Polineuropatia motora em cão adulto / Motor polyneuropathy in an adult dog

Background: Nonambulatory flaccid tetraparesis can be the result of diseases of the peripheral nervous system and it is characterized by generalized lower motor neuron (LMN) signs, as weakness, tetraparesis/tetraplegia, decreased muscle tone and reflexes. The term polyneuropathy is used for dysfunction of multiple peripheral nerves. In Brazil, there are several etiologies for polyneuropathy in dogs, such as acute idiopathic polyradiculoneuritis, botulism and myasthenia gravis. Toxoplasma gondii is an uncommon cause of LMN diseases in dogs. The aim of this report was to describe a case of flaccid tetraplegia toxoplasmosis in an adult dog with a Toxoplasma gondii serology with a markedly elevated IgG titer of 1:4096. Case: A 4-year-old intact mongrel male dog, weighing 19.6 kg, was referred to the Veterinary Medical Teaching Hospital of the Universidade Estadual de Londrina (UEL) with a 5-day history of weakness that progressed to tetraparesis. Physical examination revealed no significant changes other than the dull and unkempt coat. Neurologic examination revealed severe tetraparesis that was worse in the pelvic limbs, with decreased muscle tone in all four limbs. Postural reactions and the interdigital reflex were absent in all four limbs, as was the patellar reflex, but pain perception was present. There were no clinical signs of dysfunction on examination of the cranial nerves. Laboratory tests were performed, and creatine kinase was elevated (819 U/L). Blood was drawn to look for antibodies to Toxoplasma gondii and Neospora caninum class IgG using the indirect immunofluorescence technique. The antibody titer for Toxoplasma gondii (IgG) was 1:4096. A chest radiograph was performed to look for megaesophagus, and a pulmonary pattern suggestive of mild diffuse pneumonia was observed. Treatment was performed with sulfamethoxazole and trimethoprim, and the dog's condition improved slightly. Discussion: Based on lower motor neuron findings, the neurologic lesion was localized in the nerve roots, peripheral nerves, neuromuscular junctions, or muscles. The most important diseases in the list of differential diagnoses were immune-mediated or infectious polyradiculoneuritis (toxoplasmosis, neosporosis), myasthenia gravis, toxic polyneuropathy (botulism, chronic organophosphate poisoning), and paraneoplastic polyneuropathy. Among these differential diagnoses, polyradiculoneuritis is one of the most common. It is an idiopathic inflammatory disease. Exposure to raccoon saliva (in the U.S.), vaccination, or infection have been proposed as precipitating causes, but the triggers of this disease remain unknown. Serology for neosporosis was negative, while IgG titers for toxoplasmosis were 1:4096. In a previous study, dogs with acute polyradiculoneuritis were more likely to have T. gondii IgG serum antibody titers than dogs without neurologic signs. Infection with the protozoa T. gondii and N. caninum can cause intense polyradiculoneuritis in dogs accompanied by myositis, especially in puppies. One treatment trial was based on the administration of sulfonamide-trimethoprim with pyrimethamine, whose efficacy in the treatment of toxoplasmosis in dogs has also been reported in the literature. Neurologic deficits improved slightly, and there is a possibility that certain signs may not disappear completely because of the permanent damage caused by inflammation of the nervous system, as observed in the present case. The case had the limitation that it was not possible to perform other laboratory tests to demonstrate histopathologically the presence of Toxoplasma gondii organisms in muscles or nerves. Recovery of normal function is less likely in protozoan polyradiculoneuritis than in noninfectious polyradiculoneuritis. Thus, in the present case, the main suspicion was polyradiculoneuritis secondary to toxoplasmosis. Although it is a rare condition, it is important to consider toxoplasmosis in dogs with LMN-type tetraparesis or tetraplegia.

Axon microdissection and transcriptome profiling reveals the in vivo RNA content of fully differentiated myelinated motor axons.

Axonal protein synthesis has been shown to play a role in developmental and regenerative growth, as well as in the maintenance of the axoplasm in a steady state. Recent studies have begun to identify the mRNAs localized in axons, which could be translated locally under different conditions. Despite that by now hundreds or thousands of mRNAs have been shown to be localized into the axonal compartment of cultured neurons in vitro, knowledge of which mRNAs are localized in mature myelinated axons is quite limited. With the purpose of characterizing the transcriptome of mature myelinated motor axons of peripheral nervous systems, we modified the axon microdissection method devised by Koenig, enabling the isolation of the axoplasm RNA to perform RNA-seq analysis. The transcriptome analysis indicates that the number of RNAs detected in mature axons is lower in comparison with in vitro data, depleted of glial markers, and enriched in neuronal markers. The mature myelinated axons are enriched for mRNAs related to cytoskeleton, translation, and oxidative phosphorylation. Moreover, it was possible to define core genes present in axons when comparing our data with transcriptomic data of axons grown in different conditions. This work provides evidence that axon microdissection is a valuable method to obtain genome-wide data from mature and myelinated axons of the peripheral nervous system, and could be especially useful for the study of axonal involvement in neurodegenerative pathologies of motor neurons such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophies (SMA).

DMT1 iron uptake in the PNS: bridging the gap between injury and regeneration.

Previous studies by our group demonstrated the key role of iron in Schwann cell maturation through an increase in cAMP, PKA activation and CREB phosphorylation. These studies opened the door to further research on non-transferrin-bound iron uptake, which revealed the presence of DMT1 mRNA all along SC progeny, hinting at a constitutive role of DMT1 in ensuring the provision of iron in the PNS. In light of these previous results, the present work evaluates the participation of DMT1 in the remyelination process following a demyelinating lesion promoted by sciatic nerve crush--a reversible model of Wallerian degeneration. DMT1 was observed to colocalize with a SC marker S100ß at all survival times analyzed. In turn, the assessment of DMT1 mRNA expression exhibited an increase 7 days post-injury, while DMT1 protein levels showed an increase 14 days after crush at the lesion site and distal stump; finally, an increase in iron levels became evident as from 14 days post-injury, in parallel with DMT1 values. To sum up, the present work unveils the role of DMT1 in mediating the neuroregenerative action of iron.

Neurotrauma and inflammation: CNS and PNS responses.

Traumatic injury to the central nervous system (CNS) or the peripheral nervous system (PNS) triggers a cascade of events which culminate in a robust inflammatory reaction. The role played by inflammation in the course of degeneration and regeneration is not completely elucidated. While, in peripheral nerves, the inflammatory response is assumed to be essential for normal progression of Wallerian degeneration and regeneration, CNS trauma inflammation is often associated with poor recovery. In this review, we discuss key mechanisms that trigger the inflammatory reaction after nervous system trauma, emphasizing how inflammations in both CNS and PNS differ from each other, in terms of magnitude, cell types involved, and effector molecules. Knowledge of the precise mechanisms that elicit and maintain inflammation after CNS and PNS tissue trauma and their effect on axon degeneration and regeneration is crucial for the identification of possible pharmacological drugs that can positively affect the tissue regenerative capacity.

Stimulation of peripheral kappa opioid receptors inhibits inflammatory hyperalgesia via activation of the PI3Kγ/AKT/nNOS/NO signaling pathway.

BACKGROUND: In addition to their central effects, opioids cause peripheral analgesia. There is evidence showing that peripheral activation of kappa opioid receptors (KORs) inhibits inflammatory pain. Moreover, peripheral µ-opioid receptor (MOR) activation are able to direct block PGE(2)-induced ongoing hyperalgesia However, this effect was not tested for KOR selective activation. In the present study, the effect of the peripheral activation of KORs on PGE(2)-induced ongoing hyperalgesia was investigated. The mechanisms involved were also evaluated. RESULTS: Local (paw) administration of U50488 (a selective KOR agonist) directly blocked, PGE(2)-induced mechanical hyperalgesia in both rats and mice. This effect was reversed by treating animals with L-NMMA or N-propyl-L-arginine (a selective inhibitor of neuronal nitric oxide synthase, nNOS), suggesting involvement of the nNOS/NO pathway. U50488 peripheral effect was also dependent on stimulation of PI3Kγ/AKT because inhibitors of these kinases also reduced peripheral antinociception induced by U50488. Furthermore, U50488 lost its peripheral analgesic effect in PI3Kγ null mice. Observations made in vivo were confirmed after incubation of dorsal root ganglion cultured neurons with U50488 produced an increase in the activation of AKT as evaluated by western blot analyses of its phosphorylated form. Finally, immunofluorescence of DRG neurons revealed that KOR-expressing neurons also express PI3Kγ (≅ 43%). CONCLUSIONS: The present study indicates that activation of peripheral KORs directly blocks inflammatory hyperalgesia through stimulation of the nNOS/NO signaling pathway which is probably stimulated by PI3Kγ/AKT signaling. This study extends a previously study of our group suggesting that PI3Kγ/AKT/nNOS/NO is an important analgesic pathway in primary nociceptive neurons.

Harpejamento em eqüinos no Rio Grande do Sul / Stringhalt in horses from the state of Rio Grande do Sul, Brazil

São relatados a epidemiologia, os sinais clínicos e aspectos macro e microscópicos de casos de harpejamento ocorridos de 2000 a 2005 em eqüinos de oito propriedades rurais de seis municípios do Rio Grande do Sul. Pelo menos 10 eqüinos foram afetados, com idades variando entre 1 e 13 anos (média de 6,2 anos) e 1-2 eqüinos foram afetados por propriedade. Dentre os fatores que podem ter influenciado o aparecimento da doença está incluída a escassez de forragem devido à seca. A presença da planta Hypochaeris radicata, freqüentemente implicada como causa de harpejamento em eqüinos, foi observada na pastagem de três entre cinco propriedades onde a ocorrência dessa planta foi investigada; em seis dessas propriedades a forragem era pouca devido à falta de chuva. A morbidade foi estimada em 17,3 por cento e a letalidade foi perto de zero, embora dois eqüinos tenham sido submetidos à eutanásia para serem necropsiados. Os sinais clínicos característicos incluiam hiperflexão dos membros pélvicos, dificuldade de caminhar e andar com saltos tipo pulos de coelho. Foi feita uma graduação da intensidade dos sinais clínicos em um escore de números de 1 a 5, os números mais altos indicando um grau de intensidade maior. Três eqüinos foram graduados como 1, um eqüino como 2, três eqüinos como 3, um eqüino como 4 e dois eqüinos como 5. O tratamento com fenitoína em dois eqüinos e com fenitoína associada a tenectomia em um outro não resultou em melhora do quadro clínico. Quatro dos 10 cavalos com harpejamento examinados clinicamente se recuperaram sem tratamento após uma doença clínica com evolução de 2-4 meses e quatro cavalos não se recuperaram mesmo após 9-17 meses de doença clínica, quando foram examinados pela última vez. Os achados de necropsia incluíam atrofia dos músculos esqueléticos das grandes massas musculares, confirmada histologicamente. A avaliação histológica dos nervos periféricos de um eqüino afetado submetido à eutanásia revelou redução ou ausência ...(AU)

The epidemiology, clinical, gross and histological findings of cases of stringhalt occurring in horses from eight farms in six counties in the State of Rio Grande do Sul, Brazil from 2000-2005 are reported. At least 10 horses were affected. Ages of affected horses were 1-13 years (average 6.2 years) and 1-2 horses were affected in each farm. Factors that might have influenced the appearance of the disease included dearth of forage due to insufficient rainfall. The presence of the plant Hypochaeris radicata, often implicated as a cause of stringhalt in horses, was observed in the pasture of three out of five evaluated farms and in six of these farms the pasture was poor due to scarse precipitation. Estimated morbidity was 17.3 percent and lethality was close to zero although two horses were euthanatized for necropsy. Characteristic clinical signs included excessive flexion of the stifle and hock joints, impaired ambulation and bunny hop-type of gait. Clinical disease was graded by number scores from 1-5, higher numbers indicating increasing severity. Three horses were graded as 1, one horse as 2, three horses as 3, one horse as 4 and two horses as 5. Treatment with phenytoin in two horses and with phenytoin and tenectomy in another one did not result in amelioration of the clinical signs. Four out of ten clinical examined horses with stringhalt recovered with no treatment within 2-4 months of clinical disease and four affected horses did not recover even after 9-17 months of clinical disease, when they were lastly examined. Necropsy findings included atrophy of skeletal muscle of the large muscular groups which was confirmed histologically. Histological evaluation of peripheral nerves of one of the euthanatized horses revealed reduction or absence of myelinated fibers. Ultrastructural findings included signs of demyelination, regeneration and remyelination of peripheral nerves.(AU)

Harpejamento em eqüinos no Rio Grande do Sul / Stringhalt in horses from the state of Rio Grande do Sul, Brazil

São relatados a epidemiologia, os sinais clínicos e aspectos macro e microscópicos de casos de harpejamento ocorridos de 2000 a 2005 em eqüinos de oito propriedades rurais de seis municípios do Rio Grande do Sul. Pelo menos 10 eqüinos foram afetados, com idades variando entre 1 e 13 anos (média de 6,2 anos) e 1-2 eqüinos foram afetados por propriedade. Dentre os fatores que podem ter influenciado o aparecimento da doença está incluída a escassez de forragem devido à seca. A presença da planta Hypochaeris radicata, freqüentemente implicada como causa de harpejamento em eqüinos, foi observada na pastagem de três entre cinco propriedades onde a ocorrência dessa planta foi investigada; em seis dessas propriedades a forragem era pouca devido à falta de chuva. A morbidade foi estimada em 17,3 por cento e a letalidade foi perto de zero, embora dois eqüinos tenham sido submetidos à eutanásia para serem necropsiados. Os sinais clínicos característicos incluiam hiperflexão dos membros pélvicos, dificuldade de caminhar e andar com saltos tipo pulos de coelho. Foi feita uma graduação da intensidade dos sinais clínicos em um escore de números de 1 a 5, os números mais altos indicando um grau de intensidade maior. Três eqüinos foram graduados como 1, um eqüino como 2, três eqüinos como 3, um eqüino como 4 e dois eqüinos como 5. O tratamento com fenitoína em dois eqüinos e com fenitoína associada a tenectomia em um outro não resultou em melhora do quadro clínico. Quatro dos 10 cavalos com harpejamento examinados clinicamente se recuperaram sem tratamento após uma doença clínica com evolução de 2-4 meses e quatro cavalos não se recuperaram mesmo após 9-17 meses de doença clínica, quando foram examinados pela última vez. Os achados de necropsia incluíam atrofia dos músculos esqueléticos das grandes massas musculares, confirmada histologicamente. A avaliação histológica dos nervos periféricos de um eqüino afetado submetido à eutanásia revelou redução ou ausência ...

The epidemiology, clinical, gross and histological findings of cases of stringhalt occurring in horses from eight farms in six counties in the State of Rio Grande do Sul, Brazil from 2000-2005 are reported. At least 10 horses were affected. Ages of affected horses were 1-13 years (average 6.2 years) and 1-2 horses were affected in each farm. Factors that might have influenced the appearance of the disease included dearth of forage due to insufficient rainfall. The presence of the plant Hypochaeris radicata, often implicated as a cause of stringhalt in horses, was observed in the pasture of three out of five evaluated farms and in six of these farms the pasture was poor due to scarse precipitation. Estimated morbidity was 17.3 percent and lethality was close to zero although two horses were euthanatized for necropsy. Characteristic clinical signs included excessive flexion of the stifle and hock joints, impaired ambulation and bunny hop-type of gait. Clinical disease was graded by number scores from 1-5, higher numbers indicating increasing severity. Three horses were graded as 1, one horse as 2, three horses as 3, one horse as 4 and two horses as 5. Treatment with phenytoin in two horses and with phenytoin and tenectomy in another one did not result in amelioration of the clinical signs. Four out of ten clinical examined horses with stringhalt recovered with no treatment within 2-4 months of clinical disease and four affected horses did not recover even after 9-17 months of clinical disease, when they were lastly examined. Necropsy findings included atrophy of skeletal muscle of the large muscular groups which was confirmed histologically. Histological evaluation of peripheral nerves of one of the euthanatized horses revealed reduction or absence of myelinated fibers. Ultrastructural findings included signs of demyelination, regeneration and remyelination of peripheral nerves.

Adenomyomatous hyperplasia of the gallbladder with perineural invasion: revisited.

We report 9 examples of segmental adenomyomatous hyperplasia of the gallbladder with perineural invasion. Five patients were women and 4 men. Their ages ranged from 49 to 81 years (mean age 64 y). Eight patients had gallbladder calculi. The original pathologic diagnosis of adenocarcinoma was made in 5 patients and of "adenoma malignum" in one. Six patients are disease-free for 2 to 11 years following cholecystectomy, 1 patient died of unrelated causes and 2 were lost to follow-up. Histologically 2 types of adenomyomatous hyperplasia were recognized. The first one characterized by numerous Rokitansky-Aschoff sinuses (RASs) was accompanied by smooth muscle hyperplasia and an expanded subserosal layer containing numerous nerve trunks (6 cases). The second type was characterized by an extensively fibrotic gallbladder wall with numerous RASs but with few or no smooth muscle bundles and an expanded subserosal layer containing abundant nerve-trunks (3 cases). Perineural (7 cases) and intraneural invasion (2 cases) was identified only in the subserosal layer. The lack of p53 reactivity and the very low MIB-1-labeling index provide additional support to the non-neoplastic nature of the lesion. The pseudoinvasive pattern of the RASs, reactive epithelial atypia, and the perineural and intraneural invasion probably contributed to the erroneous diagnosis of adenocarcinoma or "adenoma malignum." The mechanism by which the epithelial structures "invaded" the perineural spaces and the nerves is unclear. We favor the hypothesis that the migration of the benign glandlike structures into the nerves is related to the production of chemotactic factors or signaling substances and the activation of cell receptors.

Perineural invasion by transitional cell carcinoma of the bladder in patients submitted to radical cystectomy: what is the prognostic value?

OBJECTIVE: Determine the prognostic value of perineural invasion (PNI) in patients with transitional cell carcinoma (TCC) of the bladder treated with radical cystectomy. MATERIALS AND METHODS: From January 1993 to January 2005, 113 people were selected from 153 patients with TCC of the bladder treated with radical cystectomy. The association between the presence of PNI and other pathologic characteristics were analyzed through Fisher exact test. The Kaplan-Meier method was utilized to assess the survival curve and the statistical significance was determined by the Breslow test. The multivariate analysis was performed through the Cox regression model. RESULTS: The PNI was identified in 10 (8.8%) of the 113 patients. This variable significantly related to the microvascular invasion and to tumor staging. The mean segment after surgery was 31.7 +/- 28.5 months. Recurrence occurred in 5 (50%) and in 41 (39.8%) patients (p=0.363) and mortality occurred in 2 (20%) and 22 (21.9%) patients (p=0.606) with or without PNI respectively. In Cox regression analysis, patients with PNI presented with 1.53 times (IC 95% 0.60 to 3.91; p=0.371) and 1.60 times (IC 95% 0.37 to 6.95; p=0.532) the risk of recurrence and mortality when compared to patients without PNI. CONCLUSIONS: The PNI does not constitute an independent variable of disease-free and cancer specific survival in patients with TCC of the bladder treated with radical cystectomy.

Perineural invasion by transitional cell carcinoma of the bladder in patients submitted to radical cystectomy: what is the prognostic value?

OBJECTIVE: Determine the prognostic value of perineural invasion (PNI) in patients with transitional cell carcinoma (TCC) of the bladder treated with radical cystectomy. MATERIALS AND METHODS: From January 1993 to January 2005, 113 people were selected from 153 patients with TCC of the bladder treated with radical cystectomy. The association between the presence of PNI and other pathologic characteristics were analyzed through Fisher exact test. The Kaplan-Meier method was utilized to assess the survival curve and the statistical significance was determined by the Breslow test. The multivariate analysis was performed through the Cox regression model. RESULTS: The PNI was identified in 10 (8.8 percent) of the 113 patients. This variable significantly related to the microvascular invasion and to tumor staging. The mean segment after surgery was 31.7 ± 28.5 months. Recurrence occurred in 5 (50 percent) and in 41 (39.8 percent) patients (p = 0.363) and mortality occurred in 2 (20 percent) and 22 (21.9 percent) patients (p = 0.606) with or without PNI respectively. In Cox regression analysis, patients with PNI presented with 1.53 times (IC 95 percent 0.60 to 3.91; p = 0.371) and 1.60 times (IC 95 percent 0.37 to 6.95; p = 0.532) the risk of recurrence and mortality when compared to patients without PNI. CONCLUSIONS: The PNI does not constitute an independent variable of disease-free and cancer specific survival in patients with TCC of the bladder treated with radical cystectomy.

Microscopic leprosy skin lesions in primary neuritic leprosy.

The histologic diagnosis of primary neuritic leprosy (PNL) remains a public health care concern, especially when nerve biopsies cannot be performed. As such, some authors emphasize the importance of performing a skin biopsy of a hypoesthetic area even without clinically visible lesions. In this study, an attempt was made to define the histologic changes in the sensory altered skin of 42 clinically diagnosed PNL patients. Histologic alterations caused by leprosy were seen in 31% of these patients: 6 were classified as borderline tuberculoid and 7 as indeterminate. In addition, 33% showed mild, non-specific, mononuclear cell infiltrates around the blood vessels within the papillary and reticular dermis that probably reflected an early inflammatory reaction to Mycobacterium leprae infection. Only 36% of those biopsied had no significant lesions. Our results suggested that, while not all PNL patients are similar, histologic skin examination can contribute to early leprosy detection and commencement of adequate treatment.

Fisioterapia aplicada aos idosos portadores de disfunções neurológicas / Physical therapy applied to the aged carrier of neurologic dysfunctions

Enfoca as alterações do sistema nervoso central (SNC)e periférico (SNP) que ocorrem no envelhecimento normal, comparando-as, posteriormente, aos distúrbios neurológicos mais freqüentes relacionados com a idade e que comprometem as atividades funcionais nesta faixa etária

Alterações do sistema nervoso central e periférico / Alterations of the central and peripheral nervous system

As complicações que acontecem no sistema nervoso central e periférico continuam presentes mesmo com novas técnicas de cirurgia cardíaca, também contribuindo para isso o aumento da média de idade dos pacientes. As encefalopatias tóxicas e metabólicas são comuns, porém de controle clínico satisfatório na maioria das vezes. As alterações comportamentais agudas e crônicas estão amplamente demonstradas. O acidente vascular cerebral isquêmico é complicação com alta morbidade, sendo mais comum em cirurgias intracardíacas. As artérias aorta e carótida também têm papel importante na causa de acidente vascular cerebral. O acidente vascular cerebral hemorrágico é menos freqüente. O diagnóstico e o tratamento são específicos para cada tipo. A encefalopatia anóxica pode levar a coma transitório, com recuperação ou estado vegetativo permanente. As convulsões podem ter manifestação isolada ou associada a outras complicações. Existe tratamento medicamentoso específico. As lesões do sistema nervoso periférico mais comuns são as do plexo braquial.

El sistema APUD en la oftalmología IV. tumor del sistema nervioso periférico / APUD system in ophthalmology IV. pheripheral nervous system tumors

Los tumores del sistema periférico en oftalmología son poco frecuentes y algunos excepcionales. Los derivados de las simpaticogonias o neuroblastos constituyen el espectro de los neuroblastomas, ganglioneuroblastomas y ganglioneuromas; los derivados de los troncos nerviosos son los neurofibromas, schwannomas y neuromas. Los paragangliomas y quimiodectomas son excepcionales y el tumor de tritón es una verdadera rareza. Algunas de estas neoplasias se encuentran formando parte de síndromes complejos con clara connotación heredofamiliar. Se realiza una revisión clinicopatológica cuidadosa de estas entidades.

Ultrastructural changes in limb distal nerves of rats with alcoholism and/or malnutrition before and after dietary correction.

To study peripheral nerves changes in chronic alcoholism and in malnutrition, we examined ultrastructurally the distal nerve branches of the digits of rats treated with four different dietary schemes, as follows: controls (n = 22), fed standard rodent diet plus water ad libitum; alcoholism (n = 12), fed the standard diet and 2-12% ethanol in drinking water; malnutrition (n = 21), fed with corn tortillas instead of standard diet; and alcoholism and malnutrition combined (n = 22). After 10 months under these conditions, a proportion of animals from each group were sacrificed. The remaining rats of the malnutrition and alcoholism alone groups were deferred a standard diet. The combined alcohol + malnutrition group was subdivided into standard diet, malnutrition and ethanol. After a further 4 months under these new conditions, the animals were sacrificed. Ultrastructural examination of limb distal nerve branches showed that glycogen-like particles were more common in malnourished animals, whereas remyelinating axons were more numerous in ethanol-treated rats. Bands of regeneration were present in both groups, but were more common in animals treated with ethanol. These features decreased significantly when the respective nutritional factor was reversed. The results confirm that ethanol plays a definitive role in the development of alcoholic neuropathy and that malnutrition accentuates, the histopathological abnormalities.