The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients: is there correlation between genotype and phenotype?

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most commonly recognized defect of mitochondrial beta-oxidation. It is potentially fatal, but shows a wide clinical spectrum. The aim of the present study was to investigate whether any correlation exists between MCAD genotype and disease phenotype. We determined the prevalence of the 14 known and seven previously unknown non-G985 mutations in 52 families with MCAD deficiency not caused by homozygosity for the prevalent G985 mutation. This showed that none of the non-G985 mutations are prevalent, and led to the identification of both disease- causing mutations in 14 families in whom both mutations had not previously been reported. We then evaluated the severity of the mutations identified in these 14 families. Using expression of mutant MCAD in Escherichia coli with or without co-overexpression of the molecular chaperonins GroESL we showed that five of the missense mutations affect the folding and/or stability of the protein, and that the residual enzyme activity of some of them could be modulated to a different extent depending on the amounts of available chaperonins. Thus, some of the missense mutations may result in relatively high levels of residual enzyme activity, whereas the mutations leading to premature stop codons will result in no residual enzyme activity. By correlating the observed types of mutations identified to the clinical/biochemical data in the 14 patients in whom we identified both disease-causing mutations, we show that a genotype/phenotype correlation in MCAD deficiency is not straightforward. Different mutations may contribute with different susceptibilities for disease precipitation, when the patient is subjected to metabolic stress, but other genetic and environmental factors may play an equally important role.      

Elevated nocturnal blood pressure assessed by ambulatory automatic monitoring during a stay at high altitude

The aim of this study was to explore, in healthy children, the arterial blood pressure response to a 3-week stay at high altitude (4200 m). An auscultatory automatic ambulatory pressuremeter was used to avoid undue environmental influence on the measurement. The blood pressure was monitored three times in a group of ten boys, aged 10.5 (CI 0.9 years): at sea level (control values), at an altitude of 2100 m after at least 24 h of acclimatization and after at least 24 h at 4200 m altitude. Each period of monitoring extended over 24 h with 10-min intervals between successive measurements. Arterial blood pressure was evaluated separately for the night and day periods. Nocturnal recordings revealed an increase with altitude in systolic as well as in the diastolic blood pressure. Because of the technique used to gather data, this is thought to have represented an independent effect of altitude without interference from the medical environment or diurnal activity.     

Gamma-tubulin during the differentiation of spermatozoa in various mammals and man

The distribution of gamma-tubulin as a marker of microtubule organizing centres (MTOC) was studied during spermiogenesis in rodents and in rabbit, monkey and man. A polyclonal antibody directed against human gamma-tubulin was used both for indirect immunofluorescence (IIF) and post-embedding immunogold procedures. In all species, gamma-tubulin was detected in the proximal and distal centrioles of round spermatids. In elongating spermatids, gamma-tubulin was predominantly found in the pericentriolar material (PCM) of both centrioles and particularly around the adjunct of the proximal centriole. At this level, some labelling was also associated with manchette microtubules, but other parts of the manchette and the nuclear ring were never labelled. We propose a role for distal centriole gamma-tubulin in axoneme nucleation and centriolar adjunct gamma-tubulin in manchette nucleation. The disappearance of gamma-tubulin in mature spermatozoa indicates that sperm aster nucleation should be dependent on oocyte gamma-tubulin. Remnants of gamma-tubulin in some human spermatozoa suggest that paternal gamma-tubulin also could contribute to sperm aster formation.      

Postoperative urinary retention after inguinal hernia repair: a single institution experience

Purpose

Inguinal hernia repair is a common general surgery procedure with low morbidity. However, postoperative urinary retention (PUR) occurs in up to 22% of patients, resulting in further extraneous treatments.This single institution series investigates whether patient comorbidities, surgical approaches, and anesthesia methods are associated with developing PUR after inguinal hernia repairs.

Methods

This is a single institution retrospective review of inguinal hernia from 2012 to 2015. PUR was defined as patients without a postoperative urinary catheter who subsequently required bladder decompression due to an inability to void. Univariate and multivariate logistic regressions were performed to quantify the associations between patient, surgical, and anesthetic factors with PUR. Stratification analysis was conducted at age of 50 years.

Results

445 patients were included (42.9% laparoscopic and 57.1% open). Overall rate of PUR was 11.2% (12% laparoscopic, 10.6% open, and p = 0.64). In univariate analysis, PUR was significantly associated with patient age >50 and history of benign prostatic hyperplasia (BPH). Risk stratification for age >50 revealed in this cohort a 2.49 times increased PUR risk with lack of intraoperative bladder decompression (p = 0.013).

Conclusions

At our institution, we found that patient age, history of BPH, and bilateral repair were associated with PUR after inguinal hernia repair. No association was found with PUR and laparoscopic vs open approach. Older males may be at higher risk without intraoperative bladder decompression, and therefore, catheter placement should be considered in this population, regardless of surgical approach.

     

Vaccine Safety Datalink project: a new tool for improving vaccine safety monitoring in the United States. The Vaccine Safety Datalink Team

OBJECTIVE: To fill the large "gaps and limitations" in current scientific knowledge of rare vaccine adverse events identified in recent reviews of the Institute of Medicine. METHODS: Computerized information on immunization, medical outcomes, and potential confounders on more than 500 000 children 0 to 6 years of age is linked annually at several health maintenance organizations to create a large cohort for multiple epidemiologic studies of vaccine safety. RESULTS: Analysis of 3 years of follow-up data shows that 549 488 doses of diphtheria-tetanus-pertussis (DTP) and 310 618 doses of measles-mumps-rubella (MMR) vaccines have been administered to children in the study cohort. Analyses for associations between vaccines and 34 medical outcomes are underway. Screening of automated data shows that seizures are associated with receipt of DTP on the same day (relative risk [RR], 2.1; 95% confidence interval [CI], 1.1 to 4.0) and 8 to 14 days after receipt of MMR (RR, 3.0; 95% CI, 2.1 to 4.2). The diversity of vaccination exposures in this large cohort permits us to show that an apparent association of seizures 8 to 14 days after Haemophilus influenzae type b vaccine (RR, 1.6; 95% CI, 1.2 to 2.1) was attributable to confounding by simultaneous MMR vaccination; the association disappears with appropriate adjustment (RR, 1.0; 95% CI, 0.7 to 1.4). CONCLUSION: Preliminary design, data collection, and analytic capability of the Vaccine Safety Datalink project has been validated by replication of previous known associations between seizures and DTP and MMR vaccines. The diversity in vaccine administration schedules permits potential disentangling of effects of simultaneous and combined vaccinations. The project provides a model of public health-managed care collaborations in addition to an excellent infrastructure for safety and other studies of vaccines.     

Body temperature regulation in the newborn infant: interaction with sleep and clinical implications

Thermoregulation in newborn infant differs from that of adult. Comparisons between sleep stages show that, during rapid eye movements (REM) sleep, the impairment of thermoregulatory responses in adult is not observed in newborn. Both behavioral and autonomic temperature regulations are always operative in the range of air temperatures usually imposed. The interaction between sleep and thermoregulation seems to be less important in newborns than in adults, suggesting that sleep processes are well protected, reducing the probability of occurrence of central dysfunction. According to the model describing thermoregulation during sleep on the basis of changes in the hierarchical dominance of brain structures, either the influence of diencephalic structures is never depressed in REM sleep or the functional autonomy of the rhombencephalon is still relevant in the immature encephalon of the newborn. The thermoregulatory model also allows understanding of inter-individual differences in thermoregulation and levels of thermoneutrality. An attempt has also been made to learn the role of heat stroke in the production of sudden infant death syndrome when body heat loss is hampered.

Résumé

La régulation thermique du nouveau-né est différente de celle de l'adulte. Les comparaisons entre les stades de sommeil montrent que les mécanismes autonomes et comportementaux de la thermorégulation ne sont pas déprimés en sommeil paradoxal, contrairement à l'adulte. Ainsi les interactions entre le sommeil et la thermorégulation semblent moins importantes chez le nouveau-né, ce qui suggère que le sommeil est bien protégé et qu 'un dysfonctionnement du système nerveux central est moins probable. Selon le modèle décrivant les processus thermorégulateurs selon une hiérarchie de dominances fonctionnelles de structures cérébrales, variable selon le stade de sommeil, il semble que l'influence diencéphalique persiste au cours du sommeil paradoxal du nouveau-né ou que l'autonomie fonctionnelle du rhombencéphale reste intacte dans le cerveau en maturation. Le modèle des dominances fonctionnelles hiérarchiques permet d'expliquer les différences interindividuelles de températures de neutralité et de réponse thermorégulatrice au chaud et au froid. Cette revue de la littérature tente également de montrer les influences du stress thermique sur la mort subite du nourrisson lorsque les pertes de chaleur de l'enfant sont réduites.     

Fos expression in the cat brainstem after unilateral vestibular neurectomy

Immediate early genes are generally expressed in response to sensory stimulation or deprivation and can be used for mapping brain functional activity and studying the molecular events underlying CNS plasticity. We immunohistochemically investigated Fos protein induction in the cat brainstem after unilateral vestibular neurectomy (UVN), with special reference to the vestibular nuclei (VN) and related structures. Fos-like immunoreactivity was analyzed at 2, 8, and 24 h, and 1 and 3 weeks after UVN. Data from these subgroups of cats were quantified in light microscopy and compared to those recorded in control and sham-operated animals submitted to anesthesia and anesthesia plus surgery, respectively. Results showed a very low level of Fos expression in the control and sham conditions. By contrast, Fos was consistently induced in the UVN cats. Asymmetrical labeling was found in the medial, inferior, and superior VN (ipsilateral predominance) and in the prepositus hypoglossi (PH) nuclei and the β subnuclei of the inferior olive (βIO) (contralateral predominance). Symmetrical staining was observed in the autonomic, tegmentum pontine, pontine gray, locus coeruleus and other reticular-related nuclei. As a rule, Fos expression peaked early (2 h) and declined progressively. However, some brainstem structures including the ipsilateral inferior VN and the bilateral pontine gray nuclei displayed a second peak of Fos expression (24 h–1 week). By comparing these data to the behavioral recovery process, we conclude that the early Fos expression likely reflects the activation of neural pathways in response to UVN whereas the delayed Fos expression might underlie long-term plastic changes involved in the recovery process.     

Diffusion imaging in asymptomatic focal vasospasm. Apropos of a case

We report a case of an asymptomatic vasospasm with a focal, reversible apparent diffusion coefficient (ADC) decrease after a middle cerebral artery aneurysm rupture. This isolated decrease of ADC has not yet been reported in this pathological situation. It could be interesting to predict the risk of ischemic delayed complications of vasospasm.