Subtle Pathological Changes Research Articles

Identification and characterization of heterogeneous neuronal injury and death in regions of diffuse brain injury: evidence for multiple independent injury phenotypes.

Diffuse brain injury (DBI) is a consequence of traumatic brain injury evoked via rapid acceleration-deceleration of the cranium, giving rise to subtle pathological changes appreciated best at the microscopic level. DBI is believed to be comprised by diffuse axonal injury and other forms of diffuse vascular change. The potential, however, that the same forces can also directly injure neuronal somata in vivo has not been considered. Recently, while investigating DBI-mediated perisomatic axonal injury, we identified scattered, rapid neuronal somatic necrosis occurring within the same domains. Moving on the premise that these cells sustained direct somatic injury as a result of DBI, we initiated the current study, in which rats were intracerebroventricularly infused with various high-molecular weight tracers (HMWTs) to identify injury-induced neuronal somatic plasmalemmal disruption. These studies revealed that DBI caused immediate, scattered neuronal somatic plasmalemmal injury to all of the extracellular HMWTs used. Through this approach, a spectrum of neuronal change was observed, ranging from rapid necrosis of the tracer-laden neurons to little or no pathological change at the light and electron microscopic level. Parallel double and triple studies using markers of neuronal degeneration, stress, and axonal injury identified additional injured neuronal phenotypes arising in close proximity to, but independent of, neurons demonstrating plasmalemmal disruption. These findings reveal that direct neuronal somatic injury is a component of DBI, and diffuse trauma elicits a heretofore-unrecognized multifaceted neuronal pathological change within the CNS, generating heterogeneous injury and reactive alteration within both axons and neuronal somata in the same domains.

Sonography of the hand and wrist

In the recent years US has gained wide diffusion as a useful imaging tool in the evaluation of musculoskeletal disorders. Recognized advantages of US over the other imaging modalities are low costs, non-invasiveness, possibility to perform a dynamic examination and readiness. Unfortunately, US has a long learning curve and allows good results only when performed by well-trained and experienced examiners. Specifically, utilization of the recent small transducers allows to perform dynamic examination of the hand during flexion-extension movements of the fingers, while their high frequency (till 15 MHz) have increased the possibility to evaluate small anatomic structures of the hand and wrist as well as to detect subtle pathologic changes. The purpose of this article is to present first the normal basic anatomy and US appearance. Then the main pathological conditions including joint and tendon disorders, foreign bodies and other traumatic lesions, entrapment neuropathies and expansible lesions will be presented.

Histology of the developing digestive system and the effect of food deprivation in larval green sturgeon ( Acipenser medirostris)

The histological development of the digestive tract in hatchery-reared green sturgeon ( Acipenser medirostris) larvae and the effects of food deprivation on the digestive system organization were studied from hatching until 31 days post-hatching (dph). At hatching, the larval digestive system consisted of two rudiments: a large endodermal yolk sac and a primordial hind-gut. During the endogenous feeding phase, the wall of the yolk sac differentiated into the stomach (glandular and non-glandular regions) and the anterior and intermediate intestine, while the hind-gut primordium differentiated into the spiral valve and rectum. At the onset of exogenous feeding (15 dph at 16 °C), the organization and cytoarchitecture of the digestive system in green sturgeon larvae was generally similar to those of juveniles and adults. Larvae deprived of food exhibited a progressive deterioration, with subtle pathological changes observed after 5-d starvation: shrinkage of digestive epithelia, tissue degeneration, and necrosis were observed at 10–15 d of starvation (30 dph). No changes were observed in the mucous secretion of different regions of the digestive tract of food-deprived larvae. The histological analysis of the larval digestive system may be used to evaluate the nutritional condition of larval green sturgeon in their nursery habitats in spawning rivers, which are affected by dams and flow diversions.

The relationship between lesion and normal appearing brain tissue abnormalities in early relapsing remitting multiple sclerosis.

In multiple sclerosis (MS), pathological changes have been found both in macroscopic lesions and normal appearing tissue. Magnetisation transfer ratio (MTR) and T1 relaxation time are abnormal in normal appearing tissues in established MS. This study used these MR techniques in early MS to study normal appearing tissues and lesions. The purpose was to determine whether abnormalities are already detectable in normal appearing tissues in early MS, and if so how they correlate with lesion characteristics. Twenty two patients with early relapsing remitting (RR) MS (median disease duration 2 years, range 7 months-3 years) and 11 age-matched controls were studied. MTR and T1 relaxation times were measured in 9 regions of normal appearing white matter (NAWM) and 7 of normal appearing grey matter (NAGM). Gadolinium enhancing, T1-hypointense and T2 lesion loads were measured in all patients. When all regions were combined, there was a significant difference between patient and control NAWM for both T1 and MTR; T1 was abnormal in 6/9 and MTR in 3/9 NAWM regions. Global assessment of NAGM revealed a significant difference between patients and controls for Ti but not for MTR; T1 was significantly abnormal only in frontal NAGM. There was no significant correlation between NAWM T1 or MTR and any of the lesion load measurements. This study reveals quantitative MR abnormalities in both NAWM and NAGM in early RR MS, with more extensive changes in the former. The lack of correlation between NAWM and lesion abnormalities suggests that they have developed by at least partly independent mechanisms. T1 may be more sensitive than MTR in detecting subtle pathological changes in NAWM and NAGM.

Widespread anatomical abnormalities of grey and white matter structure in tuberous sclerosis

Neuroimaging studies of tuberous sclerosis complex (TSC) have previously focused mainly on tubers or subependymal nodules. Subtle pathological changes in the structure of the brain have not been studied in detail. Computationally intensive techniques for reliable morphometry of brain structure are useful in disorders like TSC, where there is little prior data to guide selection of regions of interest. Dual-echo, fast spin-echo MRI data were acquired from 10 TSC patients of normal intelligence and eight age-matched controls. Between-group differences in grey matter, white matter and cerebrospinal fluid were estimated at each intracerebral voxel after registration of these images in standard space; a permutation test based on spatial statistics was used for inference. CSF-attenuated FLAIR images were acquired for neuroradiological rating of tuber number. Significant deficits were found in patients, relative to comparison subjects, of grey matter volume bilaterally in the medial temporal lobes, posterior cingulate gyrus, thalamus and basal ganglia, and unilaterally in right fronto-parietal cortex (patients -20%). We also found significant and approximately symmetrical deficits of central white matter involving the longitudinal fasciculi and other major intrahemispheric tracts (patients -21%); and a bilateral cerebellar region of relative white matter excess (patients +28%). Within the patient group, grey matter volume in limbic and subcortical regions of deficit was negatively correlated with tuber count. Neuropathological changes associated with TSC may be more extensive than hitherto suspected, involving radiologically normal parenchymal structures as well as tubers, although these two aspects of the disorder may be correlated.

Widespread anatomical abnormalities of grey and white matter structure in tuberous sclerosis

Background. Neuroimaging studies of tuberous sclerosis complex (TSC) have previously focused mainly on tubers or subependymal nodules. Subtle pathological changes in the structure of the brain have not been studied in detail. Computationally intensive techniques for reliable morphometry of brain structure are useful in disorders like TSC, where there is little prior data to guide selection of regions of interest. Methods. Dual-echo, fast spin-echo MRI data were acquired from 10 TSC patients of normal intelligence and eight age-matched controls. Between-group dierences in grey matter, white matter and cerebrospinal fluid were estimated at each intracerebral voxel after registration of these images in standard space; a permutation test based on spatial statistics was used for inference. CSF-attenuated FLAIR images were acquired for neuroradiological rating of tuber number. Results. Significant deficits were found in patients, relative to comparison subjects, of grey matter volume bilaterally in the medial temporal lobes, posterior cingulate gyrus, thalamus and basal ganglia, and unilaterally in right fronto-parietal cortex (patients fi20%). We also found significant and approximately symmetrical deficits of central white matter involving the longitudinal fasciculi and other major intrahemispheric tracts (patients fi21%); and a bilateral cerebellar region of relative white matter excess (patients ›28%). Within the patient group, grey matter volume in limbic and subcortical regions of deficit was negatively correlated with tuber count. Conclusions. Neuropathological changes associated with TSC may be more extensive than hitherto suspected, involving radiologically normal parenchymal structures as well as tubers, although these two aspects of the disorder may be correlated.

Normal-appearing white matter changes in multiple sclerosis: the contribution of magnetic resonance techniques.

Several magnetic resonance (MR) techniques have proved to be sensitive enough to detect the subtle pathological changes that post-mortem studies showed to occur in the normal-appearing white matter (NAWM) from patients with multiple sclerosis (MS). Although these abnormalities can be detected in other neurological conditions, they seem to be more frequent and diffuse in MS. However, the contribution of NAWM changes to the diagnosis is still unclear. Their nature is also unknown and perhaps differs in different phases and clinical manifestations of the disease. Nevertheless, the extent and severity of NAWM damage seems to be relevant in causing disability and influencing the clinical evolution in MS patients. This review will summarize the present knowledge about MR-detected NAWM changes in MS and their relevance to the diagnosis and the understanding of disease evolution.

Normal-appearing white matter changes in multiple sclerosis: the contribution of magnetic resonance techniques

Several magnetic resonance (MR) techniques have proved to be sensitive enough to detect the subtle pathological changes that post-mortem studies showed to occur in the normal-appearing white matter (NAWM) from patients with multiple sclerosis (MS). Although these abnormalities can be detected in other neurologkal conditions, they seem to be more frequent and diffuse in MS. However, the contribution of NAWM changes to the diagnosis is still unclear. Their nature is also unknown and perhaps differs in different phases and clinical manifestations of the disease. Nevertheless, the extent and severity of NAWM damage seems to be relevant in causing disability and influencing the clinical evolution in MS patients. This review will summarize the present knowledge about MR-detected NAWM changes in MS and their relevance to the diagnosis and the understanding of disease evolution.

Spinal Cord Neuropathology in Rat Experimental Autoimmune Encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease of the central nervous system (CNS) in which clinical neurological signs and histopathologic changes of disease can be suppressed by feeding CNS myelin proteins. Using immunohistochemistry and image analysis, the cellular immune response was quantified over the rostral-caudal axis of the spinal cord in rats with EAE and in animals fed high- or low-dose myelin basic protein (MBP) prior to inducing EAE (tolerized animals). In a subset of rats, MBP was fed 9 days after MBP immunization to examine the effect of oral tolerance on the progression of CNS pathology. In unfed rats or rats fed vehicle only, activated microglia and macrophages were co-localized with T-lymphocytes throughout the spinal cord, but greater cellular reactions were evident in gray matter relative to white matter. In all tolerized animals, the CNS inflammatory response was reduced relative to controls. Subtle pathologic changes were occasionally observed in the CNS of MBP-fed animals, but the distribution of inflammatory cells in the dorso-ventral axis was more polarized in animals fed high-dose MBP. In this group, more T-cells and activated microglia were present in the dorsal spinal cord, specifically in the gray matter. In the group fed MBP after disease induction, clinical disease progressed as in control non-fed rats, but recovery from disease appeared to be accelerated. Thus, the results presented here provide a comprehensive analysis of the distribution and magnitude of inflammatory cells within the spinal cord in EAE and challenge the theory that MBP-induced EAE is only a white matter disease. These data also describe how the activation and distribution of immune effector cells is altered by oral tolerance and may help predict a range of neurological deficits not previously appreciated in EAE, particularly those effected by gray matter pathology.

Staging of alzheimer's disease-related neurofibrillary changes

Specific immunocytochemical methods (AT8) permit evaluation of neuronal changes well before the actual formation of neurofibrillary tangles and neuropil threads. Initial changes are found in the transentorhinal region (temporal lobe). From here the destructive process encroaches upon the entorhinal region, Ammon's horn, and neocortex. Initial changes occur in comparatively young individuals and can also be observed at the same predilection sites in a few species of old aged domestic animals. In a later state of destruction, AT8 immunoreactive neurons develop typical argyrophilic neurofibrillary tangles and neuropil threads. Six stages of disease propagation can be distinguished with respect to the location of the tangle-bearing neurons and the severity of changes (transentorhinal stages I–II: clinically silent cases; limbic stages III–IV: incipient Alzheimer's disease; neocortical stages V–VI: fully developed Alzheimer's disease). Whole mount techniques reveal the lesional pattern of the particularly severely involved superficial entorhinal layer as seen from the free surface of the parahippocampal gyrus. This approach facilitates recognition of even subtle pathologic changes throughout the entire extent of cortical territories such as the transentorhinal and entorhinal regions.

Endothelium-derived nitric oxide synthase inhibition. Effects on cerebral blood flow, pial artery diameter, and vascular morphology in rats.

We determined the effects of inhibiting the production of cerebral endothelium-derived nitric oxide on pial artery diameter, cortical blood flow, and vascular morphology. An inhibitor of endothelium-derived nitric oxide synthesis, NG-nitro-L-arginine methyl ester hydrochloride (L-NAME), or an equivalent volume of 0.9% saline was infused into rats intra-arterially in a retrograde fashion via the right external carotid artery at a rate of 3 mg/kg/min to a total dose of 190 mg/kg or intravenously at 1 mg/kg/min to a total dose of 15 mg/kg. Large pial arteries were continuously visualized through an operating microscope, and cortical cerebral blood flow was monitored by laser-Doppler flowmetry. To localize areas of morphological interest, the protein tracer horseradish peroxidase was injected 15 minutes before termination of the L-NAME infusion and the rats were perfusion-fixed 15 minutes later for light and electron microscopic analysis. Infusion of L-NAME significantly raised arterial blood pressure at both doses (for 190 mg/kg, from 103.2 +/- 3.4 to 135 +/- 3.4 mm Hg; for 15 mg/kg, from 125 +/- 2.8 to 144.4 +/- 4.0 mm Hg). Pial arteries constricted within 10 minutes after the start of the intracarotid infusion to 40% of the preinfusion diameter, while cortical cerebral blood flow decreased to an average of 72.5% of that at baseline. Morphological abnormalities in the experimental rats included microvascular stasis and focal areas of blood-brain barrier disruption to protein. Ultrastructural examination of cortical leaky sites revealed constricted arterioles with many endothelial pinocytotic vesicles and microvilli. These observations suggest that inhibition of endothelium-derived nitric oxide synthesis affects the relation between cerebral arterial diameter and cerebral blood flow and can lead to subtle cerebral vascular pathological changes consistent with focal brain ischemia.

Simultaneous comparison of pre- and post-microanastomotic hemodynamic profiles using a Tandem Doppler Probe

The use of High-Frequency Pulsed Doppler Ultrasound (HFPDU) for evaluation of microvascular hemodynamics is well established. Due to technical limitations of existing probes, quantitation of anastomotic stenoses and detailed waveform analyses are difficult to perform and impractical for clinical use. We present a new Tandem Doppler Probe (TDP) for simple and accurate study of blood flow in vessels smaller than 1 mm in diameter. Its unique ability to compare the pre- and post-anastomotic waveforms simultaneously allows for quantitative detection of anastomotic narrowing of as little as 5%, as well as identification of subtle pathologic anastomotic waveform changes not seen with single probes. Such early and precise delineation of anastomotic problems in the operating room can provide an invaluable, objective assessment of the technical adequacy of the anastomoses as well as an important baseline for later post-operative monitoring of free-tissue transfers with implantable Doppler devices.

Digital chest imaging using a 57-cm image intensifier: A receiver-operating characteristic study of user performance

Chest radiography provides one of the great challenges to digital diagnostic imaging because of (1) the relatively large size of the chest field, (2) the contrast range required to resolve subtle pathological changes in soft tissue density, and (3) the high degree of spatial resolution required to discriminate pathological detail. The field size problem was resolved by using a 57-cm image intensifier whose video output of the chest could be digitized. The issue of contrast resolution was addressed in a recently completed receiver-operating characteristic study of the detectability of low-contrast densities in a humanoid chest phantom. The latter indicated that, despite the smaller size of the digital image, they were adequate for resolving clinically significant soft-tissue densities. The question of spatial resolution in digital diagnostic images is addressed in the study presented. A set of 41 clinical cases were selected to provide the typical range of diagnostic type experienced in routine diagnostic radiology. The images were each presented as conventional film, digital laser-printer, and digital video images. The results of an ROC analysis of five readers' performance in each of the viewing modes is presented.

Unilateral Absence of a Palpable Vas Deferens-Reply

In Reply.— Unilateral absence of the kidney has been reported by Rubin 1 in 30% of patients with bilateral congenital absence of the vas deferens. In reviewing many case reports for our article, the incidence of unilateral renal agenesis in the presence of bilateral absence of the vas deferens was approximately 15% to 20%. We feel it is definitely warranted to perform a renal ultrasound examination in patients who present with bilateral absence of the vas deferens. We disagree with Dr Schneiderman regarding the use of gloves in the scrotal examination. Gloves should not be worn except in rare circumstances: patients with acquired immunodeficiency syndrome who have fistulas, patients with draining scrotal abscesses, etc. Gross scrotal abnormalities can be easily detected on examination whether gloves are worn or not. The more subtle scrotal pathological changes and, in particular, the one abnormality that can be fatal to the patient, the testis tumor,

Electron Microscopy of the Pathology and Chemotherapy of Legionella pneumophila Infection in the Chick Embryo

The ultrastructural pathology induced in organs of chick embryos previously infected with 100 times the yolk sac LD50 of Legionella pneumophila was examined by electron microscopy. Subtle pathological changes were observed three days post-inoculation while more extensive cellular and sub-cellular necrosis occurred at four days post-inoculation. Selected antimicrobial agents were administered three days after infection and evaluated for their ability to reduce or reverse ultrastructural lesions. In this study, ciprofloxacin was the only antibiotic that reversed tissue damage induced in response to infection with L. pneumophila while doxycycline, erythromycin, and rifampicin were also effective, but to a lesser degree. These results demonstrated the superior antimicrobial activity of ciprofloxacin and further illustrated the efficacy of the fertile hen's egg as a useful in vivo assay system for the evaluation at the ultrastructural level of putative chemotherapeutic agents for the treatment of Legionnaires' disease.

Freeze-fracture elucidation of hepatocyte membrane alterations following β-pyridylcarbinol application

The effect of beta-pyridylcarbinol on mice was investigated in long-term studies (21 days, daily dose of 0.1 mg) making use of thin-sectioning and freeze-fracture techniques. Thin sectioning merely revealed only subtle pathological changes including dilatation of the intercellular space and foundation of hepatocytic vacuoles. Only upon investigation using freeze-fracture was it possible to demonstrate more profound alterations, primarily involving the cell contacts, i.e. the gap and tight junctions. The organized structure of the tight junctions appeared dissipated. The meshwork was disorganized in some cases and reduced in size. Large, proliferative tight junctional maculae were frequently observed on the plasmalemma. In some cases the gap junctions had lost their round to oval shape and had increased in size to form large plaques protruding at numerous points. Moreover, even the bile canaliculi, which presented no pathological alterations on ultrathin section, exhibited damage as seen in freeze-fracture preparations. The lumen was uneven in contour and processes were visible extending into the adjacent cytoplasm. The present investigation shows that hepatocytic damage primarily affecting the membranes was first made evident using freeze-fracture technique. The issue is addressed as to the extent to which freeze-fracture technique should be employed in routine investigations of pharmaceuticals.

Slit-Lamp Biomicroscopy

Slit-lamp biomicroscopy provides brilliant illumination and high magnification, revealing subtle pathological changes that suggest or corroborate provisional diagnoses. This technique is not difficult and can be mastered quickly. The detection of dry eye syndrome prior to blepharoplasty should alert the surgeon to the possibility of painful post-operative exposure keratitis if lid closure is interfered with. Visualization of pathological features allows almost certain diagnosis of small basal cell carcinomas, and better appreciation of the true extent of the neoplasm for planning excisional margins. Certain oculocutaneous syndromes can be diagnosed and involvement of ocular adnexal and periocular tissues can be appreciated prior to facial plastic surgery.