Temporally Distinct Roles for the Zinc Finger Transcription Factor Sp8 in the Generation and Migration of Dorsal Lateral Ganglionic Eminence (dLGE)-Derived Neuronal Subtypes in the Mouse.

Progenitors in the dorsal lateral ganglionic eminence (dLGE) are known to give rise to olfactory bulb (OB) interneurons and intercalated cells (ITCs) of the amygdala. The dLGE enriched transcription factor Sp8 is required for the normal generation of ITCs as well as OB interneurons, particularly the calretinin (CR)-expressing subtype. In this study, we used a genetic gain-of-function approach in mice to examine the roles Sp8 plays in controlling the development of dLGE-derived neuronal subtypes. Misexpression of Sp8 throughout the ventral telencephalic subventricular zone (SVZ) from early embryonic stages, led to an increased generation of ITCs which was dependent on Tshz1 gene dosage. Additionally, Sp8 misexpression impaired rostral migration of OB interneurons with clusters of CR interneurons seen in the SVZ along with decreased differentiation of calbindin OB interneurons. Sp8 misexpression throughout the ventral telencephalon also reduced ventral LGE neuronal subtypes including striatal projection neurons. Delaying Sp8 misexpression until E14-15 rescued the striatal and amygdala phenotypes but only partially rescued OB interneuron reductions, consistent with an early window of striatal and amygdala neurogenesis and ongoing OB interneuron generation at this late stage. Our results demonstrate critical roles for the timing and neuronal cell-type specificity of Sp8 expression in mouse LGE neurogenesis.

Kikuchi's disease: an uncommon cause of cervical lymphadenopathy.

Kikuchi Fujimoto's disease is a benign self limiting disorder presenting with localised cervical lymphadenopathy, fever, weight loss and night sweats. It is a rare disease with worldwide distribution but commonly reported from Asia. It is diagnosed by excision biopsy of the lymph nodes. Clinical features suggest a viral aetiology though not proven. It is often misdiagnosed as either systemic lupus erythematosus or malignant lymphoma. Better understanding as well as high clinical suspicion would aid in the diagnosis of the disease. Treatment is mainly symptomatic, with non-steroidal analgesics and antipyretics. Corticosteroids are rarely indicated. Although patients show a spontaneous recovery in 1-4 months, a follow-up of several years would be required to study the development of SLE in these patients.

Hematological changes following early ligation of splenic artery during splenectomy in shunt surgery for portal hypertension.

OBJECTIVE AND BACKGROUND DATA: Reduction in cellular elements of blood, secondary to hypersplenism is an established component of non-cirrhotic portal hypertension. Prior transfusion of blood or blood components is frequently required for safe surgical intervention. Due to thrombocytopenia, epidural catheter insertion for effective and durable analgesia is not possible. The aim of the present study was to objectively demonstrate the gain in blood components following early ligation of splenic artery for splenectomy in shunt surgery. METHODS: From Jan 2008 to July 2010, 30 patients underwent elective proximal spleno renal shunt for portal hypertension, for various indications and were analyzed prospectively. We followed the standard protocol of ligating the splenic artery in situ, first in the lesser sac. Proximal spleno shunt was done. After the surgical procedure and before extubation, an epidural catheter was placed for effective and durable analgesia. 5ml of venous blood was drawn in the following order of sequence: prior to induction of anesthesia, immediately after the ligation of splenic artery, 30 minutes after ligation of splenic artery and 30 minutes after splenectomy. Samples were sent for complete hemogram and values were analyzed in respective order. Patients requiring transfusion of blood or blood components during surgery were excluded from the study. RESULTS: 30 patients (M - 9, F- 21) with mean age of 29.4 years (11-60 years) were analyzed (NCPF- 20, EHPVO- 9, cirrhosis- 1). We objectively demonstrated a significant gain in RBCs (p = 0.016) and platelets (p = 0.000) using this standard protocol. As there were no intrinsic abnormalities in RBCs, red blood cell indices (MCV, MCH, MCHC) showed no changes as expected (p-0.9). CONCLUSION: By following this standard protocol, in addition to reduction in blood loss there was a significant gain in RBCs and platelets. This gain allows the surgeon to perform the surgical procedure safely and the anesthetist to secure an epidural catheter immediately after surgery for effective and durable analgesia without prior transfusion.

Proposed Mayo Clinic criteria for the diagnosis of Tako-Tsubo cardiomyopathy and long-term prognosis.

Tako-Tsubo cardiomyopathy (TTC) is a reversible cardiomyopathy with a clinical presentation indistinguishable from myocardial infarction. TTC is estimated to represent 1%-2% of patients presenting with acute myocardial infarction. It most commonly occurs in postmenopausal women and is frequently precipitated by a stressful event. Chest pain and dyspnea are the typical presenting symptoms. Transient ST-segment elevation on ECG and a small rise in cardiac biomarkers are common. Characteristic wall motion abnormalities extend beyond the territory of a single epicardial coronary artery in the absence of obstructive coronary lesions. Supportive treatment leads to spontaneous rapid recovery in nearly all patients. The prognosis is excellent, and recurrence occurs in < 10% of patients. In this article, we review the clinical features of TTC that form the basis of the Mayo Clinic diagnostic criteria, as well as the long-term prognosis for this type of cardiomyopathy.

Stress hormone and circulating biomarker profile of apical ballooning syndrome (Takotsubo cardiomyopathy): insights into the clinical significance of B-type natriuretic peptide and troponin levels.

OBJECTIVE: To evaluate the stress neurohumoral and cardiac biomarker profile of patients with apical ballooning syndrome (ABS). METHODS: Plasma-free metanephrines, B-type natriuretic peptide (BNP), high sensitivity C-reactive protein (hsCRP) and troponin T, as well as 24-hour urine catecholamines, metanephrines and free cortisol were measured in 19 ABS and 10 ST-elevation myocardial infarction (STEMI) patients. RESULTS: An antecedent stressful event was identified in 15 ABS patients. There were no differences in plasma normetanephrine (median 0.64 (IQ range 0.43-0.97) nmol/l vs 0.53 (0.32-0.77) nmol/l, p = 0.44), metanephrine (0.10 (0.10-0.22) nmol/l vs 0.16 (0.10-0.38) nmol/l, p = 0.29), or cortisol levels (16.0 (7.3-44.0) microg/dl vs 13.0 (10.5-23.5) microg/dl, p = 0.95) between ABS and STEMI patients. The 24-hour urine metanephrines, catecholamines and cortisol levels were normal in the majority of ABS patients. Troponin T levels were lower (0.62 (0.18-0.84) ng/ml vs 3.80 (2.04-6.57) ng/ml, p<0.001), but BNP levels were higher in ABS compared with STEMI (944 (650-2022) pg/ml vs 206 (140-669) pg/ml, p = 0.009). HsCRP was similarly elevated in the two groups (11.0 (5.1-110.8) mg/l and 24.3 (8.1-88.6) mg/l, p = 0.78). CONCLUSIONS: Catecholamine and cortisol levels were not elevated in our cohort of ABS, suggesting that routine measurement of these stress hormones is unlikely to be of diagnostic value in practice. In contrast to STEMI, ABS is characterised by a greater elevation in BNP and less myonecrosis.

Recurrent paediatric supratentorial extraventricular ependymoma associated with genetic mutation at exon 4 of p53 gene.

Recurrent supratentorial extraventricular ependymoma in a four-year-old Malay boy treated twice surgically in combination with cranial radiotherapy is reported. He presented with symptoms of raised intracranial pressure and a history of focal seizure. Computed tomography of the brain showed a left supratentorial extraventricular cystic lesion causing a mass effect. The tumour histology was ependymoma (WHO grade II). The clinical course, radiological characteristics and management of this tumour are discussed. Molecular genetic analysis of p53 and p27 genes revealed substitution of nucleotide G to C at location nucleotide 12139, exon 4 of gene p53. No alteration was detected at exon 5-6 and 8 of p53 gene and exon 1 and 2 of p27 gene.

Isolated mesenteric fibromatosis.

Fibromatosis is a rare, locally aggressive but non-metastasising fibrous mass often associated with familial adenomatous polyposis in Gardner's Syndrome (GS). Although sporadic cases occur, unlike in GS, they are predominantly extra-abdominal. We report the case of a 40-year-old lady who underwent laparotomy for a large isolated abdominal mass three years after a Whipple's procedure for adenocarcinoma of the distal common bile duct. A spherical, football sized tumour was found in the jejunal mesentery. Resection of the tumour with jejunum was carried out. No metastasis was detected. This case is peculiar in that mesenteric fibromatosis occurred in a patient with prior history of periampullary carcinoma and without history of familial adenomatous polyposis.

Multidrug resistance 1 gene expression and AgNOR in childhood acute leukemias.

The multidrug resistance 1 (MDR1) gene product, P-glycoprotein (Pgp/p170) is a membrane protein, which acts as an ATP dependant efflux pump that expels a wide variety of organic compounds including chemotherapeutic agents from the cell. Pgp over expression has been demonstrated to be linked with poor treatment outcome and poor prognosis in a number of malignant tumors. AgNORs is a simple, reliable and inexpensive method of evaluating the proliferative activity of a tumor. We have studied MDR1 expression and AgNORS in 41 cases of acute leukemia in children. In this study, AgNOR counts in patients with acute lymphoblastic leukemia (ALL) L2 subtype (FAB classification) were significantly higher as compared to the ALL L1 subtype. Similarly, mean AgNOR count in the acute myeloid Leukemia (AML) M2 subtype was significantly higher as compared to the ALL L1 subtype. However, there was no correlation between AgNOR and treatment outcome or between AgNOR counts and MDR1 expression in any of the subtypes of acute leukemia included in this series. In AML, MDR1 gene expression was found to be related to reduced remission induction rates and hence poorer prognosis. In ALL, our study has shown no difference in remission induction between MDR1 positive and MDR1 negative cases. This would suggest that factors other than MDR1 may be of relevance in Pediatric ALL.

Intra-cranial metastatic lacrimal gland tumour.

We report a case of an adult who presented with progressive swelling in the right eye with suggestive of intracranial lesion on imaging. Histopathological revealed a lacrimal gland malignant mixed tumour.

Epilepsy surgery on dysembryoplastic neuroepithelial tumours.

Two rare cases of intractable epilepsy caused by Dysembryoplastic Neuroepithelial Tumours (DNET) are reported and their different management discussed. The first case required vagal nerve stimulation and radiosurgery while the later was operated with the help of neuronavigation. Both had good outcome according to Engel classification after a one year follow up.

The association of mitochondrial DNA 5178 C > a polymorphism with plasma lipid levels among three ethnic groups.

Mitochondria are eukaryotic cytoplasmic organelles responsible for oxidative phosphorylation. The C to A nucleotide transversion in the NADH dehydrogenase subunit 2 (MT-ND2) coding region of mitochondrial DNA has been reported to be associated with plasma lipid levels, adult onset diseases and longevity. We have examined the role of this polymorphism in relation to plasma lipid levels and age in a total of 713 healthy individuals belonging to 3 ethnic groups in Singapore. The frequency of the A allele was significantly higher (p < 0.05) among the Chinese (0.15) in comparison to the Malays (0.05) and Indians (0.02). No significant difference in the frequency of the allele was observed between healthy and coronary artery disease subjects, and between age-stratified subjects. We found that the polymorphism is significantly associated in an ethnic- and gender-specific manner with plasma apoB levels in the Chinese males (p < 0.05). This is the first epidemiological report of the mt5178 C > A polymorphism and its association with plasma lipid levels in Asian populations outside Japan.

Extradural spinal cord and intraabdominal ganglioneuroblastoma.

We report a rare case of a giant extradural and intraabdominal ganglioneuroblastoma in a young Malay girl who presented to a paediatrician initially at 5 days of life with a palpable abdominal mass. Unfortunately, the parents refused any form of surgical intervention until the child was 3 years old. She subsequently underwent vascular embolisation followed by the removal of this large tumour both via the abdomen and through a laminectomy approach and subsequently refused chemotherapy. The c-myc amplication in this patient was absent and there were no chromosomal aberrations, During the 2 year folow-up the patient remained well, and ambulatory with no tumour recurrence.

Primary pulmonary adenoid cystic carcinoma: report of a case diagnosed by fine-needle aspiration cytology.

Adenoid cystic carcinoma of the lower respiratory tract is an uncommon tumor that can arise in the mainstem bronchus and often presents as an endobronchial mass lesion causing bronchial obstruction with post obstructive atelectasis and pneumonia. Exfoliative cytology is seldom useful in the diagnosis of primary bronchial adenoid cystic carcinoma, because these neoplasms usually have a submucosal location with often intact mucosa. Since most endobronchial adenoid cystic carcinomas are endoscopically visible, bronchoscope-guided fine-needle aspiration constitutes an excellent approach to establish a pathologic diagnosis. The fine-needle aspiration cytology of primary pulmonary adenoid cystic carcinoma has been rarely described. We report a case of primary adenoid cystic carcinoma of the lung having characteristic cytologic features and correlate with computed tomography, bronchoscopic, and histological findings. Bronchoscope-guided aspiration cytology provided a conclusive diagnosis of adenoid cystic carcinoma, which was further corroborated by histology in the pneumonectomy specimen. Diagn. Cytopathol. 2004;30:51-56.

Nm23H1 and p53 proteins are differentially correlated to metastasis in breast carcinoma.

The prognostic significance of nm23H1 and p53 proteins as predictors of nodal involvement and distant recurrence was evaluated in 63 cancer and 47 benign lesions of the breast. Assessment was carried out by immunohistochemical staining using nm23H1 and p53 antibodies. Results show no relation of nm23H1 either to the malignant nature when compared to benign lesions or to the nodal status. P53 protein, on the other hand, showed significantly increased expression in malignant lesions (p=0.001) and correlated well with nodal positivity (p=0.03). A follow-up study of 5 years showed that among the cases showing recurrence, those with positive mn23H1 showed a shorter distant recurrence free survival (DRFS, p=0.01), while p53 expression had no effect. This result did not agree with the previous reports showing nm23H1 as an antimetastatic gene. This is the first report of positive correlation between nm231-11 and distant recurrence in breast cancers, though such a correlation was reported earlier in certain other cancers. Since nm23H1 is an NDP kinase, having more involvement in signal transduction of cell proliferation, it is not difficult to comprehend such a role for nm23H1 during recurrence. Combining the expression of both proteins, lesions positive for both p53 and nm23H1 had significantly reduced distant recurrence free survival (DRFS), when compared to those negative for both proteins (p=0.0006). It can be concluded that nni23H1 alteration has a potential in predicting DRFS, while p53 alteration has the potential to predict lymph node involvement.

Apoptotic index: use in predicting recurrence in breast cancer patients.

Apoptosis maintains tissue homeostasis through its ability to control cell population and has been extensively studied in human cancers. Relation of apoptosis to prognosis is still controversial. In this study, we analyzed the prognostic significance of apoptotic and mitotic indices (AI & MI) using hematoxylin and eosin stained slides by light microscopy in breast cancer patients. In our study, apoptotic index was significantly associated with predicting relapse free survival (RFS), distant recurrence free survival (DRFS) and overall survival (OS) with lesions having higher apoptotic index showing poor prognosis. Our results also point out that quantitation of apoptotic index by simple light microscopy as a routine practice along with histological diagnosis, could provide additional prognostic information in patients who are at high risk of developing recurrence with breast cancers.

A rare case of bleeding in a cerebellopontine angle epidermoid cyst.

Epidermoid cysts of the central nervous system are described as rare, benign, slow growing lesions with a history of high rate of recurrence even after surgical removal. This lesion is rarely located at the cerebellopontine angle and is found to be composed of solid and cystic components with close adherence to vital neurovascular structures that might complicate its removal. We present a rare case of a twenty-five year old housewife with signs and symptoms of increased intracranial pressure due to the above pathology after multiple episodes of intra-tumoral bleeding. Microneurosurgical techniques were used for tumour dissection and excision. The patient recovered well after a three-year follow-up. This is the fourth example in the index medicus of bleeding seen in a histopathologically proven cerebellopontine angle intraepidermoid cyst.

Cadherins as predictive markers of nodal metastasis in breast cancer.

Adhesion molecules, particularly cadherins play a pivotal role in cancer invasion and metastasis. Because the therapeutic management of tumors with and without nodal metastasis differs considerably, our idea was to identify tumors with metastatic potential. We studied the expression of E-cadherin and P-cadherin immunohistochemically in 51 cases of breast cancer that included 29 node-negative and 22 node-positive cases. Expression of the cadherins was mainly membranous, with cytoplasmic staining in a few lesions. Both E-cadherin and P-cadherin showed significant down-regulation of their expression in node-positive tumors in comparison to node-negative tumors. Logistic regression analysis revealed that the positive expression of E-cadherin and P-cadherin showed low odds ratios of 0.1 and 0.2, respectively, and were statistically significant. On multivariate analysis, both the cadherins were found to be of independent prognostic value. This suggests that cadherin expression could be a marker of nodal metastasis. An observation of interest was that the expression of E-cadherin and P-cadherin were highly correlated (correlation coefficient = 0.5873), which requires further evaluation for confirmation of a common regulatory pathway that could be activated in the early onset of nodal metastasis.

Anterior uveal and episcleral metastases from carcinoma of the breast.

Breast carcinoma is the most common primary tumor producing intraocular metastasis. Metastases to the iris and ciliary body are relatively rare. The authors report a case of a 61-year-old lady, operated for carcinoma of the left breast 3 years back, who presented with symptoms and signs of acute narrow-angle glaucoma in the right eye. A diffuse whitish plaque-like mass in the upper nasal quadrant of the iris with an episcleral nodule on the limbus in the corresponding area and all the signs of acute narrow-angle glaucoma were present in the right eye. Intraocular pressure was controlled medically. Fine-needle aspiration cytology from the episcleral nodule showed malignant cells. Histopathology of the excised nodule showed metastatic poorly differentiated carcinoma, and the cellular pattern was similar to the carcinoma of the breast. There was no other metastasis anywhere in the body. Fine-needle aspiration cytology from an external lesion of the eye is a less invasive and easier procedure than paracentesis to diagnose the metastatic nature of the lesions. The rare features in our case are the clinical presentation as acute glaucoma and the ocular structures being the first and only site of metastasis.