Rani Kanthan

Progressive decrease in extracellular GABA concentrations in the post-ischemic period in the striatum : a microdialysis study

Repetitive cerebral ischemia in gerbils produces delayed neuronal damage in the substantia nigra reticulata (SNr). This damage begins 4 to 5 days after the insult and is severe by day 7. The damage can be attenuated by GABA agonists. There is a prominent GABAergic striatal pathway to the SNr. Damage to this pathway leads to progressive loss of SNr neurons. This loss can be prevented by GABA agonists. We postulate that, ischemia-induced lack of GABAergic inhibitory input from the striatum to the SNr, may be responsible for this delayed neuronal damage. In the present experiment, we have measured striatal extracellular GABA concentrations with or without nipecotic acid, a GABA-reuptake inhibitor, in gerbils exposed to repetitive ischemia. GABA levels were measured on days 1, 3, 5, and 7 after the ischemic insult. Five control animals and a similar number of ischemic animals were monitored on each day. Extracellular fluid was collected using in vivo microdialysis and GABA levels were measured by electrochemical detection with HPLC. The extracellular striatal GABA levels were very low in the initial three specimens collected, both in the control and in the ischemic animals. However, addition of nipecotic acid resulted in an immediate increase of GABA in measurable range. In comparison to the controls, the increase in GABA on day 1 and 3 were significantly higher in animals with repetitive ischemia (two-way ANOVA with repeated measures). Subsequent measurements showed a gradual decrease in GABA levels when compared to controls. The increase in GABA with nipecotic acid was significantly lower on day 7 after the ischemic insults when compared to the controls. The increased GABA responsiveness immediately after the ischemic insults may reflect a protective effect against excitotoxicity. The subsequent decline in GABA levels after the insult may be secondary to progressive loss of striatal GABAergic neurons. This may contribute to the production of delayed neural damage in the SNr by a decrease in the inhibitory striatal input.

Effects of clomethiazole on radial-arm maze performance following global forebrain ischemia in gerbils.

The functional and neuroanatomical protective effects of clomethiazole (CMZ) were examined in an animal model of global forebrain ischemia. Gerbils underwent sham-surgery or were rendered ischemic by the application of aneurysm clips to both carotid arteries for 6 min. Three treatment groups received CMZ (50 mg/kg, 100 mg/kg, or 150 mg/kg) 30 min before ischemia, and one group was given 150 mg/kg of CMZ 30 min after ischemia. Following recovery, the gerbils were tested in a radial-arm maze to assess memory functions. Histological evaluation was assessed blindly using a percentile scoring system. The results indicate that pre-ischemic treatment with 100 mg/kg and 150 mg/kg of CMZ reduced brain damage and working memory errors significantly. Treatment dosage of 150 mg/kg of CMZ was the most effective in preventing neuronal damage in the hippocampus and eliminating the working memory deficit typically induced by ischemia.

In-vivo microdialysis study of extracellular glutamate response to temperature variance in subarachnoid hemorrhage.

Neurochemical changes may precede the development of clinical signs in neurological disease. Early identification of such changes may offer an opportunity to avoid or treat complications. Under experimental conditions, extracellular levels of glutamate and other amino acids can be monitored by in-vivo microdialysis in cerebral ischemia, head trauma and epilepsy. Data on the release of glutamate under ischemic conditions in humans are limited. There is no published data on the effects of temperature variation or other manipulations on the extracellular glutamate levels in humans. We report for the first time, the effects of changes in temperature on the extracellular cerebral glutamate levels as measured by in-vivo microdialysis, the dialysate being collected before, during and after cooling in four patients with subarachnoid hemorrhage. Three of the patients had in-vivo microdialysis carried out postoperatively. One patient underwent microdialysis three days prior to the surgical clipping of the aneurysm. In all patients, mild head cooling resulted in a significant decrease in extracellular glutamate levels. The effect of cooling was most apparent when the extracellular glutamate concentrations were high. In two patients, the extracellular glutamate levels increased sharply with fever but returned to normal once the temperature normalized. In vivo microdialysis can be used to measure extracellular glutamate and other neurotransmitters with minimal discomfort in awake humans. This technique offers a unique opportunity to monitor the neurochemistry in critically ill patients and it may aid in developing therapeutic intervention strategies to minimize undesired chemical responses.

Three uncommon adrenal incidentalomas: a 13-year surgical pathology review

BackgroundThe discovery of adrenal incidentalomas due to the widespread use of sophisticated abdominal imaging techniques has resulted in an increasing trend of adrenal gland specimens being received in the pathology laboratory. In this context, we encountered three uncommon adrenal incidentalomas.The aim of this manuscript is to report in detail the three index cases of adrenal incidentalomas in the context of a 13-year retrospective surgical pathology review.MethodsThe three index cases were investigated and analyzed in detail with relevant review of the English literature as available in PubMed and Medline. A 13-year retrospective computer-based histopathological surgical review was conducted in our laboratory and the results were analyzed in the context of evidence-based literature on adrenal incidentalomas.ResultsA total of 94 adrenal specimens from incidentalomas were identified, accounting for 0.025% of all surgical pathology cases. In all 76.6% were benign and 23.4% were malignant. A total of 53 females (56.4%) and 41 males (43.6%) aged 4 to 85u2009years were identified. The benign lesions included cortical adenoma (43.1%), pheochromocytoma (29.3%) and inflammation/fibrosis/hemorrhage (8.3%). Metastatic neoplasms were the most common malignant lesions (50%) followed by primary adrenocortical carcinomas (31.8%) and neuroblastoma (13.6%). These cases were discovered as adrenal incidentalomas that led to surgical exploration.The three index cases of adrenal incidentalomas with unusual pathologies were encountered that included (a) adrenal ganglioneuroma, (b) periadrenal schwannoma and (c) primary adrenal pleomorphic leiomyosarcoma. These cases are discussed, with a literature and clinicopathological review.ConclusionsAdrenal lesions are uncommon surgical specimens in the pathology laboratory. However, higher detection rates of adrenal incidentalomas aided by the ease of laparoscopic adrenalectomy has resulted in increased adrenal surgical specimens leading to unsuspected diagnostic and management dilemmas. Accurate pathological identification of common and uncommon adrenal incidentalomas is essential for optimal patient management.

Expression of cell cycle proteins in male breast carcinoma.

IntroductionMale breast cancer (MBC) is a rare, yet potentially aggressive disease. Although literature regarding female breast cancer (FBC) is extensive, little is known about the etiopathogenesis of male breast cancer. Studies from our laboratory show that MBCs have a distinct immunophenotypic profile, suggesting that the etiopathogenesis of MBC is different from FBCs. The aim of this study was to evaluate and correlate the immunohistochemical expression of cell cycle proteins in male breast carcinoma to significant clinico-biological endpoints.Methods75 cases of MBC were identified using the records of the Saskatchewan Cancer Agency over 26 years (1970-1996). Cases were reviewed and analyzed for the immunohistochemical expression of PCNA, Ki67, p27, p16, p57, p21, cyclin-D1 and c-myc and correlated to clinico-biological endpoints of tumor size, node status, stage of the disease, and disease free survival (DFS).ResultsDecreased DFS was observed in the majority of tumors that overexpressed PCNA (98%, p = 0.004). The overexpression of PCNA was inversely correlated to the expression of Ki67 which was predominantly negative (78.3%). Cyclin D1 was overexpressed in 83.7% of cases. Cyclin D1 positive tumors were smaller than 2 cm (55.6%, p = 0.005), had a low incidence of lymph node metastasis (38.2%, p = 0.04) and were associated with increased DFS of >150 months (p = 0.04). Overexpression of c-myc (90%) was linked with a higher incidence of node negativity (58.3%, p = 0.006) and increased DFS (p = 0.04). p27 over expression was associated with decreased lymph node metastasis (p = 0.04). P21 and p57 positive tumors were related to decreased DFS (p = 0.04). Though p16 was overexpressed in 76.6%, this did not reach statistical significance with DFS (p = 0.06) or nodal status (p = 0.07).ConclusionAberrant cell cycle protein expression supports our view that these are important pathways involved in the etiopathogenesis of MBC. Tumors with overexpression of Cyclin D1 and c-myc had better outcomes, in contrast to tumors with overexpression of p21, p57, and PCNA with significantly worse outcomes. P27 appears to be a predictive marker for lymph nodal status. Such observation strongly suggests that dysregulation of cell cycle proteins may play a unique role in the initiation and progression of disease in male breast cancer. Such findings open up new avenues for the treatment of MBC as a suitable candidate for novel CDK-based anticancer therapies in the future.

Collision tumor of the colon – colonic adenocarcinoma and ovarian granulosa cell tumor

BackgroundCollision tumors of the colon are rare. We report the first case, to our knowledge in the English literature, of a collision tumor composed of a colonic adenocarcinoma arising in a sigmoid diverticulum coexisting with a recurrent ovarian granulosa cell tumor.Case presentationA 64-year old woman presented with small bowel obstruction and a large, heterogenous, solid/cystic serosal based pelvic mass consistent with a gastrointestinal stromal tumor on imaging. Her significant past history 16-years ago included a bilateral salpingo-oophrectomy with hysterectomy. Surgical removal of the mass and pathological examination revealed the presence of a colonic adenocarcinoma arising in a large sigmoid diverticulum coexistent with a second neoplastic tumor phenotype; confirmed to be a delayed recurrent ovarian granulosa cell tumor. Though coexistent, the two tumor phenotypes respected their boundaries with no diffuse intermingling or transition between them. She developed lung metastases from the recurrent ovarian tumor within 6 months and died within a year of follow-up.ConclusionCollision tumors of the colon are rare. This is the first case reported of a collision tumor composed of adenocarcinoma colon and recurrent granulosa cell tumor representing an example of two independent tumors in a unique one-on-another collision. Clinical awareness and recognition of such tumors are important as they will dictate appropriate treatment strategies dependent on the individual biological aggressiveness of each of the tumor components. Our report highlights the need for histopathologists, surgeons, and oncologists to be aware of the rare possibility of collisions tumors. As seen in our case, the delayed recurrence of granulosa cell tumor of the ovary sixteen years after the initial presentation was the key determining factor in tumor recurrence, tumor progression, and tumor metastasis within three months, which ultimately lead to accelerated death within a year of clinical presentation. Thus accurate identification and recognition of the second neoplasm is important as prognosis and survival may be determined by this component as seen in our index case.

Pseudomyxoma peritonei – a revisit: report of 2 cases and literature review

BackgroundPseudomyxoma peritonei (PMP) is a rare, chronic, relapsing, diagnostically challenging and poorly understood disease characterized by disseminated mucinous ascites and peritoneal implants.Case presentationWe report two cases of PMP that represent the two biological variants of d isseminated p eritoneal a denom ucinosis (DPAM) – the benign variant and the p eritoneal m ucinous c arcinoma tosis (PMCA) – the malignant variant, both of which were characterized by multiple relapses and progression of the disease despite aggressive management.ConclusionEven with a better understanding and recent advances in the management of these cases, PMP remains an enigmatic disease with a protracted clinical course characterized by multiple recurrences despite surgery and/or chemotherapy. Recognition of PMP as a delayed consequence years later should alert all surgeons to be extremely vigilant when treating mucinous neoplasms of the appendix, with special care being directed towards adequate excision and thorough debridement at the initial diagnosis.

GABA concentrations in the striatum following repetitive cerebral ischemia.

GABAergic neurons in the striatum are very sensitive to the effects of ischemia. The progressive decline in striatal GABA following transient forebrain ischemia in gerbils may be secondary to either a decreased production or an increase in reuptake mechanisms or both. The current experiment was designed to evaluate release of GABA by stimulation with K+ or inhibition of its uptake with nipecotic acid or their combination (K+ nipecotic) after repetitive forebrain ischemia in gerbils by in-vivo microdialysis on Days 1, 3, 5, and 14 following the insult. Infusion of nipecotic acid or potassium chloride, resulted in a significant increase in extracellular GABA. This response was significantly decreased in the post-ischemic animals. The synergistic effect of increased GABA concentrations by the infusion of nipecotic acid+potassium chloride seen in the controls was not evident in the post-ischemic animals. In conclusion, though there is a reduction in the extracellular GABA concentrations in the first week following an ischemic insult, restorative mechanisms are operative in the second week as seen by the increasing GABA concentrations.

Solitary Plasmacytoma of the Parotid Gland with Crystalline Inclusions: A Case Report

BackgroundSolitary extramedullary plasmacytoma of the parotid gland is a rare condition. Intracytoplasmic Crystalline inclusions in the tumor are even rarer and have been reported only once in the parotid gland.Case presentationWe report here, a case of plasmacytoma of the parotid gland with intracellular crystalline inclusions in a 73-year-old womanConclusionSolitary extramedullary plasmacytoma of the parotid gland and crystalline inclusions in the tumor is of rare occurrence. The importance of such a finding with relation to tumor progression, clinical course of the disease or prognosis in general remains to be understood.

Diagnostic pitfalls in fine needle aspiration of solitary pulmonary nodules: two cases with radio-cyto-histological correlation

BackgroundFine needle aspiration is an important tool for diagnosis and preoperative evaluation of solitary nodules of the lung. It provides a definitive diagnosis in most patients at low cost with minimal trauma. However, because of the nature of the study and the presentation of the cells in a more distorted and incomplete tissue structure than a histological slide, false positive results can occur. Prior detailed clinical knowledge about the patient, procedures and methods of radiology in obtaining the aspirate specimen is extremely useful in the accurate interpretation of fine needle cytological specimens.Case presentationWe report two cases of solitary pulmonary nodules in two elderly females, which were initially diagnosed as malignant by fine needle aspiration biopsy. Both cases subsequently underwent pulmonary lobectomy in which, one turned out to be a pulmonary hamartoma and the other appeared to be a middle lobe syndrome of the right lung with liver tissue contamination at the time of fine needle aspiration of the lung.ConclusionsWe are now strong believers that much care must be taken in the interpretation of fine needle aspiration of solitary nodules of the lung. Complete study of the entire specimen, including the cell block, is warranted, since what one interprets as malignant, could have different features in another part of the sample. Last but not the least, prior knowledge of the complete clinical history of the patient together with the salient radiological findings would greatly facilitate the cytopathologist to reach an accurate diagnosis.