Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease.

Initially identified in high-grade gliomas, mutations in the PTEN tumor-suppressor are also found in many sporadic cancers and a few related autosomal dominant hamartoma syndromes. PTEN is a 3'-specific phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) phosphatase and functions as a negative regulator of PI3K signaling. We generated a tissue-specific deletion of the mouse homolog Pten to address its role in brain function. Mice homozygous for this deletion (PtenloxP/loxP;Gfap-cre), developed seizures and ataxia by 9 wk and died by 29 wk. Histological analysis showed brain enlargement in PtenloxP/loxP;Gfap-cre mice as a consequence of primary granule-cell dysplasia in the cerebellum and dentate gyrus. Pten mutant cells showed a cell-autonomous increase in soma size and elevated phosphorylation of Akt. These data represent the first evidence for the role of Pten and Akt in cell size regulation in mammals and provide an animal model for a human phakomatosis condition, Lhermitte-Duclos disease (LDD).

Effects of natural shoe wear on traction performance: a longitudinal study.

Footwear outsole design is an important factor for shoe-floor friction and for preventing slipping. Shoes with small, uniformly-separated tread blocks (often included on slip-resistant shoes) have decreased slip risk due to their increased friction and better under-shoe fluid drainage. However, these traction performance metrics (friction and fluid drainage) diminish with wear. This study quantifies shoe traction performance in response to natural wear and compares the relationship between common wear metrics: time, distance walked, and worn region size (WRS). Participants wore two pairs of shoes in the workplace for up to 11 months and the distance walked was tracked with a pedometer. After each month of wear, traction performance and WRS of each shoe were measured. Traction performance was quantified by the under-shoe available coefficient of friction and fluid force during a simulated slip condition. Increased wear (months worn, distance walked, and WRS) was associated with decreased traction performance. A WRS of 800 mm2 was associated with reductions in friction of 16-38% and increases in fluid force by 286-528%. Three and six months of wear were associated with WRS values of 251 mm2 and 462 mm2 and distances of 203 km and 519 km, respectively. A walking distance of 500 km was associated with a WRS of 406 mm2. This study showed that all these wear metrics are good indicators of shoe traction performance loss. Thus, the most practical metric in a particular application can be selected. We argue that WRS may be the best indicator due to variations in wear rate from the user and environment. Therefore, tracking footwear usage and monitoring outsole wear can aid in shoe replacement recommendations to reduce slips and falls.

A research model--forecasting incident rates from optimized safety program intervention strategies.

UNLABELLED: INTRODUCTION/PROBLEM: Property damage incidents, workplace injuries, and safety programs designed to prevent them, are expensive aspects of doing business in contemporary industry. The National Safety Council (2002) estimated that workplace injuries cost $146.6 billion per year. Because companies are resource limited, optimizing intervention strategies to decrease incidents with less costly programs can contribute to improved productivity. METHOD: Systematic data collection methods were employed and the forecasting ability of a time-lag relationship between interventions and incident rates was studied using various statistical methods (an intervention is not expected to have an immediate nor infinitely lasting effect on the incident rate). RESULTS/SUMMARY: As a follow up to the initial work, researchers developed two models designed to forecast incident rates. One is based on past incident rate performance and the other on the configuration and level of effort applied to the safety and health program. Researchers compared actual incident performance to the prediction capability of each model over 18 months in the forestry operations at an electricity distribution company and found the models to allow accurate prediction of incident rates. IMPACT ON INDUSTRY: These models potentially have powerful implications as a business-planning tool for human resource allocation and for designing an optimized safety and health intervention program to minimize incidents. Depending on the mathematical relationship, one can determine what interventions, where and how much to apply them, and when to increase or reduce human resource input as determined by the forecasted performance.

Idh1 protects murine hepatocytes from endotoxin-induced oxidative stress by regulating the intracellular NADP(+)/NADPH ratio.

Isocitrate dehydrogenase-1 (Idh1) is an important metabolic enzyme that produces NADPH by converting isocitrate to α-ketoglutarate. Idh1 is known to reduce reactive oxygen species (ROS) induced in cells by treatment with lipopolysaccharide (LPS) in vitro. Here, we used Idh1-deficient knockout (Idh1 KO) mice to investigate the role of Idh1 in antioxidant defense in vivo. Idh1 KO mice showed heightened susceptibility to death induced by LPS and exhibited increased serum levels of inflammatory cytokines such as tumor necrosis factor-α and interleukin-6. The serum of LPS-injected Idh1 KO mice also contained elevated levels of AST, a marker of inflammatory liver damage. Furthermore, after LPS injection, livers of Idh1 KO mice showed histological evidence of elevated oxidative DNA damage compared with livers of wild-type (WT) mice. Idh1 KO livers showed a faster and more pronounced oxidative stress than WT livers. In line with that, Idh1 KO hepatocytes showed higher ROS levels and an increase in the NADP(+)/NADPH ratio when compared with hepatocytes isolated from WT mice. These results suggest that Idh1 has a physiological function in protecting cells from oxidative stress by regulating the intracellular NADP(+)/NADPH ratio. Our findings suggest that stimulation of Idh1 activity may be an effective therapeutic strategy for reducing oxidative stress during inflammatory responses, including the early stages of septic shock.

Neocortical projections of the suprageniculate and posterior thalamic nuclei in the marsupial brush-tailed possum, Trichosurus vulpecula (Phalangeridae), with a comparative commentary on the organization of the posterior thalamus in marsupial and placental mammals.

Axonal transport methods were used to determine the extent and organisation of neocortical projections from the suprageniculate (SG) and posterior (PO) thalamic nuclei in the brush-tailed possum. Our findings show that SG projects extensively to the auditory cortex, overlapping the cortical projection field of the medial geniculate nucleus, and to the immediately neighbouring association cortex. Though the input relationships of SG appear similar to those reported for other mammals, placental and marsupial, a strong SG projection to auditory cortex has not been reported previously. Neocortical relationships of PO are characterised by an orderly point-to-point projection to all but the most rostral parts of the motor-somaesthetic cortex. There is also a substantial projection to the entire posterior parietal association cortex. The PO-neocortex projection is reciprocally organised. The PO-neocortical projection in the possum is similar to that reported in the Virginia opossum, rat, and several other mammals. There is a major difference in organisation in comparison with certain monkeys where the PO projection is much more restricted and does not involve the motor and somaesthetic cortex. We conclude that PO is similarly organised in many, though not all, mammals, including the marsupials, rodents, insectivores, and prosimian primates. The possum SG, on the other hand, is clearly distinct from other mammals in its extensive projection to auditory cortex, though we cannot say at present whether this a general property of marsupial mammals or a peculiarity restricted to this species and possibly its close relatives.

Retinal projections in the Tasmanian devil, Sarcophilus harrisii.

Retinal projections were mapped in Tasmanian devils which had one eye injected with 3H-proline. The retinal fibers terminate in seven regions in the brain. These are (1) dorsal lateral geniculate nucleus (LGNd), (2) ventral lateral geniculate nucleus, (3) lateral posterior nucleus, (4) pretectum, (5) superior colliculus, (6) hypothalamus and (7) accessory optic system. The pattern of retinal input to six of these regions is similar to that seen in other marsupials. The pattern of retinal projections to the LGNd, while basically similar to that observed in other polyprotodont marsupials, is much simpler than that seen in the related native cat, Dasyurus viverrinus. The LGNd of Sarcophilus presents the simplest cytoarchitectural organisation of any marsupial examined so far. Each LGNd receives overlapping projections from both eyes. Suggestions of an intermittent lamination are seen in the LGNd contralateral to an eye injection of 3H-proline. On the ipsilateral side there are two patches of label, a large lateral patch and a smaller medial patch, both of which occupy areas receiving contralateral input. The monocular segment, occupying the ventral 40% of the nucleus, is more extensive than has been reported in any other polyprotodont marsupial.

The dorsal lateral geniculate nucleus of macropodid marsupials: cytoarchitecture and retinal projections.

The anatomy of the dorsal lateral geniculate nucleus (LGd) is described in five macropodid species, including two rat kangaroos (bettong and potoroo), two wallabies (pademelon and tammar), and the large grey kangaroo. The distribution of retinal terminals in the LGd was examined following intraocular injections of tritiated amino acids. There are considerable differences in both LGd cytoarchitecture and the patterns of retinal terminations among the five species. Cytoarchitecture in the bettong LGd is relatively simple, displaying a minimal regional differentiation. In contrast, the potoroo LGd is quite complex and displays several well-defined cell laminae, each of which is associated with input from a single eye. Both rat kangaroos display the same basic pattern of retinal termination with three bands of terminals from the contralateral eye and four from the ipsilateral eye. The bands are less sharply defined in the bettong, in which terminals from each eye overlap to a greater extent than is seen in the potoroo. The wallabies and kangaroos display a more complex LGd architecture and patterning of retinal terminal bands. Bilateral retinal projections within the same LGd lamina are unusual in these large macropodids. The number of terminal bands reaches ten in the grey kangaroo--four from the contralateral eye and six from the ipsilateral eye. The pademelon LGd is unusual in that it shows intraspecies variation with some animals displaying five ipsilateral terminal bands and others only four. The results are discussed in comparison with the patterns of LGd organisation observed in other mammalian lines, placental and marsupial. We conclude that LGd lamination and the segregation of retinal inputs to the LGd in marsupials are likely to be the result of evolutionary factors which differ from those which have produced ocular segregation and complex lamination in several lines of placental mammals.

Follow-up families who experience a perinatal death.

We conducted a retrospective study by telephone interview (10 to 22 months later) of 26 families who had experienced a perinatal death. Six of 26 mothers had a prolonged grief reaction (12 to 20 months). Those mothers with a surviving twin or subsequent pregnancy less than five months following the death were at higher risk for a prolonged grieving period than were those without subsequent pregnancy or one more than six months later. Half of the families obtained information about the cause of death and risk of recurrence only during hospitalization; subsequent contact, weeks to months later, provided additional information for the other half. Twenty-two of 26 mothers met predetermined criteria for having an adequate understanding of cause of death and risk of recurrence; four of 26 knew neither. Sixty percent of the mothers who had adequate understanding and who had no prolonged grief response felt totally dissatisfied or only partially satisfied with the information they received and the way they received it. Follow-up contact by phone or in person increased understanding significantly; mothers who had had in-person follow-up were more likely to be satisfied with the information they received.

Comparison of direct and indirect measurements of respiratory airflow: implications for hypopneas.

The purpose of this study was to compare indirect methods for measuring respiratory airflow, such as temperature difference between inspired and expired air, thoracoabdominal movements, and nasal respiratory-airflow pressures-with a more direct measurement of minute ventilation using a head-out body plethysmograph. Measurements were obtained in healthy, awake, seated subjects during sequences of different levels of voluntary hypoventilations at 20 breaths/minute and analyzed to determine how well different methods could identify hypopneas (defined as reduction in minute ventilation by 50% or more). The results varied widely between different methods. Sensitivities ranged from 0 to 1, specificity ranged from 0.33 to 1, positive predictive values (PPV) ranged from 0 to 0.73, negative predictive values (NPV) ranged from 0.68 to 0.93. Cohen's kappa varied between 0 and 0.65 The poorest agreement was for the thermistor method, and the best agreement was obtained when a combination of thoraco-abdominal movements and nasal respiratory-airflow pressure was employed (sensitivity = 0.86, specificity = 0.83, PPV = 0.71, NPV = 0.92, Cohen's kappa = 0.65). We conclude that none of the indirect methods investigated, individually or in combination, proved adequate for identification of voluntary hypopneas in awake individuals.

A new method for the remote collection of nasal and exhaled nitric oxide.

STUDY OBJECTIVES: The present study introduces a method that has been developed to improve the remote collection and transportation of gas samples from the nose and lungs. DESIGN: Assessment of agreement between two methods of clinical measurements. SETTING: Noninvasive exhaled gas measurement at a respiratory research laboratory. PARTICIPANTS: Ten nonsmoking adult volunteers (median age, 44 years; age range, 33 to 53 years; men, 6; women, 4) were recruited. MEASUREMENTS AND RESULTS: Exhaled nitric oxide (ENO) and nasal nitric oxide (NNO) outputs were measured directly (on-line) and remotely (off-line). With the velum closed, lung air was exhaled at fixed flows (ie, 6, 8, and 10 L/min) (ENO) or room-air was aspirated through the nose in series at one fixed flow (ie, 5 to 8 L/min) (NNO). The off-line nitric oxide (NO) measurements were achieved by a gas collection tube system, which consisted of a flow control unit, a tube reservoir with one-way valves at both ends, and an interrupter valve allowing the trapping of gas inside the tube and eliminating the inclusion of "dead space." After clamping, the reservoir may store and transport the gas samples for delayed analysis. The coefficient of variation of three consecutive NO measurements was < 3% for both on-line and off-line ENO and NNO. The correlations between on-line and off-line measurements in both ENO and NNO outputs were high (r = 0.99; R(2) = 0.99), and, unlike previous studies using bag-collection, the ENO outputs for on-line and off-line measurements were in good agreement (Bland-Altman test) at all flows tested. CONCLUSIONS: The tube gas collection system eliminates the dead space and contamination during the gas sampling and permits the cost-effective and reliable off-line collection of both nasal and exhaled gas samples.

How thick should a retina be? A comparative study of mammalian species with and without intraretinal vasculature.

In this study we describe a measurement method which closely approximates in vivo retinal thickness. Using this method we examined the laminar organisation of vascular and avascular retinae from placental and marsupial mammals. Thickness measurements on retinal wholemounts show that the avascular retinae of the placental guinea pig (140 microns) and the marsupial brushtail possum (170 microns) are thinner and show less centroperipheral taper than do the vascular retinae of placental cats (250 microns), rats (220 microns) and marsupial quolls (220 microns). In general, limitation in thickness of avascular retinae is borne by most retinal layers, but most particularly by the inner plexiform layer, the synaptic region farthest removed from the choroidal blood supply. Except for the absence of blood vessels, the histological organisation of the brushtail possum's retina resembles closely that of its fellow marsupial, the quoll's. In contrast, intraretinal organisation differs amongst the two avascular retinal species with the guinea pig displaying a much coarser photoreceptor grain.

Is the nasal cycle an artifact? The role of asymmetrical postures.

Both the nasal cycle and postural asymmetries between the lateral halves of the body will cause the patent cavity of the nasal airway to change sides. Therefore, the cycle might result from adjustments of posture during prolonged periods of nasal resistance measurements. Posterior rhinometric measurements of unilateral nasal resistance were made three times for 5 to 7 hours on a patient in whom 11 periods of lateral recumbency had not induced nasal resistance changes. A nasal cycle was observed. It is concluded that the cycle is not the product of asymmetrical body pressures.

The site and function of the nasal valve.

Previous observers have suggested that the main site of respiratory airflow resistance is localized to the vestibular region of the nose. This resistive segment of the airway was investigated using a "head-out" body plethysmograph in subjects with anatomically normal noses (a) untreated, (b) congested and (c) decongested. In all three conditions, 2/3 of the total nasal airflow resistance was found within the bony cavum in the vicinity of the pyriform aperture and about 1/3 in the cartilaginous vestibule. As might be expected, caval resistance changed proportionately with the degree of mucosal congestion; but, more surprisingly, vestibular resistance changed similarly. This was due in part to the observed forward expansion of the anterior ends of the inferior turbinates with congestion. EMG recordings in subjects breathing through both nostrils demonstrated a gradation of inspiratory alar dilator muscle activity with increased minute ventilation and with mucosal congestion, and there was no evidence of inspiratory alar collapse. But with elevated ventilation through one nostril only, or when the alar muscles were paralyzed by lidocaine block of the VIIth nerve, alar collapse occurred. These findings are of importance in the management of the congested but anatomically normal nose and in surgery of the nasal tip.

Mechanisms of nasal obstruction in sleep.

Pathophysiological aspects of the nasal and pharyngeal airways are discussed with particular reference to breathing disorders in sleep. Hypotonus of dilator muscles in sleep permits the pharynx to comply with inspiratory pressures. If airflow resistances are increased by nasal disease, complete inspiratory obstructive closure of the pharynx and apnea can result from nasal breathing in sleeping subjects. Recumbency increases resistive swelling of inflamed nasal mucosa. Furthermore in patients with normal mucosa and unilateral nasal obstruction, contralateral recumbency induces contralateral obstruction which increases resistance to nasal breathing; and in either dorsal or lateral recumbency the congestive phase of the spontaneous nasal cycle acts in a similar way. Examples of breathing disorders in sleep and impaired quality of sleep in patients with obstructive mucosal disease and both bilateral and unilateral structural abnormalities are cited.

Changes in pharyngeal properties after uvulopalatopharyngoplasty.

Uvulopalatopharyngoplasty is a commonly used modality for surgical treatment of snoring and obstructive sleep apnea. Although this procedure is thought to alter pharyngeal properties, its effect on pharyngeal mechanics has not been studied. The acoustic reflection technique was used to measure pharyngeal area at functional residual capacity and residual volume before and after uvulopalatopharyngoplasty in eight patients referred because of loud snoring. We also calculated the lung volume dependence of pharyngeal area, defined as the percent change in pharyngeal area between functional residual capacity and residual volume, normalized to the area at functional residual capacity. This parameter, which may be related to pharyngeal collapsibility, was obtained before and after uvulopalatopharyngoplasty. Preoperative sleep studies showed that one patient had obstructive sleep apnea (apnea index greater than 10). Uvulopalatopharyngoplasty resulted in a significant increase (p less than 0.01) in pharyngeal area (from 3.14 +/- 0.71 cm2 to 4.25 +/- 1.07 cm2) and residual volume (from 2.49 +/- 0.53 cm2 to 3.91 +/- 0.83 cm2). Following uvulopalatopharyngoplasty, the pharynx became stiffer, as manifested by a reduction in lung volume dependence of pharyngeal area from 19 +/- 12% to 8 +/- 13% (p less than 0.05). Six patients, including the patient with obstructive sleep apnea, reported improvement in snoring. Two patients reported worsening in snoring. One of the two was found to have reduction in pharyngeal area and lung volume dependence of pharyngeal area, and an increase in apnea index from 3 to 33. In selected snorers, uvulopalatopharyngoplasty results in improvement in snoring with a concomitant increase in pharyngeal area and a tendency toward lower pharyngeal collapsibility.

Sleep and posture.

Computer-assisted open catheter studies of 10 healthy, nose-breathing men in dorsal and in lateral recumbent sleep demonstrated stable intrasubject transpharyngeal differential pressures and airflow resistances. They averaged 19.6 Pa (+/- standard deviation [SD] 11.9) and 0.103 Pa/cm3 per second (+/- SD 0.065) in the dorsal posture and stage II sleep during quiet breathing and were not significantly different in the lateral posture or in stage I sleep. Five subjects were snorers, and their pharyngeal airflow pressures and resistances increased substantially during quiet breathing on assumption of recumbency and much more in sleep. In the 5 subjects who were nonsnorers, postural changes were not significant and sleep increases were moderate. During snoring, transpharyngeal pressures and resistances increased even further, averaging 188 Pa and 1.02 Pa/cm3 per second for the whole group. Transpharyngeal differential pressures and hypopharyngeal transmural pressures frequently exceeded 300 Pa in inspiration and in expiration during periods of snoring. Yet, transpharyngeal differential pressures and resistances did not reveal appreciable differences between phases that would indicate compliant change of pharyngeal cross section. Breathing frequency was unchanged, but ventilation was significantly diminished at elevated upper airway resistances (P < .01). Transpharyngeal resistances and differential pressures varied independently from widely differing nasal resistances. As with our earlier studies, pressure measurements alone clearly demonstrated breathing patterns and events.

Site of airway obstruction in patients with obstructive sleep apnea before and after uvulopalatopharyngoplasty.

This study describes a simple method, based on a movable catheter technique, for use during routine polysomnography to identify the site of obstruction, and this has been applied to 51 patients with suspected sleep apnea. The obstruction was found to be retropalatal in 30, retrolingual in 7, and could not be determined in 14 patients (12 had no sleep apnea, 1 did not sleep, and 1 had central sleep apnea). Twelve of these patients had uvulopalatopharyngoplasty with preoperative and postoperative polysomnograms to determine the site of obstruction. The preoperative obstruction was retropalatal in nine and retrolingual in three. Postoperatively, four patients (one with retrolingual obstruction and three with retropalatal obstruction) no longer had sleep apnea. In the remaining eight patients, the site of obstruction was unchanged from the preoperative one. Several conclusions result: 1. the movable catheter technique offers a simple way to determine the site of obstruction in patients with significant obstructive sleep apnea, 2. most such patients obstruct in the retropalatal region, and 3. preoperative localization of the site of obstruction to the retropalatal region does not seem to improve the surgical outcome of uvulopalatopharyngoplasty.

Laryngeal resistance to respiratory airflow in humans.

Although vocal cord adduction has been observed during expiration, measurements of absolute values of resistance changes in man have not been reported in the literature. The authors measured resistance to translaryngeal respiratory airflow in inspiratory and expiratory phases of the respiratory cycle of four healthy, awake men during nasal breathing. It was found that, during quiet breathing through a decongested nose, translaryngeal resistance was 1.245 cm H2O/L per second in expiration and 0.354 cm H2O/L per second in inspiration (.005 < P < or = .01), for a percentage of approximately 25% and 50% of extrathoracic expiratory and inspiratory resistances, respectively. Voluntary hyperventilation decreased expiratory resistance, and a partial nasal obstruction abolished the statistical difference between translaryngeal inspiratory and expiratory resistance. These results are in agreement with previous observations of vocal cord movement and are consistent with an expiratory braking effect on airflow.

Resistance to respiratory airflow of the extrapulmonary airways.

Resistances to respiratory airflow of nasal, pharyngeal, laryngeal, and tracheobronchial airway segments were determined by computer processing of digitized differential pressure and flow signals in four healthy, awake, male adults seated and breathing spontaneously at rest, exclusively through decongested noses. Resistances of the nasal and pharyngeal segments in Pa/cm3 per second averaged 0.139 (SD +/- 0.044) and 0.081 (SD +/- 0.051), respectively, with no resistive evidence of compliance with airflow pressures. The laryngeal segment exhibited the reciprocal of compliance, expiratory resistances exceeded those of inspiration, averaging 0.125 (SD +/- 0.037) and 0.035 (SD +/- 0.013), respectively (.005 < P < .01). Tracheobronchial resistances during spontaneous resting breathing were too small to record reliably at the calibration used, and values augmented by voluntary hyperventilation averaged only 0.012 (SD +/- 0.004). Laryngeal expiratory resistance approximated one fifth of the sum total of respiratory airflow resistances (including the pulmonary airways) and the authors suggest that, in addition to contributing to expiratory airflow braking, partial laryngeal closure induces orifice flow. This nonlaminar flow regime promotes the mucosal contact and mixing that enables greater than 30% of heat and water to be recovered from expiratory air by the human pharynx and nose.

Hypoxia depresses nitric oxide output in the human nasal airways.

OBJECTIVES: The role of oxygen in the nasal air on nasal nitric oxide (NO) output was studied in 13 adult volunteers. METHODS: Nasal NO was measured while air containing oxygen (0%-100% in nitrogen) was aspirated through the nasal airway before and after the topical application of xylometazoline. RESULTS: The mean nasal NO output of the untreated nose was 507.8 +/- 161.9 nL/min (mean +/- SD) when 21% oxygen was aspirated through the nasal cavities in series and remained unaltered by 100% O2 (P = .79). Below 10% oxygen the reduction in nasal NO output correlated positively and significantly with the decrease in oxygen concentration (r2 = 0.14). NO output was 245.2 +/- 153.4 nL/min at 0% oxygen, a significant decline from 21% oxygen (P < .0001). Nasal vasoconstriction induced by xylometazoline and alterations in the blood oxygen content by a maximal breath-holding or breathing 100% oxygen did not alter nasal NO in hypoxia (P = .41). CONCLUSIONS: Nasal NO output is markedly depressed in hypoxia and is oxygen dependent at concentrations of less than 10%. Approximately 50% of nasally generated NO is produced from oxygen in nasal air or regulated by it.