizures after KA administration. Comparison of FE and KA groups revealed that differences in the size of infarction were confined into cortical areas served by the MCA. Neither type of SE induced any obvious histologic changes in these neocortical regions before stroke induction.

Conclusions: Early in life, SE can influence the outcome of a subsequent focal ischemic insult in adulthood. The extent of the infarct is related to the duration and cause of SE. Prolonged SE induced by KA worsens the outcome, whereas FE‐SE has a neuroprotective effect.
A Clinical and EEG Study on Idiopathic Partial Epilepsies with Evolution into ESES Spectrum Disorders
Authors: Saltik Sema , Uluduz Derya , Cokar Ozlem , Demirbilek Veysi , Dervent Aysin
Published: March 2005

Summary:  Purpose: Questioning the presence of any possible prognostic predictors, this study includes a long‐term follow‐up of clinical and EEG characteristics of 16 patients with idiopathic partial epilepsy (IPE) who subsequently developed epilepsy with electrical status epilepticus during slow sleep (ESES) spectrum disorders.

Methods: Epilepsy, cognitive and behavioral parameters, and waking and non–rapid eye movement (NREM) EEG data were evaluated and scored for initial stage (i.e., IPE stage), preESES, ESES, and ESES remission periods, individually, on a chronologic basis. Data from 25 healthy subjects who had had IPE at the appropriate ages served for comparison with the patients' data during the IPE stage.

Results: Results revealed a higher incidence in seizure frequency and variability in the ESES group and a resistance to a single antiepileptic drug (AED), as compared with controls, during the IPE stage. Mean age at onset of epilepsy was younger in the ESES group versus controls (5.5 and 7.3 years, respectively). At least one of the premonitory clinical features for development of ESES [an increase in the seizure frequency and/or addition of new types of seizures (93%), appearance of cognitive and/or behavioural changes (81.2%), or a progression in EEG abnormalities (66%)] was present in all patients. Epilepsy remitted in patients within the ESES spectrum at a similar age as in controls in 81.2%, as ESES findings in the EEG disappeared by age 13 years in 94%. Seizure prognosis proved to be the most favorable among the questioned parameters.

Conclusions: An increase in seizure frequency or development of new seizure types, a deviance in behavior or decrease in cognitive performance, or a spreading tendency of the previously focal abnormalities in control EEGs may be premonitory features of a developing ESES and necessitate close follow‐ups with sleep EEGs in children with IPEs.
Atypical Language Representation in Patients with Chronic Seizure Disorder and Achievement Deficits with Magnetoencephalography
Authors: Breier Joshua I. , Castillo Edwardo M. , Simos Panagiotis G. , Billingsley‐Marshall Rebecca L. , Pataraia Ekaterina , Sarkari Shirin , Wheless James W. , Papanicolaou Andrew C.
Published: March 2005

Summary:  Purpose: To characterize the relation between hemispheric asymmetries in language‐specific brain activity and reading/spelling achievement by using magnetoencephalography (MEG).

Methods: Patients (n = 83) with medically intractable complex partial seizures of either left‐ or right‐hemisphere origin were classified as having reading and/or spelling deficits (RS) or as not impaired (NI) by using standard achievement tests. All patients had undergone noninvasive functional mapping of receptive language cortex by using MEG as part of a preoperative seizure surgery evaluation.

Results: RS patients with left‐hemisphere seizure onset exhibited relatively greater activation and earlier onset of late, language‐specific MEG activity in posterior temporal and inferior parietal areas of the right as compared with the left hemisphere than did NI patients. These findings also were evident on an individual basis and were independent of global intellectual abilities.

Conclusions: Reading and spelling achievement deficits in patients with complex partial seizures of left‐hemisphere origin are associated with atypical language organization, possibly secondary to reorganization of language function to right‐hemisphere areas that are not as efficient as homotopic areas in the left hemisphere in supporting reading and spelling functions.
Surgery for Epilepsy Due to Cortical Malformations: Ten‐year Follow‐up
Authors: Hamiwka Lorie , Jayakar Prasanna , Resnick Trevor , Morrison Glenn , Ragheb John , Dean Patricia , Dunoyer Catalina , Duchowny Michael
Published: March 2005

Summary:  Children with malformations of cortical development represent a significant proportion of pediatric epilepsy surgery candidates. From a cohort of 40 children operated on between 1980 and 1992 with malformation of cortical development, 38 were alive and had data 10 years after surgery. Age at surgery ranged from 6 months to 18 years (mean, 9.6 years). Thirty‐six had partial seizures, and two had infantile spasms; 20 were nonlesional. Pathologic diagnoses were cortical dysplasia (n = 31) and developmental tumor (n = 7). At 10‐year follow‐up, 15 (40%) were seizure free, 10 (26%) had >90% seizure reduction, and 13 (34%) were improved or unchanged. Children seizure free at two‐year follow‐up were likely to remain seizure free. Ten‐year seizure freedom was 72% in children with developmental tumors and 32% in the cortical dysplasia group. Complete resection was statistically significant for favorable outcome, and no patient with an incomplete resection was seizure free.
Can You Predict an Immediate, Complete, and Sustained Response to the Ketogenic Diet?
Authors: Than Khoi D. , Kossoff Eric H. , Rubenstein James E. , Pyzik Paula L. , McGrogan Jane R. , Vining Eileen P. G.
Published: March 2005

Summary:  Purpose: Although the ketogenic diet has been in use for >80 years, little agreement exists as to which patients are most likely to have dramatic, sudden, and complete seizure control.

Methods: A case–control study was performed of children with intractable epilepsy started on the ketogenic diet at our institution since June 2001. Patients with a dramatic response were defined as those becoming seizure free within 2 weeks of diet onset. These children were compared with all other patients treated with the diet over the same time period in terms of patient demographics, epilepsy characteristics, and diet parameters.

Results: Eighteen early, dramatic responders over a 3‐year period were identified and compared with 89 patients who were not similarly improved. The absence of complex partial seizures as the predominant seizure type (0 vs. 23%; p = 0.02) correlated with this dramatic success. The presence of infantile spasms (39% vs. 20%; p = 0.09) approached significance, but all other variables did not.

Conclusions: An early, dramatic response to the ketogenic diet is more likely in patients with predominant seizure types other than complex partial. It may also be more likely to occur in children who have infantile spasms. In all other patient demographics and diet parameters, an equal likelihood of similar success was found.
Smoking Cessation a Byproduct of EEG Telemetry Monitoring
Authors: Ahmed Syed Nizamuddin , Quigley Daphne , Siddiqi Zaeem A.
Published: March 2005

Summary:  Smoking is a common problem in epilepsy patients. The inpatient video‐EEG monitoring (VEEG) unit provides a unique and conducive environment for epilepsy patients to participate actively in a smoking‐cessation program. The restrictions and confinement to the telemetry bed impose a forced abstinence from smoking. It has been suggested that patients who are hospitalized may be more receptive to smoking‐cessation advice. We report two patients who were successfully able to quit smoking after admission for VEEG.
Simple Partial Seizures with Hemisensory Phenomena and Dysgeusia: An Insular Pattern
Authors: Rossetti Andrea O. , Mortati Kathrine A. , Black Peter M. , Bromfield Edward B.
Published: March 2005

Summary:  Insular seizures are rarely described, in part owing to the complex anatomy of this brain region. We present a patient with simple partial seizures, recorded intracranially, originating in the right insula and characterized by dysgeusia and contralateral somatosensory phenomena. This rare clinical pattern seems to be characteristic of the insula and may be undetectable with surface EEG.
Emergency Transcallosal Resection of Hypothalamic Hamartoma for “Status Gelasticus”
Authors: Ng Yu‐tze , Rekate Harold L.
Published: March 2005

Summary:  Hypothalamic hamartomas are rare developmental malformations of the inferior hypothalamus. Typically they result in symptomatic, refractory mixed seizure disorder with trademark gelastic or laughing seizures. We present a 30‐month‐old boy with a hypothalamic hamartoma and a nearly 2‐month history of near‐continuous gelastic seizures, which we have labeled “status gelasticus.” The seizures were refractory to multiple antiepileptic drugs (AEDs), and emergency transcallosal resection of the hypothalamic hamartoma was performed with resultant near‐immediate cessation of the seizures. At 12‐month follow‐up, the patient was averaging one brief gelastic seizure every 2 weeks, with a longest seizure‐free period of 2 months.
Epileptic Seizures and Epilepsy: Definitions Proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE)
Authors: Fisher Robert S. , Boas Walter van Emde , Blume Warren , Elger Christian , Genton Pierre , Lee Phillip , Engel Jerome
Published: March 2005

Summary:  The International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE) have come to consensus definitions for the terms epileptic seizure and epilepsy. An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological, and social consequences of this condition. The definition of epilepsy requires the occurrence of at least one epileptic seizure.
Metal allergy in Singapore
Authors: Goon Anthony T. J. , Goh C. L.
Published: March 2005

This is a clinical epidemiologic study to determine the frequency of metal allergy among patch‐tested patients in the years 2001–2003. The results are compared with those of previous studies. All patients diagnosed as having allergic contact dermatitis in the National Skin Centre, Singapore, from January 2001 to December 2003 were studied retrospectively. The frequency of positive patch tests to the following metals were nickel 19.9%, chromate 5.6%, cobalt 8.2% and gold 8.3%. The frequency of nickel allergy has been steadily rising over the last 20 years. The most common sources of nickel allergy are costume jewellery, belt buckles, wristwatches and spectacle frames. After declining from 1984 to 1990, chromate and cobalt allergies have also been steadily increasing subsequently. The most common sources of chromate allergy were cement, leather and metal objects. Most positive patch tests to cobalt are regarded as co‐sensitization due to primary nickel or chromate allergies. There has been a steep increase in positive patch tests to gold from 2001 to 2003, which is difficult to explain because the relevance and sources of such positive patch tests can rarely be determined with certainty. There has been an overall rise in the frequency of metal allergy in the last 20 years.
An epidemic of occupational contact dermatitis from an acrylic glue
Authors: Kiec‐Swierczynska Marta , Krecisz Beata , Swierczynska‐Machura Dominika , Zaremba Joanna
Published: March 2005

Dermatological examinations were performed in 81 workers involved in the manufacture of electric coils for television displays, who had worked for 4 years in contact with a glue containing isobornyl acrylate, acrylic acid, N,N dimethyleneacrylamide, phosphine oxide, bis(2,6‐dimethoxybenzoyl) (2,4,4‐trimethylpentyl)‐ and beta‐carboxyethyl acrylate. The glue was cured by 350–500‐nm ultraviolet and visible radiations. Acrylate‐specific dermal lesions were detected in 21 (25.9%) people. Occupational irritant contact dermatitis was diagnosed in 12 (15%) of the workers and occupational allergic contact dermatitis in 9 (11.2%). 12 people reacted to acrylates. Cross‐reactions with methacrylates were not observed. The highest number of positive tests was obtained with triethyleneglycol diacrylate (10 people) and diethyleneglycol diacrylate (9), followed by 1,6‐hexanediol diacrylate (5), 1,4‐butanediol diacrylate (4), beta‐carboxyethyl acrylate (3), tripropyleneglycol diacrylate (2) and pentaerythritol triacrylate (2). No cases of allergy to isobornyl acrylate, N,N‐methylenebisacrylamide or phosphine oxide were noted.
Prognosis of contact dermatitis in epoxy resin workers
Authors: Cahill Jennifer , Keegel Tessa , Dharmage Shyamali , Nugriaty Dhini , Nixon Rosemary
Published: March 2005

Between January 1993 and February 2002, 40 of 1354 (3%) workers who attended a tertiary referral occupational dermatology clinic were diagnosed with allergic contact dermatitis (ACD) from epoxy resin systems (ER). 20 of these patients were followed up at least 2 years post‐diagnosis to establish prognosis. Characteristics collected at diagnosis, including age, atopic status and severity, were compared between the follow‐up and not followed‐up groups. No significant differences were observed. A clinician contacted patients and administered a telephone questionnaire based on variables identified from the literature, which were considered of importance for prognosis. All patients reported improvement of their skin condition since diagnosis. 12 of the 20 {60%[95% confidence interval (CI) 56–94%]} patients had applied for workers' compensation; all of these claims were successful. 16 had ceased working with ER. Of these, 9 [56% (95% CI 29–80%)] reported complete healing and 7 [44% (95% CI 19–70%)] reported ongoing dermatitis. Although no conclusions could be drawn because of the small sample size, factors that may be associated with a poor prognosis were age, atopy, duration of symptoms and severity at diagnosis. The prognosis of ACD from ER is not always favourable, even if a worker ceases exposure.
Allergic contact dermatitis in Iran
Authors: Kashani Mansour Nassiri , Gorouhi Farzam , Behnia Feraydoun , Nazemi Mohammad Javad , Dowlati Yahya , Firooz Alireza
Published: March 2005

The frequency of sensitization to contact allergens varies in different countries because of both genetic and, more importantly, allergen exposure variations. The objective is to determine the frequency of sensitization to contact allergens in Iranian patients with dermatitis. 250 patients with a clinical diagnosis of contact dermatitis and/or atopic dermatitis were evaluated with a 28‐allergen screening series recommended by the German Contact Dermatitis Research Group from September 2002 to April 2004 in Tehran, Iran. The patches were applied on the back of the patients, removed after 24 hr and the readings were taken on 24 hr, 48 hr and 72 hr after application. 126 patients (50.4%) showed at least 1 positive reaction, and 23 patients (9.2%) had more than 2 positive reactions. 189 (84.4%) of 224 positive reactions had past and/or present clinical relevance. The 5 most common allergens were nickel sulfate 70 (28.0%), cobalt chloride 32 (12.8%), paratertiarybutyl phenol formaldehyde resin 20 (8.0%), potassium dichromate 13 (5.2%) and colophony 13 (5.2%). Contact allergy to nickel sulfate was significantly more common in female patients and in patients under 40 years of age (P < 0.05). Nickel sulfate is the most common contact allergen in Iran, mostly affecting women and younger patients probably because of more exposure.
Upregulation of MMP‐9/TIMP‐1 enzymatic system in eosinophilic meningitis caused by Angiostrongylus cantonensis
Authors: Chen Ke‐Min , Lee Hsiu‐Hsiung , Chou Hui‐Lin , Liu Jer‐Yuh , Tsai Bo‐Cyuan , Lai Shih‐Chan
Published: March 2005

Proteolysis depends on the balance between the proteases and their inhibitors. Matrix metalloproteinase‐9 (MMP‐9) and its specific inhibitors, tissue inhibitors of metalloproteinases (TIMP), contribute to eosinophilic inflammatory reaction in the subarachnoid space of the Angiostrongylus cantonensis‐infected mice. The expression of MMP‐9 in cerebrospinal fluid (CSF) was significantly increased in mice with eosinophilic meningitis, compared to that in uninfected ones. However, the TIMP‐1 levels were unchanged and remained at basal levels at all time points, even in uninfected mice. Elevated MMP‐9 mRNA expression coincided with protein levels and proteolytic activity, as demonstrated by means of positive immunoreactivity and gelatin zymography. CSF protein contents correlated significantly with MMP‐9 intensity and CSF eosinophilia. In addition, immunohistochemistry demonstrated MMP‐9 and TIMP‐1 localization in eosinophils and macrophages. When the specific MMP inhibitor, GM6001, was added, MMP‐9 enzyme activity was reduced by 45.4%. The percentage of eosinophil increased significantly upon the establishment of infection, but subsided upon inhibition. These results show that MMP‐9/TIMP‐1 imbalance in angiostrongyliasis may be associated with eosinophilic meningitis.
A transmission electron microscopic study of microglia/macrophages in the hippocampal cortex and neocortex following chronic exposure to valproate
Authors: Sobaniec‐Lotowska Maria E.
Published: March 2005

In chronic administration of sodium valproate to rats, significant disorders of structural integrity of the hippocampal gyrus and the neocortex of the temporal lobe, observed in the last two stages of the experiment (after 9 and 12 months), coexisted with increased number of microglial cells and, especially after 12 months, with intense phagocytic activity within these cells. At the ultrastructural level, phagocyte microglial cells were hypertrophied with several broadened processes. Their cytoplasm contained rich lysosomal apparatus, numerous lipofuscin‐like structures, lipid droplets and multilaminated bodies. The nuclei of these cells were characteristic oval or round and sometimes triangle in shape with dense and highly clumped heterochromatin, distinctly accumulated under nuclear envelope, and sparse euchromatin. Microglia/macrophages were frequently present in a close vicinity of changed neuronal somata and also close to the altered elements of the neuropil pyramidal layer of the cortex. Microglial response may, together with abnormalities in neurones, astroglia and blood–brain barrier, play a significant role in the development of experimental valproate encephalopathy.
Effects of neutrophil depletion in the local pathological alterations and muscle regeneration in mice injected with Bothrops jararaca snake venom
Authors: Teixeira Catarina F. P. , Chaves Fernando , Zamunér Stella R. , Fernandes Cristina M. , Zuliani Juliana P. , Cruz‐Hofling María Alice , Fernandes Irene , Gutiérrez José María
Published: March 2005

In order to study the role of neutrophils in the acute local pathological alterations induced by Bothrops jararaca snake venom, and in the process of skeletal muscle regeneration that follows, an experimental model was developed in mice pretreated with either an anti‐mouse granulocyte rat monoclonal immunoglobulin G, which induces a profound neutropenia, or an isotype‐matched control antibody. B. jararaca venom induced prominent haemorrhage and oedema, but only a moderate myonecrosis. No significant differences were observed in the extent of local haemorrhage, oedema and myonecrosis between neutropenic and control mice, suggesting that neutrophils do not play a determinant role in the acute pathological alterations induced by B. jararaca venom in this experimental model. Moreover, no differences were observed in skeletal muscle regeneration between these two experimental groups. In both the cases, limited areas of myonecrosis were associated with a drastic damage to the microvasculature and a scarce inflammatory infiltrate, with the consequent lack of removal of necrotic debris during the first week, resulting in a poor regenerative response at this time interval. Subsequently, a similar regenerative process occurred in both groups, and by 30 days, necrotic areas were substituted by groups of small regenerating muscle fibres. It is suggested that the drastic effect exerted by B. jararaca venom in the microvasculature precludes an effective access of inflammatory cells to necrotic areas, thereby compromising an effective removal of necrotic debris; this explains the poor regenerative response observed during the first week and the fact that there were no differences between neutropenic and control mice. As neutropenia in this model lasted only 7 days, the successful regenerative process observed at 30 days is associated with revascularization of necrotic regions and with a successful removal by phagocytes of necrotic debris in both groups.
Enhancement of the repair of meniscal wounds in the red–white zone (middle third) by the injection of bone marrow cells in canine animal model
Authors: Abdel‐Hamid Mohammed , Hussein Mahmoud R. , F. Ahmad Ahmad , Elgezawi Ebtisma M.
Published: March 2005

Bone marrow stem cells (BMSCs) can differentiate into several cells that participate in the healing of meniscal wounds. To test this hypothesis, we examined the effects of injected BMSCs on the healing of meniscal wounds. Autologous BMSCs from eight adult dogs were injected into meniscal wounds (knee joints). After 12 weeks, the healing process was clinically and immunomorphologically evaluated using: (i) histochemical stains (haematoxylin and eosin, Masson trichrome and periodic acid–Schiff) and (ii) immunoperoxidase staining methods (CD3, CD79a, CD68, CD31 and alpha smooth‐muscle actin for T, B lymphocytes, macrophages, endothelial cells and smooth‐muscle lineage). Complete (six vs. three), partial (one vs. one) and no healing (one vs. four animals) of the meniscal wounds were observed in the injected and noninjected menisci. As compared with the noninjected menisci, examination of the tissues from the injected ones revealed: (i) marked angiogenesis (microvessel density: 3.22 ± 0.66 vs. 6.50 ± 2.10); (ii) chondrogenesis; (iii) prominent immune cell infiltrate (4.07 ± 0.78 vs. 9.56 ± 1.69, 8.33 ± 0.77 vs. 3.67 ± 1.00 and 4.38 ± 0.62 vs. 11.1 ± 1.43 for the total numbers of immune cells, lymphocytes and macrophages, respectively); and (iv) proliferation of the fibroblasts with marked deposition of collagen fibres (2.0 ± 0.84 vs. 2.66 ± 0.48). These values were statistically significantly higher for the injected menisci as compared with the noninjected ones (P ≥ 0.05). Autologous BMSCs can improve meniscal wound healing. Whether this improvement occurs through BMSC differentiation into cells operational in the repair process, the release of certain mediator or other unknown mechanisms mandates further investigations.
Differences in the effects of age on intestinal proliferation, crypt fission and apoptosis on the small intestine and the colon of the rat
Authors: Mandir Nikki , FitzGerald Anthony J. , Goodlad Robert A.
Published: March 2005

The increase in gastrointestinal epithelial tissue mass and the development of the gut can occur through three main mechanisms, namely elevated cell production from the intestinal crypts, by raised crypt number, which occurs through the process of crypt fission or by altered apoptosis. The small bowel and the colon have various rates of these, which were studied in rats of various ages. Wistar rats were fed ad libitum, and were killed at 3, 4, 6, 9, 12, 18, 26 and 48 weeks of age. Tissue was later stained and microdissected and the number of native mitoses and apoptotic figures per crypt and the percentage of crypts in fission were determined. There was an almost linear increase in body weight from 3 to 9 weeks, followed by a more gradual rise until 18 weeks. The weight of the stomach and the small intestine reached maximum values at 9 weeks, whereas the caecum and the colon approached this at 12 weeks. Mitotic activity per crypt in the small intestine increased from 3.8 ± 0.1 at 3 weeks to 7.8 ± 0.4 mitoses per crypt (P < 0.001) at 9 weeks and then decreased slightly; crypt fission increased from 4.6% ± 0.8 at 3 weeks to 8.4 ± 0.9% at 6 weeks and then decreased gradually reaching a value of 1.5 ± 0.4% at 48 weeks. Apoptosis also peaked at 6 weeks and was then very low. In the colon, the proliferation decreased from 4.2 ± 0.2 mitoses per crypt in the young (3 weeks) rat and reached a plateau by 9 weeks (2.5 ± 0.1 mitoses per crypt, P < 0.001). Crypt fission also declined rapidly in the first 9 weeks (from 67.6 ± 4.2 to 23.1 ± 4.6%, P < 0.01) and then continued to decline, although at a lower rate. The crypt fission index at 48 weeks was 9.8 ± 1.0. Apoptosis in the colon persisted throughout the duration of the study, 0.19 ± 0.06 apoptotic bodies per crypt were seen at week 48. The development of the small intestine is more dependent on cell proliferation, whereas in the colon crypt fission is far more predominant, with the colon having fission indices approximately six times greater than those of the small intestine. Proliferative activity in the colon was approximately half that of the small intestine.
Intramuscular pressure and tissue oxygenation during low‐force static contraction do not underlie muscle fatigue
Authors: Blangsted A. K. , Vedsted P. , Sjøgaard G. , Søgaard K.
Published: March 2005

Aim:  To test the hypothesis that time‐wise increase in intramuscular pressure (IMP) and subsequent decrease in muscle tissue oxygenation (TO2) results in muscle fatigue development during a non‐exhaustive, low‐force contraction evidenced by changes in electromyogram (EMG) and particular mechanomyogram (MMG).

Methods:  Seven subjects performed static elbow flexion at 10% maximal voluntary contraction (MVC) for 10 min (10% MVC10 min). Surface EMG, MMG, IMP and TO2 measured by near‐infrared spectroscopy was recorded from m. biceps brachii during 10% MVC10 min and during 5% MVC test contractions of 1 min duration performed before 10% MVC10 min, 10 and 30 min post‐exercise. EMG and MMG were analysed for root mean square (rms) and mean power frequency (mpf).

Results:  During 10% MVC10 min MMGrms increased from initial level of 0.04 ± 0.01 to 0.11 ± 0.07 m s−2 in the last minute and MMGmpf and EMGmpf decreased from 34.9 ± 8.2 to 21.3 ± 3.8 Hz and from 71.7 ± 10.9 to 61.7 ± 10.0 Hz respectively. Similar changes were present in 5% MVC test contractions 30 min post‐exercise. Initially, TO2 decreased by 6.9 ± 6.5% of resting level but returned to rest within 1 min. IMP remained constant during the contraction after an initial fourfold increase from resting level of 12.2 ± 10.4 mmHg.

Conclusions:  IMP was anticipated to increase with time of contraction due to e.g. increased muscle water content; but this was not confirmed. Consequently, muscle blood flow was unlikely to be impeded with contraction time, which may account for the maintenance of TO2. Thus, decreased TO2 did not underlie either acute or long‐term muscle fatigue development evidenced by changes in EMG and particular MMG variables.
Measuring bronchodilation in COPD clinical trials
Authors: Borrill Z. L. , Houghton C. M. , Woodcock A. A. , Vestbo J. , Singh D.
Published: March 2005

Aims

The aim of this study was to compare the variability and sensitivity of impulse oscillometry (R5, X5 and RF), plethysmography (Raw and sGaw) and spirometry (FEV1, FVC and MMEF) in order to determine the most powerful technique for assessing bronchodilation in COPD clinical trials.

Methods

Twenty‐four patients with COPD had impulse oscillometry, plethysmography and spirometry measured twice 30 mins apart, to determine variability. Then ascending doses of salbutamol (20, 50, 100, 200, 400 and 800 µg) were given and the same measurements made after each dose. Significant changes greater than variability were determined for each performed measurement (expressed as mean percentage improvement with 95% CI).

Results

Significant effects (P < 0.05) were detected after 20 µg by X5 (18.5% CI 9.8–27.2) RF (11.1% CI 7.2–15.0) and sGaw (21.5% CI 10.1–32.9), and after 50 µg by R5 (16.7% CI 10.8–22.5) and Raw (19.7% CI 13.0–26.4). FEV1 was less sensitive, detecting significant bronchodilation at 100 µg (10.2% CI 7.4–12.9).

Conclusions

We conclude that impulse oscillometry and plethysmography should be considered the preferred techniques for measuring bronchodilation in COPD clinical trials.
Therapeutic innovation in the European Union: analysis of the drugs approved by the EMEA between 1995 and 2003
Authors: Motola Domenico , De Ponti Fabrizio , Rossi Pasqualino , Martini Nello , Montanaro Nicola
Published: March 2005

Since January 1995, all European Union applications for marketing approval for medicinal products derived from biotechnology and other drugs considered potentially innovative follow the EMEA centralized procedure. In order to assess the overall degree of therapeutic innovation of these drugs, we considered, for each approved agent, its target, the availability of previous treatments and the extent of its therapeutic effect. The following scores for therapeutic innovation were assigned through a consensus process: ‘A’ (important), ‘B’ (moderate) and ‘C’ (modest). The overall degree of important/moderate therapeutic innovation was 47% of all therapeutic agents (32% important; 15% moderate). Most (80%) of the EMEA‐approved therapeutic agents were for serious diseases. The remaining ones were for risk factors (7%) or nonserious diseases (13%).
Pharmacogenetic profiling across the irinotecan pathway in Asian patients with cancer
Authors: Zhou Qingyu , Sparreboom Alex , Tan Eng‐Huat , Cheung Yin‐Bun , Lee Ann , Poon Donald , Lee Edmund J. D. , Chowbay Balram
Published: March 2005

Aims

The aim of this exploratory study was to investigate associations between irinotecan pharmacokinetic parameters and allelic variants in genes encoding for drug transporters and drug metabolizing enzymes that are involved in irinotecan disposition in Asian patients with cancer.

Methods

Irinotecan was administered at 100 mg m−2 over 90 min on a weekly schedule to 29 nasopharyngeal carcinoma patients and pharmacokinetic analysis was performed during the first cycle. All patients were genotyped for allelic variants in genes encoding drug metabolizing enzymes (CYP3A4, CYP3A5, UGT1A1) and drug transporters (ABCB1, ABCC2 and ABCG2) that are involved in irinotecan disposition.

Results

Of the six candidate genes that were analyzed, 11 genetic variants were found. Significant genotypic–phenotypic associations were apparent only for transporter genes. The Cmax of irinotecan was significantly lower in patients carrying the CC genotype at exon 26 of the ABCB1 gene compared with those harbouring at least one variant allele (P = 0.047). Patients harbouring the wild type ABCG2 CTCA genotype were associated with significantly higher values for relative extent of conversion (REC) of irinotecan to SN‐38 compared with patients carrying at least one deletion CTCA allele (P = 0.019).

Conclusions

The present exploratory study shows that genetic polymorphisms in drug transporter genes, particularly in ABCB1 and ABCG2 genes, may be important in influencing the pharmacokinetics of irinotecan and its metabolites. The predictive value of the identified allelic variants in the ABCG2 and ABCB1 genes on irinotecan disposition should be further investigated in a larger patient population as well as in other ethnic populations.
Ineffectiveness of lipid‐lowering therapy in primary care
Authors: Van Ganse E. , Souchet T. , Laforest L. , Moulin P. , Bertrand M. , Le Jeunne P. , Travier N. , Yin D. , Alemao E. , De Pouvourville G.
Published: March 2005

Background

Evidence confirms the positive effects of lipid‐lowering agents on the risk of cardiovascular disease. Local guidelines in France (AFSSAPS) have defined therapeutic objectives for LDL‐cholesterol. These objectives vary with the number of cardiovascular risk factors in addition to dyslipidaemia. We determined the proportions of patients at therapeutic objective in different classes of cardiovascular risk to test the hypothesis that compliance with guidelines varies across the levels of risk. Comparison with international guidelines (ANDEM) was also performed.

Methods

A group of 3173 dyslipidaemic patients treated with lipid‐lowering agents and managed by general practitioners was randomly selected from BKL‐Thales panel, a French computerized database. For each patient, history of coronary heart disease and the number of cardiovascular risk factors were documented. Compliance with guidelines was assessed from achievement of therapeutic objective.

Results

The study population included 79% primary prevention patients (1.6, 25.5, 31.7 and 20.1%, with 1, 2, 3, and >3 risk factors, respectively) and 21.0% secondary prevention patients. Applying AFSSAPS guidelines, the proportions of primary prevention patients not at LDL‐cholesterol objectives varied across risk categories (P < 0.0001), from 3.9% for patients with one risk factor to 46.5% for patients with >3 risk factors, and therapeutic failure reached 39.9% in secondary prevention. Only 26% of patients who were at high cardiovascular risk (>3 risk factors or prior coronary heart disease) and not at therapeutic objective received high doses (>standard recommended doses) of lipid‐lowering agents in monotherapy. Applying ANDEM guidelines, 74% of secondary prevention patients were not at treatment goal.

Conclusion

Compliance with guidelines varied inversely with the level of cardiovascular risk. Besides, most patients not at therapeutic objective were not up‐titrated. The use of lipid‐lowering agents is inadequate, depriving many patients of an effective protection against cardiovascular diseases.
Self treatment with one of three self selected, ultramolecular homeopathic medicines for the prevention of upper respiratory tract infections in children. A double‐blind randomized placebo controlled trial
Authors: Steinsbekk Aslak , Bentzen Niels , Fønnebø Vinjar , Lewith George
Published: March 2005

Aims

Homeopathic medicines are frequently purchased over the counter (OTC). Respiratory complaints are the most frequent reason for such purchases. Children with upper respiratory tract infection (URTI) are frequent users of homeopathy. This study investigates the effect of self treatment with one of three self selected ultramolecular homeopathic medicines for the prevention of childhood URTI.

Methods

A double‐blind randomized parallel group placebo controlled trial was carried out in 251 children below the age of 10 years, recruited by post from those previously diagnosed with URTI when attending a casualty department. The children were randomly assigned to receive either placebo or ultramolecular homeopathic medicines in C‐30 potency (diluted 10−60) administered twice weekly for 12 weeks. Parents chose the medicine based on simplified constitutional indications for the three medicines most frequently prescribed by Norwegian homeopaths for this group of patients. The main outcome measure relates to the prevention of new episodes of URTI measured with median total symptom score over 12 weeks.

Results

There was no difference in the predefined primary outcome between the two groups (P = 0.733). Median URTI scores over 12 weeks in the homeopathic medicine group were 26.0 (95% confidence interval (CI) 16.3, 43.7) and for placebo 25.0 (95% CI 14.2, 38.4). There was no statistical difference between the two groups in median number of days with URTI symptoms or in the use of conventional medication/care.

Conclusions

In this study there was no effect over placebo for self treatment with one of three self selected, ultramolecular homeopathic medicines in preventing childhood URTI. This can be due to the lack of effect of the highly diluted homeopathic medicines or the process of selection and type of medicines.
Steady‐state pharmacokinetics and pharmacodynamics of CHF3381, a novel antineuropathic pain agent, in healthy subjects
Authors: Astruc Béatrice , Tarral Antoine , Dostert Philippe , Mariotti Fabrizia , Fabbri Laura , Imbimbo Bruno P.
Published: March 2005

Aims

To evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic profiles of CHF3381, a dual NMDA and MAO‐A inhibitor, after multiple oral doses in healthy subjects.

Methods

Forty‐eight young males received CHF3381 at doses of 100 mg twice daily, 200 mg twice daily, 400 mg twice daily or placebo for 2 weeks according to a double‐blind, randomized, parallel group design. Plasma and urine concentrations of the parent drug and of two major metabolites (CHF3567 and 2‐aminoindane) were measured over time. MAO‐A activity in plasma was estimated by measuring plasma concentrations of 3,4‐dihydroxyphenylglycol. Sustained attention, memory and sedation were assessed throughout the study with standard psychometric tests.

Results

Most of the adverse events were mild in intensity, with dose regimens of 100 mg twice daily and 200 mg twice daily being indistinguishable from placebo. After 400 mg twice daily, the most frequent adverse events were mild dizziness, asthenia and insomnia. At steady‐state, 400 mg twice daily slightly increased supine heart rate (+ 9 ± 2 beats min−1) and diastolic blood pressure (+6 ± 2 mmHg) compared with placebo. There were no dose‐dependent or consistent effects of CHF3381 on attention, motor co‐ordination or memory, but 400 mg twice daily significantly decreased alertness compared with placebo. Plasma concentrations of CHF3381 peaked at around 3 h and were dose‐proportional. The elimination half‐life of CHF3381 was estimated to be 4–6 h. At steady‐state, significant CHF3381 plasma concentrations were detected at predose with a modest accumulation (1.3–1.5 times), showing that the drug given twice daily is active over the entire 24 h period. Plasma concentrations of CHF3567 and of 2‐aminoindane were also proportional to the dose of CHF3381. CHF3381 dose‐dependently inhibited MAO‐A activity with peak effects at steady‐state of 27 ± 4%, 46 ± 2% and 65 ± 5% after 100 mg twice daily, 200 mg twice daily and 400 mg twice daily, respectively. There were no significant effects of CHF3381 on attention (rapid visual information processing), motor co‐ordination (body sway) or memory (learning memory task) at any of the doses. At steady‐state, there was a significant decrease in alertness (Bond & Lader visual analogue scale) in the 400 mg twice daily group compared with placebo.

Conclusions

A twice daily regimen of CHF3381 appears to be adequate from a pharmacokinetic and pharmacodynamic perspective. Plasma concentrations reached with 400 mg twice daily exceeded those observed in animals receiving pharmacologically active doses in chronic pain models.
Diltiazem inhibits human intestinal cytochrome P450 3A (CYP3A) activity in vivo without altering the expression of intestinal mRNA or protein
Authors: Pinto A. G. , Horlander J. , Chalasani N. , Hamman M. , Asghar A. , Kolwankar D. , Hall S. D.
Published: March 2005

Aims

To determine the effect of diltiazem on intestinal CYP3A activity and protein and mRNA expression in vivo in healthy subjects.

Methods

Intestinal biopsies were obtained from ten healthy controls and from ten healthy subjects after receiving diltiazem 120 mg bid for 7 days. Intestinal CYP3A activity, CYP3A4 protein and mRNA concentrations were quantified in both groups. Intestinal CYP3A activity was determined by incubation of small bowel homogenate with midazolam (25 µM) and NADPH for 5 min and the rate of formation of 1’‐hydroxymidazolam was quantified.

Results

All subjects in the treatment group had detectable diltiazem concentration in the serum. While there was no significant difference in CYP3A4 protein and mRNA expression between the control and treatment groups, the formation of 1’‐hydroxymidazolam (446 pmol min−1 mg−1 6 (control) vs. 170 (CI 112, 228) pmol min−1 mg−1 95% confidence interval (CI 269, 623) (diltiazem group)) was significantly reduced (P < 0.05).

Conclusion

Diltiazem decreased small bowel CYP3A activity by 62% as a result of irreversible inhibition with no corresponding change in intestinal CYP3A4 mRNA or protein concentrations.
New therapies for rheumatoid arthritis
Authors: Goldblatt F , Isenberg D A
Published: March 2005

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease, which continues to cause significant morbidity in affected persons. In the past few years, a number of new exciting therapeutic options have become available. These reflect the application of knowledge obtained from advancements in understanding of disease pathogenesis and underlying molecular mechanisms. A number of these therapies are outlined in the following review, including the various biological modifiers, in particular, anti-tumour necrosis factor-α agents and interleukin-1 (IL-1) receptor antagonists, which have been developed in recognition of the role of pro-inflammatory cytokines in RA. Also notable, is the current interest centring on the development and trials with B cell depletion therapies, specifically rituximab, in patients with RA. This demonstrates acknowledgment for a more significant role for B cells in the aetiology of RA, in contrast to the long held view that RA was a predominantly T cell mediated disease. To evaluate this therapeutic option for RA, salient features from recent rituximab trials have been collated. Finally, a selection of other therapeutic alternatives, including anti-IL-6 receptor monoclonal antibody and tacrolimus, and newer anti-rheumatic therapies presently in development are summarized.
CD4+ CD25+ T cells with the phenotypic and functional characteristics of regulatory T cells are enriched in the synovial fluid of patients with rheumatoid arthritis
Authors: Möttönen M , Heikkinen J , Mustonen L , Isomäki P , Luukkainen R , Lassila O
Published: March 2005

CD4+ CD25+ regulatory T (Treg) cells play a critical role in the maintenance of peripheral tolerance and the prevention of autoimmunity. In the present study, we have explored the characteristics of CD4+ CD25+ Treg cells in patients with rheumatoid arthritis (RA). The frequency and phenotype of CD4+ CD25+ T cells in paired samples of synovial fluid (SF) and peripheral blood (PB) from patients with RA and PB from normal controls were analysed. An increased frequency of CD4+ cells T cells expressing CD25 was detected in SF compared to PB from patients with RA. No significant difference was observed in the numbers of CD4+ CD25+ T cells in PB from patients and controls. SF CD4+ CD25+ T cells expressed high levels of CTLA-4 (both surface and intracellular), GITR and OX40, as well as Foxp3 transcripts. Functionally, SF CD4+ CD25+ T cells were impaired in their proliferative responses and could suppress the proliferation of their CD4+ CD25– counterparts. In conclusion, these data demonstrate that CD4+ CD25+ Treg cells, with the potential to regulate the function of effector T cells and antigen-presenting cells, accumulate in the synovium of patients with RA.
Constant IFNγ mRNA to protein ratios in cord and adult blood T cells suggests regulation of IFNγ expression in cord blood T cells occurs at the transcriptional level
Authors: Gupta A Kumar , Rusterholz C , Holzgreve W , Hahn S
Published: March 2005

Low levels of IFNγ produced by umbilical cord blood (UCB) T lymphocytes upon activation may be due to the need for a high threshold of activation or to intrinsic blocking transcription/translation. We examined IFNγ mRNA accumulation and protein expression in pharmacologically stimulated human UCB and adult blood (AB) T cells. Our data indicate that both IFNγ mRNA accumulation and protein synthesis were significantly lower in stimulated UCB T cells than the AB T cells. Since the RNA dependent kinase PKR, an inhibitor of translation, can be activated by low levels of IFNγ mRNA, we measured its involvement. Treatment with 2-amino-purine, an inhibitor of PKR, did not enhance IFNγ protein expression in UCB T cells. Furthermore, our studies indicated that IFNγ promoter hypermethylation does not appear to regulate IFNγ expression either, as treatment with the demethylating agent, 5-aza-2′-deoxycytidine, did not lead to a significant increase in IFNγ mRNA accumulation in UCB T cells. What is readily evident from our studies is that the IFNγ mRNA to protein ratio was similar in UCB and AB T cells and it was not altered by any of the treatments used. These results therefore suggests that IFNγ expression in UCB T cells is suppressed at the transcriptional level by an unknown mechanism(s).