ATN status in amnestic and non-amnestic Alzheimer's disease and frontotemporal lobar degeneration.

Under the ATN framework, CSF analytes provide evidence of the presence or absence of Alzheimer's disease pathological hallmarks: amyloid plaques (A), phosphorylated tau (T), and accompanying neurodegeneration (N). Still, differences in CSF levels across amnestic and non-amnestic variants or due to co-occurring pathologies might lead to misdiagnoses. We assess the diagnostic accuracy of CSF markers for amyloid, tau, and neurodegeneration in an autopsy cohort of 118 Alzheimer's disease patients (98 amnestic; 20 non-amnestic) and 64 frontotemporal lobar degeneration patients (five amnestic; 59 non-amnestic). We calculated between-group differences in CSF concentrations of amyloid-ß1-42 peptide, tau protein phosphorylated at threonine 181, total tau, and the ratio of phosphorylated tau to amyloid-ß1-42. Results show that non-amnestic Alzheimer's disease patients were less likely to be correctly classified under the ATN framework using independent, published biomarker cut-offs for positivity. Amyloid-ß1-42 did not differ between amnestic and non-amnestic Alzheimer's disease, and receiver operating characteristic curve analyses indicated that amyloid-ß1-42 was equally effective in discriminating both groups from frontotemporal lobar degeneration. However, CSF concentrations of phosphorylated tau, total tau, and the ratio of phosphorylated tau to amyloid-ß1-42 were significantly lower in non-amnestic compared to amnestic Alzheimer's disease patients. Receiver operating characteristic curve analyses for these markers showed reduced area under the curve when discriminating non-amnestic Alzheimer's disease from frontotemporal lobar degeneration, compared to discrimination of amnestic Alzheimer's disease from frontotemporal lobar degeneration. In addition, the ATN framework was relatively insensitive to frontotemporal lobar degeneration, and these patients were likely to be classified as having normal biomarkers or biomarkers suggestive of primary Alzheimer's disease pathology. We conclude that amyloid-ß1-42 maintains high sensitivity to A status, although with lower specificity, and this single biomarker provides better sensitivity to non-amnestic Alzheimer's disease than either the ATN framework or the phosphorylated-tau/amyloid-ß1-42 ratio. In contrast, T and N status biomarkers differed between amnestic and non-amnestic Alzheimer's disease; standard cut-offs for phosphorylated tau and total tau may thus result in misclassifications for non-amnestic Alzheimer's disease patients. Consideration of clinical syndrome may help improve the accuracy of ATN designations for identifying true non-amnestic Alzheimer's disease.

Patterning of the neocortical projections from the raphe nuclei in perinatal rats: investigation of potential organizational mechanisms.

Serotoninergic (5-HT) fibers in the cerebral cortex of perinatal rats have a pattern that coincides with the boundaries of primary sensory areas and within the primary somatosensory cortex form the rattunculus. This patterned immunoreactivity (IR) appears about 60 hours after birth and disappears between postnatal days (P-) 12 and 15. Three experiments were carried out to evaluate mechanisms that might underlie the precise patterning of the 5-HT-IR. Retrograde labelling with fluorescent tracers in perinatal rats revealed only a coarse rostrocaudal topography in the raphe-cortical projection and the existence of raphe cells projecting to multiple cortical locations. Thus, a precise point-to-point, raphe-cortical projection does not underlie the patterned cortical 5-HT-IR. Ablation of the thalamus prior to the age at which patterned 5-HT-IR could be seen in the developing cortex caused a complete loss of patterned immunoreactivity. This suggests that 5-HT fibers may require the presence of thalamocortical axons to achieve the pattern observed in normal animals. Serotoninergic raphe neurons transplanted to the cortices of newborn rats exhibited extensive axonal outgrowth, but did not form a somatotopic pattern. This result also suggests that specific spatiotemporal interactions between growing 5-HT and thalamocortical axons may be necessary for the somatotopic patterning of the former fibers.

Increased serotoninergic innervation of the hamster's superior colliculus alters retinotectal projections.

Anterograde tracing with horseradish peroxidase (HRP) was used to compare the organization of retinotectal projections in normal adult hamsters and in animals that sustained subcutaneous injections of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) on the day of birth. Neonatal injection of this neurotoxin decreases the density of the serotoninergic (5-HT) innervation of the cerebral and cerebellar cortices, but increases the density of these fibers in the brainstem including the superior colliculus (SC). Analysis of tissue from the retinorecipient laminae of the SC by high-pressure liquid chromatography indicated that these lesions increased the amount of 5-HT in the adult SC by 47%. The increased serotoninergic innervation of SC was associated with a marked change in the distribution of the uncrossed retinotectal projection. In normal adult hamsters, fibers from the ipsilateral eye form dense clusters in the lowermost stratum griseum superficiale (SGS) and stratum opticum (SO). A small number of uncrossed fibers are also visible in the more caudal portions of these layers. In the animals that sustained neonatal 5,7-DHT injections, uncrossed retinotectal fibers formed a nearly continuous band in rostral SO and lower SGS, and numerous labeled fibers were present in the caudal SC, primarily in the SO. Neonatal treatment with 5,7-DHT also produced alterations in the crossed retinotectal pathway and in the crossed and uncrossed retinogeniculate projections. These results indicate that the 5-HT input to the developing brainstem may strongly influence the development of retinofugal projections.

Serotonin 1B receptors form a transient vibrissa-related pattern in the primary somatosensory cortex of the developing rat.

Serotonin (5-HT)-immunoreactive axons have a patterned distribution in the primary sensory cortices of developing rodents. This distribution becomes apparent shortly after birth and disappears around the end of the second postnatal week. We employed binding of [125I]cyanopindolol in the presence of isoproterenol to determine whether 5-HT1B receptors have a similar transient spatiotemporal distribution. In rats killed on postnatal day (P-) 8, 5-HT1B receptors have a distribution closely matching that of 5-HT-immunoreactivity. The receptors are very dense in lamina IV of both the primary visual and somatosensory cortices and, like 5-HT immunoreactive axons within the somatosensory cortex, form patches matching the distribution of the mystacial vibrissae. In adult animals, the density of these receptors in lamina IV and the supragranular layers of the visual and somatosensory cortices is reduced relative to that in the surrounding cortex. Autoradiograms of the flattened cortices of adult rats yield a 'negative image' of the pattern observed in perinatal animals. Thus, one subclass of 5-HT receptors, the 5-HT1B receptor, has a spatial distribution in cortex which changes in development much like that for serotoninergic axons.

Respiratory impairment in inflammatory bowel disease: does it vary with disease activity?

Serial assessments of respiratory function were made in 44 patients with inflammatory bowel disease. Pulmonary function tests were performed at the initial assessment and after three months to see if abnormality was associated with alteration in disease activity, drug therapy or with evidence of immunological disturbance. Fourteen patients (32%) had some abnormality of respiratory function when first investigated. Seven (16%) had a reduced gas transfer factor but these abnormalities were not related to disease activity, drug therapy or any immunological variable. Elevation of both functional residual capacity and residual volume was found in nine (20%) patients at the initial assessment. These abnormalities appeared to be associated with active inflammatory bowel disease and in four of these patients lung volumes returned to normal at 3 months when the bowel disease was in remission.

Serotonin 1B receptors in the developing somatosensory and visual cortices are located on thalamocortical axons.

Serotonin (5-HT)-immunoreactive axons are densely distributed in the primary visual and somatosensory cortices of rats, mice, and hamsters for the first 2 weeks of life, and a recent study from this laboratory has demonstrated that 5-HT1B receptors assume a pattern that exactly matches that of the serotoninergic axons. The differential distribution of these receptors is also transient. In the present study, we combined receptor binding autoradiography with neurochemical ablation of 5-HT axons or electrolytic lesions of the dorsal thalamus in an effort to determine the neural elements upon which the 5-HT1B receptors were located. Subcutaneous injections of the toxin 5,7-dihydroxytryptamine, made on the day of birth, totally eliminated the dense and patterned 5-HT innervation of the somatosensory and striate cortices of rats killed on postnatal day 8 but had no qualitative effect upon the distribution or density of 5-HT1B receptors in either of these cortical regions in animals killed at the same age. Conversely, electrolytic lesions of the dorsal thalamus made on postnatal day 6 resulted in a complete loss of the dense and patterned distribution of 5-HT1B receptors in rats killed on postnatal day 8. These results indicate that thalamocortical axons transiently express 5-HT1B receptors.

Effect of serotonin depletion on vibrissa-related patterns of thalamic afferents in the rat's somatosensory cortex.

To investigate the role of 5-HT in the development of the somatosensory cortex, this amine was depleted in newborn (P-0) rats with a single subcutaneous injection of the toxin 5,7-dihydroxytryptamine (5,7-DHT) and thalamocortical organization was assayed by application of the carbocyanine dye Di-I to the thalamocortical radiations or ventrobasal thalamus, or by staining cortical sections for AChE or cytochrome oxidase (CO). High-performance liquid chromatographic analysis of cortices from animals killed on P-6 or P > 60 demonstrated that 5,7-DHT treatment resulted in 85.04 +/- 12.6% and 72.5 +/- 1.5% reductions in cortical 5-HT, respectively. Alternate cortices from the brains of animals killed on P-6 processed for 5-HT immunoreactivity demonstrated a complete absence of the vibrissa-related pattern of immunoreactivity and only a small number of coarse immunoreactive axons. The 85% depletion of 5-HT did not alter the somatotopic organization of thalamocortical afferents in animals killed on P-6 or P > 60, but it did cause 30.5 +/- 7.3% and 19.1 +/- 3.7% reductions in the cross-sectional areas of the patches of thalamocortical afferents corresponding to the long mystacial vibrissae (p < 0.05). These reductions were not associated with significant reductions in either brain or cortical weight or with decreases in the dimensions of the thalamic representation of the vibrissa follicles. These results indicate that 5-HT plays a significant role in the development of the thalamic innervation of the primary somatosensory cortex.

A comparative study of two doses of salbutamol nebulized at 4 and 8 litres per minute in patients with chronic asthma.

A comparative study of the clinical response to salbutamol nebulized by an Inspiron Mini-Neb using flow rates of 4 and 8 litres/min is described. Forty patients with chronic asthma were given doses of approximately 1 mg and 5 mg of salbutamol using flow rates of either 4 or 8 litres/min. The two flow rates and the two dosages produced similar increases in FEV1 and FVC and similar changes in pulse rate. These results demonstrate that flow rates of 4 litres/min, such as can be produced by a domestic oxygen cylinder, and doses of 1 mg salbutamol are effective in the treatment of patients with chronic reversible airflow obstruction. While we do not advocate the general use of oxygen cylinders to drive nebulizers, our study shows that this form of administration produces a bronchodilator response similar to that using a flow rate of 8 litres/min.

Quality control in pulmonary function testing. A help or a hindrance?

The results of 120 sets of ventilatory capacity, lung volume (LV) and carbon monoxide transfer factor (TCOSB) measurements, 40 sets from each of three pulmonary function laboratories in one city, were examined retrospectively. Vital capacity (VC) was estimated by a forced expiratory manoeuvre (FVC), a relaxed expiratory manoeuvre (VCR) and an inspiratory manoeuvre (VCI) in the three different tests. Differences between VCR and FVC ranged from--88 ml to + 1 400 ml with a mean of + 47 ml. VCI differed from the largest estimate of expiratory VC by--1 800 ml to + 300 ml with a mean of--480 ml. Such differences, which were observed in all three laboratories, affect the calculations in each test and thus the final results quoted. Adequate quality control therefore requires comparison of estimates of VC not only within a test but also between tests. Although more time must be spent with some patients, technical errors and poor patient performance can be distinguished from true changes in pulmonary function, thus better enabling the clinician to assess the relationship between the results and the clinical condition of the patient.

B-virus from pet macaque monkeys: an emerging threat in the United States?

Of primary concern when evaluating macaque bites are bacterial and B-virus infections. B-virus infection is highly prevalent (80% to 90%) in adult macaques and may cause a potentially fatal meningoencephalitis in humans. We examined seven nonoccupational exposure incidents involving 24 persons and eight macaques. Six macaques were tested for herpes B; four (67%) were seropositive. A common observation was that children were more than three times as likely to be bitten than adults. The virus must be assumed to be a potential health hazard in macaque bite wounds; this risk makes macaques unsuitable as pets.