Bone density in the Asian thalassaemic population: a cross-sectional review.

UNLABELLED: As survival improves in beta-thalassaemia, osteoporosis is emerging as a significant problem. This study examines bone mineral density (BMD) of thalassaemic patients of Asian origin (age range 9.5-24 y) to evaluate the extent of problems in this group and identify potential risk factors. Eleven patients were scanned using dual-energy X-ray absorptiometry. BMD z-scores and the bone mineral apparent density (BMAD) z-scores were calculated, to correct for short stature. All but three patients had lumbar spine BMD and BMAD z-scores below the mean. Three patients had BMAD z-scores more than 2.5 standard deviations below the mean. A negative correlation between age and BMAD was seen, as was an association between endocrine disorders and decreased bone density. CONCLUSION: The data confirm significant reductions in BMD in the Asian thalassaemic population, even after correcting for body size. Further research is needed to identify risk factors and means of prevention.

Incidence and characteristics of fall-related emergency department visits.

OBJECTIVE: Unintentional falls are the leading cause of injury and the second most common cause of unintentional injury deaths in the United States, and place a great burden on EDs. In this study, the objective was to describe the incidence and characteristics of ED visits associated with unintentional falls in the United States. METHODS: The authors performed a secondary analysis on data from the National Center for Health Statistics' National Hospital Ambulatory Medical Care Survey for 1992-1994. An ED visit was defined as fall-related if an ICD-9-CM cause of injury code was reported as E880.0-886.9 or E888. RESULTS: There were an estimated 7,946,000 fall-related ED visits per year, corresponding to an annual rate of 3.1 per 100 persons (95% CI=2.8 to 3.4). Children under 5 years of age comprised the largest proportion of visits (14%). Among those visits coded with respect to place of occurrence, the rate of visits associated with falls occurring at home (1.7/100; 95% CI=1.6 to 1.9) was significantly higher than that associated with falls occurring in all other locations combined (1.1/100; 95% CI=1.0 to 1.2). The mean injury severity score increased significantly with the age of the patient. Fall-related ED visits resulted in an estimated 860,000 hospitalizations, 62% of which involved individuals aged 65 years and older. An estimated $2.45 billion per year was paid for fall-related ED visits. Government sources paid all or part of 41% of visits. CONCLUSIONS: This study reports nationally representative data describing the incidence and characteristics of fall-related ED visits. These data expand what is known about the epidemiology of falls and help to define the burden that fall injuries place on EDs in the United States. The results of this study could serve as a benchmark to evaluate the effectiveness of future fall prevention efforts.

Expression of phenylethanolamine n-methyltransferase in the embryonic rat heart.

Phenylethanolamine N-methyltransferase (PNMT), the final enzyme in the pathway for epinephrine biosynthesis, serves as a marker for tissues and cells producing epinephrine. The present study examines the developmental expression of PNMT in the rat embryo. A transient burst in PNMT mRNA expression begins on embryonic day 9.5 (E9.5), peaks between E10.0 and E11.0, and declines to barely detectable levels by E13.0. Regional localization of PNMT mRNA and enzyme activity demonstrates that PNMT is concentrated in the heart. PNMT has not previously been reported to be expressed at these early stages of development, and its presence in the developing heart suggests that this embryonic tissue may produce epinephrine. Because this catecholamine is known to increase cardiac output and promote the growth of cardiomyocytes, local production of epinephrine by the heart could play an important role in the development of cardiac structure and function.

Pharmacokinetics of computer-controlled alfentanil administration in children undergoing cardiac surgery.

BACKGROUND: Cardiopulmonary bypass (CPB) induces changes in the pharmacokinetics of drugs. The purpose of this study was to model the pharmacokinetics of alfentanil in children undergoing cardiac surgery to provide accurate dosage titration intraoperatively as well as in the postoperative period. METHODS: Fourteen children (aged 3 months to 8 yr) undergoing cardiac surgery with CPB were administered alfentanil via a computer-controlled infusion pump. During surgery, the computer-controlled infusion pump was set to target plasma alfentanil concentrations of 500-2500 micrograms/ml. After surgery, the computer-controlled infusion pump was set to target plasma concentrations of 200-500 micrograms/ml. Parameters for children previously published by Goresky et al. were programmed into the device. Arterial blood samples were taken throughout the infusion. Plasma samples were assayed by radioimmunoassay. Alfentanil pharmacokinetics were estimated using a pooled-data approach with a simple weight-proportional, three-compartment mamillary model with parameters expressed in volumes and clearances as well as a CPB-adjusted, three-compartment model in which the parameters were allowed to change before, during, and after CPB. The accuracy of the three models was compared using cross-validation. RESULTS: Plasma alfentanil concentrations during computer-controlled infusion pump administration exceeded target concentrations for the first 10 min of drug administration, and from 300 min to the end of the study. The median absolute performance error was 33%. Pharmacokinetic modeling estimated a set of parameters for a simple three-compartment model with a median absolute weighted residual of 18.4%. A CPB-adjusted model nominally decreased the median absolute weighted residual to 17.0%. The performance of these models as measured by cross-validation performance was 18.9% median absolute performance error for the simple model and 18.4% median absolute performance error for the CPB-adjusted model. Parameters for the simple three-compartment model are: V1 = 19.2 ml.kg-1; V2 = 99 ml.kg-1; V3 = 2344 ml.kg-1; Cl1 = 2.5 ml.kg-1.min-1; Cl2 = 38 ml.kg-1.min-1; and Cl3 = 15 ml.kg-1.min-1. In the CPB-adjusted model V1, V2, and Cl2 changed with the onset of CPB. After CPB, V1 and Cl2 returned to the initial values, while V2 was described by a third value. CONCLUSIONS: The population pharmacokinetics of alfentanil in children undergoing cardiac surgery were well described by both a simple weight-proportional, three-compartment model and a weight-proportional, CPB-adjusted three-compartment model. Cross-validation estimated an expected median inaccuracy of approximately 18-20% with the estimated models in identical experimental circumstances. The flexible CPB-adjusted pharmacokinetic model could be used for modeling any drug with linear pharmacokinetics given in the context of CPB.

High-frequency jet ventilation in children with the adult respiratory distress syndrome complicated by pulmonary barotrauma.

High-frequency jet ventilation (HFJV) was used in 29 children with severe ARDS complicated by pulmonary barotrauma (PBT). Treatment with HFJV was begun when PBT was progressing over a 24-h period while receiving conventional ventilation (CV). The mean (+/- SD) age was 0.95 +/- 1.21 years (range, 0.03-4 years). The most common diagnosis was viral pneumonia (n = 17); other diagnoses included aspiration pneumonitis (n = 4), bacterial pneumonia (n = 3), multiple trauma (n = 2), and near-drowning (n = 3). The Bunnell Life-Pulse ventilator was used at a rate of 240/min or 300/min, with inspiratory time of 0.02 sec. Twenty children survived (69%). Survivors and nonsurvivors had equal disease severity prior to HFJV as assessed by ventilator settings, alveolar-to-arterial oxygen tension gradient, oxygenation index, and blood gas values. Survivors had spent significantly less time on conventional ventilation prior to HFJV than nonsurvivors, with a mean (+/- SD) of 3.7 +/- 2.1 days vs 9.6 +/- 4.5 days, respectively (P < 0.05). Survivors underwent an average of 4.4 +/- 3.9 days of HFJV, which supported adequate gas exchange with lower airway pressures, and produced resolution or significant improvement in airleak on chest radiograph. In conclusion, we speculate that the application of HFJV early in the course of severe hypoxemic respiratory failure complicated by airleak, allows the reduction of airway pressures, thereby minimizing pulmonary barotrauma and allowing the lung to recover from the underlying insult. Further controlled evaluation of HFJV in this high risk group of patients is warranted.

A controlled trial of aerosolized ribavirin in infants receiving mechanical ventilation for severe respiratory syncytial virus infection.

BACKGROUND: Although the antiviral agent ribavirin improves the course of lower respiratory tract disease in spontaneously breathing infants with respiratory syncytial virus infection, it is not known whether ribavirin can benefit infants with severe respiratory syncytial virus disease who require mechanical ventilation. METHODS: We conducted a randomized, double-blind, placebo-controlled evaluation of ribavirin (20 mg per milliliter) administered continuously in aerosolized form to infants receiving mechanical ventilation for respiratory failure that was caused by documented respiratory syncytial virus infection. RESULTS: Of the 28 infants (mean [+/- SD] age, 1.4 +/- 1.7 months) enrolled, 7 had underlying diseases predisposing them to severe infection (mean age, 3.0 +/- 2.6 months), and 21 were previously normal (mean age, 0.8 +/- 0.9 month). Among the 14 infants who received ribavirin, the mean duration of mechanical ventilation was 4.9 days (as compared with 9.9 days among the 14 who received placebo; P = 0.01), and the mean length of supplemental oxygen use was 8.7 days (as compared with 13.5 days; P = 0.01). The mean length of the hospital stay was 13.3 days after treatment with ribavirin and 15.0 with placebo (P = 0.04). When only the 21 previously normal infants were considered, the mean length of the hospital stay was 9.0 days for the ribavirin recipients and 15.3 days for those who received placebo (P = 0.005). CONCLUSIONS: In infants who require mechanical ventilation because of severe respiratory syncytial virus infection, treatment with aerosolized ribavirin decreases the duration of mechanical ventilation, oxygen treatment, and the hospital stay.

Development of rabbit hippocampus: anatomy.

The postnatal development of the CA1 region of rabbit hippocampus was studied using a variety of light and electron microscopic (EM) techniques. Nissl and Golgi stains showed high cellular density, small cell soma area, and sparse dendritic branching in neurons of immature animals (less than 1 week old); dendritic spines were also relatively infrequent during this period. Cell branching and spine frequency reached near-adult levels by 3 weeks, with the major area of hippocampal expansion seen in the apical dendritic layer. EM examination of synapse patterns was made using osmicated and E-PTA-treated tissue. Both techniques showed that the vast majority of synapses in immature animals (less than 2 weeks old) occurred in the dendritic region and were of the asymmetric type. Axosomatic synapses became less rare by 2 weeks; they were usually of the symmetric synapse type. The pattern of synaptic contacts in immature hippocampus resembled the mature pattern by 3-4 weeks. These data suggest a relatively late development of inhibitory postsynaptic potentials in CA1 pyramidal cells.

A critical period in the development of tectal neurons in the chick, as revealed by early enucleation.

To further study the existence of a critical trophic period in the development of the chick optic tectum, during which the presence of retinal synapses is essential to the continued growth of tectal neurons, we have unilaterally enucleated embryos between stages 14--20 and allowed survival until stages 35--43. If the critical trophic period is between stages 40--44, as previously reported, then we reasoned that early removal of the eye might not have any effect on tectal development until the critical period. We assessed tectal neuron survival by staining for degeneration in the efferent projections of tectal neurons. In early enucleates, degeneration was present from stages 37--43, and the severity of the degeneration was much reduced in comparison to animals enucleated during the critical period. These findings substantiate the proposition that there is a critical period late in chick tectal development. However, because the degeneration in tectal projections is less intense than in animals enucleated during the critical period, we suggest that the early enucleation has permitted axons from the remaining eye to be routed to the deafferented tectum, where they may help to sustain a portion of the tectal neurons through the critical period. Moreover, the somewhat earlier appearance of degeneration in tectal efferent pathways of early enucleates suggests that a subtle trophic relationship between retina and tectum may exist prior to stage 40, even though this relationship is not revealed when enucleations are performed later, as between stages 35--40 (ref. 17).

Morphology of dissociated hippocampal cultures from fetal mice.

Dissociated hippocampal cultures from fetal mice (13--18 days gestational age) can be maintained for up to two months in culture. Cells grow as either isolated neurons or in small neuronal aggregates. Neurons remain small with a soma diameter of 15--20 micrometer even in mature cultures and develop extensively branched processes during the first two weeks in culture. After this time, processes become more difficult to visualize with phase-contrast optics because of a tendency to grow within the underlying non-neuronal cells. However, the presence of processes has been proved by silver-staining which demonstrates an organizational complexity ranging from a loosely reticulated neuropil to fascicles containing many fibers. More detailed study of individual neuronal morphology was carried out in cells filled with the fluorescent dye, Lucifer Yellow CH, in conjunction with the intracellular recording of synaptic and action potentials from dye-containing micropipettes. Dye-filled cells show a well-developed branching morphology. Process specializations include spines, beading, and basket-like endings. Processes tend to emanate from one side of the soma, either originating at the cell body or from a single trunk. Commonly there are 2--4 orders of branching, but up to 6 orders can occur (counted centrifugally from the soma). Electron microscopy revealed synapses distributed predominantly on dendrites with a smaller number on somata. Dendritic spines are present and are contacted principally by asymmetric synaptic junctions. Symmetric synapses are relatively more common on somata and proximal dendrites.

Postnatal dendritic development in the rabbit visual cortex.

Golgi preparations of rabbit visual cortex aged 1-25 days, as well as similar tissues from adults, were examined for the growth of the dendritic arbor, and in particular the development of dendritic spines. The layer 5 pyramidal neurons and layer 4 stellate neuron were chosen as representatives of larger classes of neurons in the visual cortex. It was determined that the growth of the dendritic arbor, determined by counts of total number of dendritic and total dendritic length, is quite similar for pyramidal and stellate neurons. Dendritic spine development, however, is more rapid in pyramidal neurons than in stellate. This disparity in the rate of dendritic spine development is discussed in the light of physiologic studies on the development of receptive field properties in the rabbit visual cortex.

Evidence for a critical period of neuronal trophism late in the development of the chick visual system.

Chick embryos and young hatchling chicks have undergone unilateral retinal ablation and the brains were subsequently prepared for modified Fink-Heimer staining to detect degenerating axoplasm. Additional animals have been injected with tritiated proline or combinations of tritiated proline and tritiated fucose. In examining the patterns of degeneration and labelling produced, it appears that during the stage 40-44 period of embryonic life there is a critical period during which damage to retinal axons produces degeneration not only in the direct targets of the optic tract (primary centers), but also in a number of nuclei not projected to by the optic tract (secondary centers). By examining various survival times following retinal ablation and animals of varying embryonic and post-hatch age, we have concluded that retinal ablation during the critical period causes a rapid and fulminant degeneration in the secondary centers because they are all targets of the projection from the optic tectum, itself a prime target of the optic projection. Presumably, interruption of the retino-tectal projection during the critical period disrupts some as yet undefined trophic relationship between these two sets of neurons. Our studies show that the observed degenerative reaction in the secondary centers occurs most strongly in chick embryos between stage 40 and stage 44. This period coincides with the onset of synaptogenesis in the retino-tectal system (Rager, '76a,b). We therefore hypothesize that during this period some property or influence is passing from the retinal to the tectal neurons such that interruption of this process leads to death of the tectal neurons.

Synaptic development in the rabbit superior colliculus and visual cortex.

The development of synapses in the visual cortex (VC) and superior colliculus (SC) of the rabbit has been examined with the electron microscope. In both areas, the number of synapses reaches adult levels by 20--25 days of postnatal age, but the development in the visual cortex is delayed in comparison to that in the superior colliculus. When S synapses (spheroidal vesicles, asymmetric thickening) are compared with F synapses (flattened vesicles, symmetric thickening), even greater differences are seen. In both the VC and SC, S synapses develop earlier than F synapses, though there is considerable overlap. Of interest is that fact that synapses in the visual cortex seem to overshoot their adult levels late in development, suggesting that an excess of synapses may be formed in this system. Multiple synapses, probably of retinal origin, increase in the first 3 weeks of synaptic development in the SC, but never are present in significant proportions in the VC. Synapse formation most often is characterized by formation of a junction and a postsynaptic thickening, followed by acquisition of synaptic vesicles. After 15 days, there is only a small number of such "non-vesicle synapses" in either the SC or VC.

Physiological and morphological identification of a nonpyramidal hippocampal cell type.

In intracellular recordings from the CA1 region of the hippocampal slice preparation, an infrequent cell type different from the predominant pyramidal cell has been characterized. The cells have very brief spikes, hyperpolarizing after-potentials, and tend to fire at a high spontaneous rate; unitary synaptic potentials are visible in the baseline. Stimulation in stratum radiatum evokes an EPSP which often triggers a short burst of spikes; an IPSP invariably follows the initial excitation. Intracellular injection of HRP into these cells shows them to be a non-pyramidal cell type with extensive local axon ramification; however, they do not resemble the classical basket cell. These cells are, nevertheless, candidates for an interneuron in hippocampus.

Postnatal maturation of neurons in the rabbit superior colliculus.

The superior colliculi of Dutch-belted rabbits aged 1 to 30 days were prepared according to Nissl and Golgi techniques and examined in comparison to the neuronal populations in the adult. It was found that the laminar dimensions of the adult are attained at 15 to 20 days, presumably due to glial and dendritic enlargement. The largest neuron in the superficial gray, the vertical cell, was found to mature earliest and to display the least evidence of dendritic development postnatally. Its dendrites do elongate from 0 to 15 days, but there are no growth cones or other unusual dendritic configurations. The intrinsic neurons of the superficial gray, the piriform and stellate cells show more evidence of postnatal dendritic development. Particularly in the case of stellate cells, there are dendritic growth cones present at birth, and early in development spines are found on the soma and large dendrites. Only at 15 to 20 days do the dendritic arbors of these cells assume normal adult shapes and sizes. These and other observations suggest that there are two phases of postnatal cellular maturation in the upper layers of the superior colliculus, one involving the smaller "interneurons." This phased maturation is compared with the known sequence of physiological maturation as studied by the method of receptive-field mapping.

Anatomical studies of a temporal visual area in the rabbit.

Using Fink-Heimer, autoradiographic and horseradish peroxidase techniques, the connections of a temporal visual cortical region of the rabbit were explored. The temporal visual area covers portions of areas T1 and T2, and is reciprocally connected with the posterior nucleus and suprageniculate nuclei of the thalamus. It was also shown that the temporal visual area projects to a similar region in the opposite hemisphere, and to intermediate laminae of the superior colliculus. The temporal visual area is discussed in comparison to other similar regions in the cortex of primate species. It is pointed out that recent evidence indicates visual areas in the occipital cortex of non-primate species may be no less numerous and complex than those in primate species.

Ontogenesis of receptive field characteristics in the dorsal lateral geniculate nucleus of the rabbit.

The responses of rabbit dorsal lateral geniculate neurons to light or optic nerve shock were tested for 415 units in 43 rabbit pups 2--20 days of age. Units were driven by optic nerve shock at the youngest ages tested, but could not be driven by light until postnatal day six. Examples of each of the three prominent categories of receptive fields found in the adult were first observed at 8 days of age. Cells with receptive field properties not characteristic of the dorsal lateral geniculate nucleus of the adult were encountered until 17 days of age. The percentage of neurons with uniform and motion sensitive receptive fields approached adult levels soon after eye opening (11--12 days) but the percentage of cells with concentric receptive fields showed a steady increase throughout the neonatal period studied. The relevance of our data to the development of the visual response in the dorsal lateral geniculate nucleus and striate cortex is discussed.

Enzyme deletions and essential fatty acid metabolism in cultured cells.

Conversion of 14C-labeled linoleic acid to dihomo-gamma-linolenic and arachidonic acids, precursors of the PG1 and PG2 series of prostaglandins, was examined in a number of mammalian cell lines in tissue culture. Diploid cells converted linoleate to arachidonate in good yield. Heteroploid or transformed cells did not desaturate linoleic acid but readily converted dihomo-gamma-[14C]linolenate to arachidonate. These observations demonstrate that separate delta6 and delta5 desaturases are involved in the conversion of linoleic to arachidonic acid in mammals. The results indicate that loss or modification of the delta6 desaturase system is a frequent occurrence in transformed cells.