Argininosuccinate lyase in enterocytes protects from development of necrotizing enterocolitis.

Necrotizing enterocolitis (NEC), the most common neonatal gastrointestinal emergency, results in significant mortality and morbidity, yet its pathogenesis remains unclear. Argininosuccinate lyase (ASL) is the only enzyme in mammals that is capable of synthesizing arginine. Arginine has several homeostatic roles in the gut and its deficiency has been associated with NEC. Because enterocytes are the primary sites of arginine synthesis in neonatal mammals, we evaluated the consequences of disruption of arginine synthesis in the enterocytes on the pathogenesis of NEC. We devised a novel approach to study the role of enterocyte-derived ASL in NEC by generating and characterizing a mouse model with enterocyte-specific deletion of Asl (Asl(flox/flox); VillinCre(tg/+), or CKO). We hypothesized that the presence of ASL in a cell-specific manner in the enterocytes is protective in the pathogenesis of NEC. Loss of ASL in enterocytes resulted in an increased incidence of NEC that was associated with a proinflammatory state and increased enterocyte apoptosis. Knockdown of ASL in intestinal epithelial cell lines resulted in decreased migration in response to lipopolysaccharide. Our results show that enterocyte-derived ASL has a protective role in NEC.

The right to ignore genetic status of late onset genetic disease in the genomic era; Prenatal testing for Huntington disease as a paradigm.

During the last decade, the field of human genome research has gone through a phase of rapid discovery that has provided scientists and physicians with a wide variety of research tools that are applicable to important medical issues. We describe a true case of familial Huntington disease (HD) in which we modified personal details to protect patient's privacy, where the proband at risk preferred not to know his disease status but wanted to know the status in his unborn child. Once we found the father to be negative, the case raised an important ethical question regarding the management of this as well as future pregnancies. This article discusses the arguments for and against the right not to know of one's carrier status, as well as professional obligations in the context of withholding unwanted information that may have direct implications not only for the patient himself but also for other family members. HD has served as a model for many other adult onset genetic diseases in terms of carrier testing guidelines. Hence, we feel it is time to revisit the issue of prenatal testing for HD and consider updating the current recommendations regarding the patient's right to "genetic ignorance", or the right not to know genetic information.

Mosaic deletion 11p13 in a child with dopamine beta-hydroxylase deficiency--case report and review of the literature.

Dopamine beta-hydroxylase (DBH) deficiency is characterized by a lack of sympathetic noradrenergic function. Affected individuals exhibit profound deficits in autonomic regulation of cardiovascular function. The diagnosis of DBH deficiency is based on clinical findings, biochemical studies, and sequencing of DBH gene. We report here the characterization of a mosaic cytogenetic abnormality detected by array-CGH in a 16-year-old female with primary DBH deficiency together with dysmorphic features. These features could not be explained by DBH deficiency leading to further investigation. Karyotype was reported normal (46,XX), while a targeted genomic array-CGH revealed a mosaic loss for a segment of at least 1 Mb across 11p13. This segmental loss included the PAX6 and WT1 genes within the WAGR syndrome critical region. Interestingly, the derivative chromosome 11 was observed only in about 28% of cells analyzed. Utilizing a genome-wide oligonucleotide-based array, the deletion segment was estimated to encompass a segment of approximately 10 Mb. Mosaic deletions of 11p13 in WAGR are extremely uncommon. In this case it is distinctly possible that the patient's bilateral iris colobomata might be a manifestation, albeit abbreviated, of the haploinsufficiency for PAX6. This case highlights the importance of cytogenetic analysis when a mutation alone cannot account for the complete phenotype. It also emphasizes the enhanced ability of high-resolution array-CGH techniques in accurately detecting subtle rearrangements in a mosaic form. Finally, it demonstrates the possible phenotypic effects of low-level PAX6 haploinsufficiency in a dosage-sensitive manner.

MtDNA mutation pattern in tumors and human evolution are shaped by similar selective constraints.

Multiple human mutational landscapes of normal and cancer conditions are currently available. However, while the unique mutational patterns of tumors have been extensively studied, little attention has been paid to similarities between malignant and normal conditions. Here we compared the pattern of mutations in the mitochondrial genomes (mtDNAs) of cancer (98 sequences) and natural populations (2400 sequences). De novo mtDNA mutations in cancer preferentially colocalized with ancient variants in human phylogeny. A significant portion of the cancer mutations was organized in recurrent combinations (COMs), reaching a length of seven mutations, which also colocalized with ancient variants. Thus, by analyzing similarities rather than differences in patterns of mtDNA mutations in tumor and human evolution, we discovered evidence for similar selective constraints, suggesting a functional potential for these mutations.

Computational model of the cockroach escape behavior: winner and losers in a population code.

I present a comprehensive biologically oriented computational model to account for the escape response of the cockroach on the ground. This model is an expansion of previous work that accounted only for discriminating left from right wind directions [Ezrachi et al. (1999) Biol Cybern 81: 89-99]. The model is composed of computational elements describing the biological processes taking place in the various neurons and includes input which emulates empirical data. With this model it is possible to obtain escape behavior that resembles natural behavior. The model is used to address an ongoing debate as to whether the cockroach's turn direction is determined by computations carried out by the entire neuronal population (PC) or rather by a "winner-take-all" (WTA) mechanism. I suggest that the computation mechanism that underlies the cockroach escape response is composed of both PC and WTA principles. Based on the properties of the suggested new mechanism I denote it a "Darwinian population code."

Relationship of core self-evaluations to goal setting, motivation, and performance.

A newly developed personality taxonomy suggests that self-esteem, locus of control, generalized self-efficacy, and neuroticism form a broad personality trait termed core self-evaluations. The authors hypothesized that this broad trait is related to motivation and performance. To test this hypothesis, 3 studies were conducted. Study 1 showed that the 4 dispositions loaded on 1 higher order factor. Study 2 demonstrated that the higher order trait was related to task motivation and performance in a laboratory setting. Study 3 showed that the core trait was related to task activity, productivity as measured by sales volume, and the rated performance of insurance agents. Results also revealed that the core self-evaluations trait was related to goal-setting behavior. In addition, when the 4 core traits were investigated as 1 nomological network, they proved to be more consistent predictors of job behaviors than when used in isolation.

Atrial tachycardia as the presenting sign of a left atrial appendage aneurysm.

A patient presented with atrial tachycardia. The work-up, guided by the tachycardia morphology, led to the diagnosis of left atrial appendage aneurysm. Surgical removal of the atrial appendage resulted in cure of the tachycardia and associated symptoms.

Upper posterior mediastinal tumor supplied by an atrial branch of the left circumflex artery.

We report a case of a 39-year-old woman with an upper posterior mediastinal tumor. The tumor was demonstrated by echocardiography and further defined by computerized tomography and magnetic resonance imaging. The tumor was fed by a large atrial branch of the left circumflex artery. Because of its location (adjacent to large vessels), it could not be resected by surgery.

Reported level of pain of upper extremities related to multi-factorial workloads among office workers during and after work hours.

OBJECTIVES: This research compared the level of reported pain between women workers with high workload (main work involved typing) and women workers with low workload (various office work where typing was not the main task). The research examined the relationship between reported pain of upper extremities (UE) and the following variables: physical strain exerted during typing on a computer keyboard, extra-work strain on UE, bio-demographic variables, psychosocial variables, and ergonomic variables. STUDY DESIGN: Participants were 60 women who worked in offices, divided into two groups. The index group included women whose main work involved typing (high workload: M=6.16 h of typing per day), and the control group did various office work where typing was not the main task (low workload: M=3.23 h of typing per day). The level of pain, physical strain, and data concerning bio-demographic variables, psychosocial variables and ergonomic variables was assessed by a self-reported questionnaire. RESULTS: The results suggested that there was a significant difference between workers with high and low typing workloads. Workers with higher typing load reported higher levels of pain. There was a significant positive correlation between level of reports of pain and levels of physical overload at work, and extra-work strain on UE both among workers with high and low workloads. It was also found that levels of pain correlated significantly with bio-demographic variables (age and number of children) and psychosocial variables (managerial responsibilities) among low workload workers only. CONCLUSIONS: The research on pain of UE indicates that pain may be affected by a multi-factorial nature of a work-related environment which includes physical strain exerted during typing on a computer keyboard, extra-work strain on UE, bio-demographic variables and psychosocial variables.

Effects of auditory/visual and lexical/non-lexical comparisons on event-related potentials in a memory-scanning task.

A late parietal positivity (P3) and behavioural measures were studied during performance of a two-item memory-scanning task. Stimuli were digits presented as memorized items in one modality (auditory or visual) while the following probe, also a digit, was presented in the same or the other modality. In a separate set of experiments, P3 and behaviour were similarly studied using only visual stimuli that were either lexical (digits) or non-lexical (novel fonts with the same contours as the digits) to which subjects assigned numerical values. Reaction times (RTs) and P3 latencies were prolonged to non-lexical compared to lexical stimuli. Although RTs were longer to auditory than to visual stimuli, P3 latencies to memorized items were prolonged in response to visually compared to auditorily presented memorized items, and were further prolonged when preceding visual probes. P3 amplitudes were smaller to auditory than to visual stimuli, and were smaller for the second memorized item when lexical/non-lexical comparisons were involved. The most striking finding was scalp distribution variations indicating changes in relative contributions of brain structures involved in processing memorized items, according to the probes that followed. These findings are compatible, in general, with a phonological memorization, but they suggest that the process is modified by memorizing the item in the same terms as the expected probe that follows.

[Acute fungal endocarditis due to Trichosporon beigelli].

We report a 59-year-old woman with acute fungal endocarditis of a prosthetic valve caused by the endogenic organism, Trichosporon beigelli. This slowly developing disease mainly effects drug addicts who use intravenous narcotics. In nonaddicts it is rare, with mortality as high as 50%. There are only sporadic reports of T. beigelli as a complication long after open heart surgery. The ongoing infection is undetected for even years after the primary infection, due to its prolonged latent phase. We present the difficulties of diagnosis, and of treating the disease with a combination of surgery and of long-term chemotherapy.

The effect of lead exposure on target detection and memory scanning differs.

Visual event-related potentials were measured in lead-exposed and control subjects, while they were performing a target detection as well as a memory scanning task. Blood lead and urinary delta-aminolevulinic acid (delta-ALA) were determined in samples taken on the same day. Lead exposure did not affect the memory scanning P300 latency, but it did delay the target detection P300 latency in a dose-dependent fashion. The P300 amplitude of lead-exposed subjects was significantly reduced for both tasks, but not in a dose-dependent fashion. The target detection, but not the memory scanning, P300 latency correlated with urinary delta-ALA. No correlation of P300 with age was found, even though the subjects ranged from 20 to 60 years of age. The difference in the effect of lead exposure on the target detection and memory scanning P300 adds to the evidence that the P300 for the two tasks arises from different generators. The absence of a correlation of the measured P300 latency for each task with age in the present study raises the possibility that this extensively reported observation might, in part, be due to inappropriately matched younger and older subjects. This study indicates that evaluation of subjects exposed to toxic substances can increase our basic understanding of evoked potentials, as well as providing evidence of their toxic manifestations.

Lexicality and modality effects on evoked potentials in a memory-scanning task.

Event-related potentials, as well as reaction times and performance accuracies, were recorded from normal young adults during the performance of a memory-scanning task, in response to the first and second items of the memorized set and to the probe. Stimuli included computer-generated digits, presented by earphones as speech (lexical auditory) or on a screen (lexical visual), meaningless voices (nonlexical auditory) with precisely the same frequency contents as the digits, or meaningless shapes with the very same colors and contours as the digits (nonlexical visual). The evoked potentials' late positivity (P3) to memorized items was earlier to auditory than to visual stimuli. P3 to memorized items and to probes was earlier to lexical than to nonlexical stimuli. P3 amplitudes to both memorized items and probes were smaller with auditory stimuli. Assuming P3 latency to reflect processing time and amplitude to reflect attentional allocation (effort) to the task-relevant stimuli, the results support phonological representations during processing in short-term memory, with nonauditory and nonlexical stimuli requiring more processing time and effort. A significant electrode x modality x lexicality interaction may suggest that stimuli of different modalities and lexicality involve variations in the relative contributions of the brain structures involved in their processing.

Auditory event-related potentials among dyslexic and normal-reading children: 3CLT and midline comparisons.

Event-related potentials (ERP's) to verbal and non-verbal auditory stimuli were recorded from normal-reading and from dyslexic children while performing a target-detection task ("oddball" paradigm). Two methods of analysis were used: (1) Peak latency and amplitude measures of P3 recorded from 3 midline electrodes; (2) P3 apex latency, amplitude and orientation in the three-channel Lissajous' trajectory (3CLT) derived from 3 orthogonal pairs of electrodes. P3 peak amplitude was significantly attenuated in dyslexic children compared to normal-reading children and in response to verbal stimuli compared to non-verbal stimuli. P3 apex latencies were longer and apex amplitudes larger in response to non-verbal compared to verbal stimuli. The most striking finding involved P3 apex orientation, which pointed in an upward-posterior direction with a slight tilt to the left among normal readers, but with a tilt to the right in dyslexics.

Erythema nodosum in the Negev area--a survey of 50 patients.

Fifty patients in the Negev area with erythema nodosum (EN) were studied retrospectively. The clinical picture and demographic characteristics did not differ markedly from those in the literature. In contrast to most European studies but like those from Egypt, we found streptococcal pharyngitis to be the major cause of EN. Conspicuously, sarcoidosis is a rare cause of EN in the Negev. The low incidence of EN in the Negev--2 cases/100,000 people per year--as opposed to Europe--14 cases/100,000 people per year--is hardly explained by the low occurrence of sarcoidosis in Israel. Other factors, unknown at present, may account for this low incidence.

Controlled destruction and temperature distributions in biological tissues subjected to monoactive electrocoagulation.

An analysis of the temperature fields developed in a biological tissue undergoing a monoactive electrical coagulating process is presented, including thermal recovery following prolonged heating. The analysis is performed for the passage of alternating current and assumes a homogeneous and isotropic tissue model which is uniformly perfused by blood at arterial temperature. Solution for the one-dimensional spherical geometry is obtained by a Laplace transform and numerical integrations. Results obtained indicate the major role which blood perfusion plays in determining the effects of the coagulating process; tissue temperatures and depth of destruction are drastically reduced as blood perfusion increases. Metabolic heat generation rate is found to have negligible effects on tissue temperatures whereas electrode thermal inertia affects temperature levels appreciably. However, electrodes employed in practice would have a low thermal inertia which might be regarded as zero for all practical purposes. It is also found that the depth of tissue destruction is almost directly proportional to the electrical power and duration of application. To avoid excessively high temperatures and charring, it would be advantageous to reduce power and increase the time of application. Results of this study should be regarded as a first approximation to the rather complex phenomena associated with electrocoagulation. They may, nevertheless, serve as preliminary guidelines to practicing surgeons applying this technique.

Possible errors in quantitative determination of phenylalanine ammonia-lyase activity by spectrophotometric methods.

A possible error in spectrophotometric determination of cinnamate, the product of phenylalanine ammonia-lyase activity, using nonpurified protein extracts has been shown.Under optimal conditions for phenylalanine ammonia-lyase activity, with borate buffer and in the presence of alpha-keto acids, phenylpyruvate is produced and its enol tautomer-borate complex formed, strongly absorbs at 290 nanometers.