Novel bioequivalence approach for narrow therapeutic index drugs.

Narrow therapeutic index drugs are defined as those drugs where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent or significant disability or incapacity. The US Food and Drug Administration proposes that the bioequivalence of narrow therapeutic index drugs be determined using a scaling approach with a four-way, fully replicated, crossover design study in healthy subjects that permits the simultaneous equivalence comparison of the mean and within-subject variability of the test and reference products. The proposed bioequivalence limits for narrow therapeutic index drugs of 90.00%-111.11% would be scaled based on the within-subject variability of the reference product. The proposed study design and data analysis should provide greater assurance of therapeutic equivalence of narrow therapeutic index drug products.

Algerian medical teachers' research output and its determinants during the 2000-2009 decade.

BACKGROUND: Publications are the primary output of scientific research. We conducted a national study to quantify Algerian medical teachers' research output and identify its determinants during the 2000-2009 decade. METHODS: The American Medline database and the French Pascal database were used. A publication was eligible only if the lead author was an Algerian medical teacher (in medicine, pharmacy, or dentistry) working in Algeria. The same questionnaire was completed by cases (teachers who were first authors of an original article during the study period) and randomly selected controls. Logistic regression analysis was used to identify factors related to research output. RESULTS: A total of 79 original articles (42.2% of publications) were retrieved, a quarter of which were listed in Pascal alone. The publication rate was 2.6 original articles per 1000 teachers per year. The journals that published these original articles had a median impact factor of 0.83. The ability to publish an original article was 4.3 times higher if the teacher had undergone training in biostatistics and/or epidemiology (adjusted odds ratio [aOR]=4.31, 95% confidence interval [CI]: 1.79-10.38). A promotion evaluation grid that did not encourage writing (aOR=3.44, 95% CI: 1.42-8.33), a doctoral thesis, seniority, foreign collaboration, and English language proficiency were found to be associated with publication output. CONCLUSIONS: Algerian medical teachers' research output was particularly low. Replacing the current promotion grid with a grid that promotes writing, developing abilities to read and write articles and developing English language proficiency are likely to improve this situation.

Child homicide and neglect in France: 1991-2008.

The aim of this study is to investigate epidemiological characteristics of the victims and the offenders in children homicide cases and to propose preventive measures. We retrospectively investigated homicides and deaths by neglect involving children aged 15 or less, which have been autopsied in the Department of Pathology and Legal Medicine of the Raymond Poincaré Hospital, Garches, France, during the 18-year period from 1991 to 2008. Cases included were analyzed for victims' age and gender, victim-assailant's relation, death cause and scenery, and offender's motivation. For the purposes of the study, victims were divided into four age groups: new born; infants (1-23 months); young children (2-5 years); and children (6-15 years). During the study period, 70 victims of homicide or fatal neglect were identified, which equates to a child homicide prevalence of 0.56 per 100,000 children per year. Slightly more than half of the victims (51.4%) were less than 1 year old. Neonaticide prevalence was 0.12 per 100,000 births with an equal distribution between genders. Neonates were most likely to be killed by their mothers while fathers were the most frequent assailants in both infants and children groups. Stepparents were involved in only one case. Familicide cases where children and spouses are killed were perpetrated only by fathers. The leading cause of death was blunt trauma (especially head trauma). In the neonaticide group, half of the victims died from passive neglect whereas gunshots were predominant in the children groups.

Post-traumatic dissection of the internal carotid artery associated with ipsilateral facial nerve paralysis: diagnostic and forensic issues.

Traumatic internal carotid artery dissection may result from a direct blow to anterolateral aspect of the neck, or an extreme extension and rotation of the neck. Traumas involved are variable ranging from high speed motor vehicle accident to trivial traumas. The most frequent presentations of carotid artery dissection are stroke, Hörner syndrome, and paralysis of a cranial nerve. Time of ischemic signs onset is very variable too, diverging from immediate to several months delay. We report the case of a 60-year-old woman, who was assaulted by a young man. Immediately, she complained of headache and posterior cervical pain. Three months later she developed a left hemifacial paralysis. MRI and MRA showed a dissection of the left internal carotid artery. The causal relationship between the trauma and the carotid artery dissection as well as forensic issues are discussed.

Gunshot fatalities: correlation between post-mortem multi-slice computed tomography and autopsy findings: a 30-months retrospective study.

In this study we compared retrospectively the autopsy and the CT-scan findings in 47 gunshot victims (96 wounds) in order to assess the accuracy of the two methods in injury and ballistic diagnoses. Firing distance was determined in 46 wounds (47.9%). Firing range was determined by autopsy alone in 37 cases (80.5%) and by CT-scan alone in three cases (6.5%). In the six remaining cases (13%), autopsy and CT-scan reports concluded both to the same firing range. Entrance wounds were detected concordantly by both CT-scan and autopsy in 63 of the 91 penetrating wounds (69.2%). Exit wounds were present in 69 shots. They were concordantly detected by autopsy and CT-scan in 36 cases (52.2%). It was possible at CT imaging to determine the track of the bullet in up to 62 wounds (72.1%). CT-scan was superior to autopsy in determining two items: face fractures and pneumencephalon. CT scan was of limited value in demonstrating skull base fractures and contusions of the brain. There was good correspondence in demonstrating subarachnoid hemorrhage. CT-scan was accurate to demonstrate presence of gas, either in the pleural cavity (pneumothorax) or in the vessels' lumen (air embolism). Both autopsy and CT-scan were concordant in demonstrating thoracic well injuries, heart lacerations and intra thoracic hemorrhage. CT-scan was far below autopsy in detecting solid organs injuries except for kidneys. The present survey shows that CT-scan is second to none in demonstrating features as pneumencephalon, facial fractures, midline shifts, air embolism, pneumothorax, and pelvic bones fractures. It may contribute to determine the firing range in cases of contact-range and of intermediate range though the firing range assessment remains beyond post-mortem imaging possibilities, at least at the current state of knowledge.

Suicidal and criminal immolations: an 18-year study and review of the literature.

We aimed to examine our autopsy data in order to analyze epidemiological and injury characteristics in criminal and suicidal immolation cases. During the 18-year period, we recorded 29 suicides and three homicides due to fire burns. In suicide group there was a majority of men (gender ratio: 3.1:1) and the mean age was 42.8 years (range 20-72). In the homicide group, the victims were two men and one woman. Their mean age was 44 years (range 39-54). The location of self-immolation was mostly the deceased's car or home and most suicides happened during the evening and the night. The main frequent motives for self-immolation were affective problems, financial problems, or both. One or several flammable fluids, usually petrol or alcohol, were used in 18 suicide cases and in one homicide. The median total body surface area burnt was 79.3% (range 10-100%) in self inflicted group and 83.3% (range 50-100%) in assault group. The sole of the feet was spared in all suicide cases. Blood CO-Hb level was measured in 27 self-immolation cases. It ranged between 1% and 10% in 11 cases and was superior to 10% in the remaining. Twenty-three self-immolation victims and one homicide victim had soot in their respiratory tracts. Soot in the respiratory tracts was associated to soot in the digestive tracts in six cases. Alcohol and drugs intoxication played a minor role. In six cases, the victim associated self incineration with one or more other methods of suicide (complex suicides). The presence of associated trauma raises the problem of vitality and interpretation of the lesions in determining the manner of death.

Transcription patterning of uncoupled proliferation and differentiation in myelodysplastic bone marrow with erythroid-focused arrays.

Because abnormal erythroid differentiation is the most common manifestation of the myelodysplastic syndromes (MDS), it was hypothesized that erythroid gene expression may be used to illustrate myelodysplastic transcription patterns. Ten normal bone marrow aspirates (NBM) were first analyzed using an erythroid-focused cDNA array to define steady-state transcription levels. Proliferation and differentiation gene subsets were identified by statistically significant differences between NBM and erythroleukemia gene expression. Next, cDNAs from 5 separate MDS aspirates were studied: refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation (RAEB-T), and RAEB-T/secondary MDS. A distinct pattern of significantly increased proliferation-associated and reduced differentiation-associated gene activity was established for MDS.

Cognitive deficits in children with gelastic seizures and hypothalamic hamartoma.

OBJECTIVE: To characterize the cognitive deficits in children with gelastic seizures and hypothalamic hamartoma and investigate the relationship of seizure severity to cognitive abilities. METHODS: Eight children with gelastic seizures and hypothalamic hamartoma completed a neuropsychological battery of standardized and age-normed tests, including the Woodcock-Johnson Psycho-Educational Battery-Revised: Tests of Cognitive Ability, Peabody Picture Vocabulary Test-III, and initial-letter word fluency measure. RESULTS: All children displayed cognitive deficits, ranging from mild to severe. Gelastic/complex partial seizure severity was correlated with broad cognitive ability standard scores (r = -0.79; r2 = 0.63; (F[1,6] = 10.28; p = 0.018]. Frequency of gelastic/complex partial seizures was also correlated with broad cognitive ability standard scores (r = -0.72; r2 = 0.52; F[1,6] = 6.44; p = 0.044). Significant intracognitive standard score differences were found, with relative weaknesses in long-term retrieval (mean = 64.1; SD = 13.3) and processing speed (mean = 67.7; SD = 21.6) and a relative strength in visual processing (mean = 97.6; SD = 12.8). Performance in visual processing differed from performance in long-term retrieval (p = 0.009) and processing speed (p = 0.029). CONCLUSION: These findings are consistent with cognitive functions and affective/emotional states associated with conduction pathways of the hypothalamus involving cortical association areas and amygdala and hippocampal formation. These abnormalities can account for the prominent deficit found in integrating information in the processing of memories.

The clinical utility of fetal cell sorting to determine prenatally fetal E/e or e/e Rh genotype from peripheral maternal blood.

OBJECTIVE: This study was undertaken to determine the fetal E/e or e/e Rh genotype prenatally from peripheral maternal blood by examining sorted fetal cells from alloimmunized and nonalloimmunized pregnancies. STUDY DESIGN: Eighteen maternal peripheral venous blood samples were obtained before amniocentesis from 15 pregnant women who were homozygous for the e allele. Five were not alloimmunized and 10 were alloimmunized. The mononuclear cell layer was isolated from the maternal blood and enriched for fetal nucleated red blood cells by flow cytometry with monoclonal antibodies to CD36 or CD71 and to glycophorin A. Eight samples were treated with CD45 monoclonal antibody-coated magnetic beads before they were sorted to deplete the maternal sample of leukocytes (CD45(+) cells). We defined the positive fetal cell fractions as the monoclonal antibody positive-sorted cells derived from the maternal samples. These included sorted cells that were CD36(+)/glycophorin A(+), CD71(+)/glycophorin A(+) and CD45(-) cells that were sorted to become CD45(-)/CD36(+)/glycophorin A(+) or CD45(-)/CD71(+)/glycophorin A(+). The negative fractions were the cells that were negative for either CD36/glycophorin A or CD71/glycophorin A or were the CD45(+) cells. Deoxyribonucleic acid was isolated from all fractions and amplified by polymerase chain reaction with allele-specific primers for the E or e Rh genes. Gel electrophoresis was performed to detect fetal E/e or e/e Rh genotype. The fetal E/e or e/e Rh genotype was confirmed by serologic and deoxyribonucleic acid testing. The accuracy of E/e or e/e Rh genotype determination from the positive cell fractions was compared with that of E/e or e/e Rh genotype determination from the negative fractions. RESULTS: Fetal E/e or e/e Rh genotype was determined correctly in 17 of 18 of the fetal cell enriched positive fractions (94%). Fetal E/e or e/e Rh genotype was determined correctly in 11 of 14 of the maternal samples in the negative unselected cell fractions (79%). Fetal E/e or e/e Rh genotype was determined correctly in 15 of 16 sample fractions that underwent magnetic bead separation with CD45 and were subsequently sorted into positive and negative fractions (94%). Fetal E/e or e/e Rh genotype was determined correctly in 13 of 13 of the samples obtained from the alloimmunized pregnancies (100%). CONCLUSIONS: The use of monoclonal antibodies for cell sorting or for magnetic separation predicted fetal E/e or e/e Rh genotype from peripheral maternal blood correctly in as many as 100% of alloimmunized pregnancies. Thus noninvasive fetal E/e or e/e Rh genotyping can be performed by polymerase chain reaction amplification of the rare fetal cells in maternal blood. The correct prediction of fetal E/e or e/e Rh genotype from the cell population not selected by the monoclonal antibodies suggests that there are fetal cell types other than fetal nucleated erythrocytes that can also be used as a source of fetal deoxyribonucleic acid for noninvasive genetic diagnosis. Improved technology may provide methods less laborious than cell sorting to accurately determine fetal Rh type from different fetal cell types that circulate in maternal blood.

Language disturbances in corticobasal degeneration.

To characterize the language deficits in corticobasal degeneration (CBD) and their relation to neuroradiologic findings, the authors administered a standardized battery of neurobehavioral tests and performed MRI studies on 15 patients with CBD. Eight patients (53%) had classifiable aphasias, including anomic, Broca's and transcortical motor aphasias. The aphasias were associated primarily with left frontal and parietal cortical damage and subcortical white matter and corpus callosum abnormalities. Our findings demonstrate that language disturbances in CBD are more frequent than previously considered.

Molecular cloning and functional characterization of KCC3, a new K-Cl cotransporter.

We isolated and characterized a novel K-Cl cotransporter, KCC3, from human placenta. The deduced protein contains 1,150 amino acids. KCC3 shares 75-76% identity at the amino acid level with human, pig, rat, and rabbit KCC1 and 67% identity with rat KCC2. KCC3 is 40 and 33% identical to two Caenorhabditis elegans K-Cl cotransporters and approximately 20% identical to other members of the cation-chloride cotransporter family (CCC), two Na-K-Cl cotransporters (NKCC1, NKCC2), and the Na-Cl cotransporter (NCC). Hydropathy analysis indicates a typical KCC topology with 12 transmembrane domains, a large extracellular loop between transmembrane domains 5 and 6 (unique to KCCs), and large NH(2) and COOH termini. KCC3 is predominantly expressed in kidney, heart, and brain, and is also expressed in skeletal muscle, placenta, lung, liver, and pancreas. KCC3 was localized to chromosome 15. KCC3 transiently expressed in human embryonic kidney (HEK)-293 cells fulfilled three criteria for increased expression of K-Cl cotransport: stimulation of cotransport by swelling, treatment with N-ethylmaleimide, or treatment with staurosporine.

Neurally mediated cardiac syncope: autonomic modulation after normal saline infusion.

OBJECTIVES: This study assessed the heart variability response to orthostatic stress during tilt table testing before and after normal saline administration. BACKGROUND: The efficacy of sodium chloride and mineralocortoid in the treatment of neurally mediated cardiac syncope is attributed to intravascular volume expansion; however, their modulation of autonomic nervous system activity has not been evaluated. METHODS: Heart rate variability analysis was performed on 12 adolescents with a history of syncope or presyncope (mean age 15.2+/-0.7 years) during tilt table testing. Subjects were upright 80 degrees for 30 min or until syncope. After normal saline administration, the patient was returned upright for 30 min. Heart rate variability analysis data were analyzed by an autoregression model (Burg method). RESULTS: All subjects reproducibly developed syncope during control tilt table testing; median time to syncope was 9.4+/-2.1 min. After normal saline infusion, none of the subjects developed syncope after 30 min upright. In the control tilt, there was an initial increase followed by a progressive decrease in low frequency power until syncope. Repeat tilt after normal saline administration demonstrates that low frequency power increased but the magnitude of initial change was blunted when compared with control. In addition, low frequency power increased during normal saline tilt sequence compared with the control tilt, during which it decreased. CONCLUSIONS: Normal saline blunted low frequency power stimulation and prevented paradoxical low frequency power (sympathetic) withdrawal. Increasing intravascular volume with normal saline alters autonomic responses that may trigger neurally mediated syncope reflexes.