Mapping of the Language Cortex.

Awake craniotomy with intraoperative neurophysiological language mapping (INLM) is an established procedure for patients undergoing surgery to resection tumors in the language cortex area. INLM and continuous neurophysiological monitoring allow assessment of the language function, which is not possible under general anesthesia. INLM of the brain areas provides a helpful tool to the operating surgeon in reducing the risks associated with tumor resection in the motor and language cortex. We present a literature review and the technical method used for INLM by utilizing direct electrical cortical stimulation. We also report the usefulness of INLM for evaluation of the language function during resection of cortical tumors, epilepsy foci, and arteriovenous malformations (AVMs) located near language areas. First, the central sulcus is identified by sensory mapping, followed by the motor cortex's identification by direct electrical cortical stimulation (DECS). Neurological assessment of the patient is done by auditory and visual feedback. The patient is asked to repeat numbers, days, words, sentences, read words, and name pictures during cortical stimulation. DECS may cause a slurring or speech arrest. Electrocorticography (ECoG) is also performed during cortical stimulation to identify any after-discharges. Examination of the patient occurs immediately after surgery, and then 24 hours, one week, six months, and 12 months postoperatively. Bipolar DECS for motor mapping with ECoG can safely and reliably be utilized to identify essential language areas with minimizing permanent language deficits and maximizing the extent of tumor resection.

1-Thiazol-2-yl-N-3-methyl-1H-pyrozole-5-carboxylic acid derivatives as antitumor agents.

A class of substituted 1-thiazol-2-yl-N-3-methyl-1H-pyrozole-5-carboxylic acid derivatives was found to have potent anti-proliferative activity against a broad range of tumor cell lines. A compound from this class (14) was profiled across a broad panel of hematologic and solid tumor cancer cell lines demonstrating cell cycle arrest at the G0/G1 interphase and has potent anti-proliferative activity against a distinct and select set of cancer cell types with no observed effects on normal human cells. An example is the selective inhibition of human B-cell lymphoma cell line (BJAB). Compound 14 was orally bioavailable and tolerated well in mice. Synthesis and structure activity relationships (SAR) in this series of compounds are discussed.

Electrolytic macrocyclizations: scalable synthesis of a diazonamide-based drug development candidate.

An electrochemical method to synthesize the core macrolactam of diazonamides is described. Large ring-forming dehydrogenation is initiated by anodic oxidation at a graphite surface. The reaction requires no tailoring of the substrate and occurs at ambient temperature in aqueous DMF in an undivided cell open to air. This unique chemistry has enabled a concise, scalable preparation of DZ-2384; a refined analog of diazonamide A slated for clinical development as a cancer therapeutic.

Bilateral hypoplasia of the internal carotid artery, presenting as a subarachnoid hemorrhage secondary to intracranial aneurysmal formation: a case report.

INTRODUCTION: Hypoplasia of the internal carotid artery is a rare congenital anomaly, with only 24 cases of bilateral internal carotid artery hypoplasia reported to date. Here, we present the case of a 48-year-old woman with bilateral internal carotid artery hypoplasia. She had a collateral circulation through the vertebrobasilar system; however given the high pressure flow she developed aneurysmal formations in the posterior communicating artery. To the best of our knowledge, only seven reported cases of internal carotid artery hypoplasia have been associated with intracranial aneurysmal formations. CASE PRESENTATION: A 48-year-old Sindhi woman from Karachi, Pakistan, presented to our emergency room with a sudden onset headache and was diagnosed as having a subarachnoid hemorrhage. Digital subtraction angiography revealed hypoplasia of her internal carotid artery bilaterally with an associated fusiform aneurysm of the posterior communicating artery. Our patient declined any operative intervention in view of the associated risks. She died of a rebleed six weeks after her initial presentation. CONCLUSION: Bilateral internal carotid artery occlusions can present with subarachnoid hemorrhages due to associated intracranial aneurysm formation. Prior knowledge about the possible existence of such angioarchitectural arrangement is mandatory for an early diagnosis. However, even with prompt diagnosis, management options with acceptable risk-benefit equations are still unavailable.

STAT6 phosphorylation inhibitors block eotaxin-3 secretion in bronchial epithelial cells.

The STAT6 (signal transducer and activator of transcription 6) protein facilitates T-helper cell 2 (Th2) mediated responses that control IgE-mediated atopic diseases such as asthma. We have identified compounds that bind to STAT6 and inhibit STAT6 tyrosine phosphorylation induced by IL-4. In the bronchial epithelial cell line BEAS-2B, compound (R)-84 inhibits the secretion of eotaxin-3, a chemokine eliciting eosinophil infiltration. (R)-84 appears to prevent STAT6 from assuming the active dimer configuration by directly binding the protein and inhibiting tyrosine phosphorylation.

A critical analysis of the current state of neurosurgery training in Pakistan.

OBJECTIVE: To observe interdepartmental variation in the availability of resources and academic activities within the various neurosurgery programs of Pakistan. METHODS: This was a proforma-based survey of neurosurgery trainees and young neurosurgeons of Pakistan, looking at the academic infrastructure and output of their programs. The proforma was filled by 36 respondents from 11 neurosurgery centers of the country. All these centers were accredited for neurosurgery training in Pakistan. RESULTS: Out of the 36 respondents, 30 were completing a Fellowship training (FCPS) and six were enrolled for a Master in Surgery (MS) program. About 80% of the participants used the Youman's Textbook of Neurosurgery as a reference book. Only 40% of the candidates had access to more than one indexed neurosurgery journal. Structured academic sessions (e.g., journal clubs and neuropathology meetings) were lacking in a majority of the training institutes, 95% of the trainees had no microsurgical laboratory experience, and modern neurosurgical tools (frameless neuronavigation system, neuroendoscopy) were in use at a few centers only. CONCLUSION: Neurosurgery training in Pakistan is not uniform and wide variations exist between the programs at the centers evaluated. We recommend exchange programs between centers at national and international levels, to allow trainees to gain first-hand exposure to training components not available in their own center.

Primary chiasmal sarcoid granuloma masquerading as glioma of the optic chiasm.

A 37-year-old woman presented with a 6 months history of headaches and memory impairment. Examination showed no neurological deficit with normal vision. MRI scans showed an enlarged optic chiasm. There was no dural or leptomeningeal enhancement or hydrocephalus. Open biopsy of the suprasellar mass showed non-caseating chronic granulomatous inflammation compatible with sarcoidosis. Systemic features of sarcoid were absent. Patient showed marked improvement on steroid therapy.

Craniocerebral aspergillosis in immunocompetent hosts: surgical perspective.

Craniocerebral aspergillosis is a rare but dangerous variety of central nervous system infections. Surgery is being widely recognized as the cornerstone of management. Due to the rarity of the disease, difficulty and delay in diagnosis and poor outcome, there is very little in the literature regarding the various surgical strategies that may be adopted in these patients. Early aggressive surgery followed by chemotherapy offers the best chances. Surgical planning would depend upon the type and location of the disease process as well as the condition of the patient. Perioperative care holds immense importance and knowledge of possible complications is essential. Aspergillosis of the central nervous system is difficult to diagnose and equally difficult to treat. Surgery remains the cornerstone of management followed by systemic antifungal medications. Results are better in immunocompetent patients as compared to those who are immunocompromised.

One miniplate versus two in the management of mandibular angle fractures: a prospective randomised study.

We compared the use of one miniplate (n=36) with that of two miniplates (n=26) for the treatment of the mandibular angle in a randomised trial. There were no significant differences between the groups in total morbidity (22/36 compared with 14/26) or for individual complications. We conclude that two miniplates seem to confer no extra benefit to patients, but a much larger trial would be required to show this conclusively.

Long scarf injuries.

Long scarf (Dopatta) traditionally worn by females in South-East Asia have been described to make the females prone to sustain specific injuries when they ride pillion on the cycle powered rickshaw or motor bike. Two cases of females have been described.

Giant pituitary macroadenoma at the age of 4 months: case report and review of the literature.

CASE REPORT: Adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma is extremely rare. Only five cases are reported in the literature to date. We report the youngest patient of Cushing's disease due to ACTH-secreting pituitary macroadenoma at the age of 4 months. The patient presented with cushingoid facial features, hypertension and optic atrophy. Serum cortisol level was 97 microg/dl, with increased secretion of urinary free cortisol; plasma ACTH level was 353 pg/ml. Magnetic resonance imaging of the brain showed a large contrast-enhancing solid mass sitting in the sellar region, with suprasellar and lateral extension. Surgical resection was done, and immunohistochemistry confirmed the diagnosis of ACTH-secreting pituitary adenoma. Postoperatively, the patient died of disseminated intravascular coagulopathy. CONCLUSION: Cushing's disease due to ACTH-secreting pituitary macroadenoma is a possible diagnosis in early infancy. This report, along with five previously reported cases in the literature, revealed a poor surgical outcome. This surgical morbidity is possibly attributed to difficult peroperative hemostasis due to vasculopathy in Cushing's disease, which leads to excessive blood loss, adverse hemodynamic changes, myocardial dysfunction and disseminated intravascular coagulopathy.

Gas-producing brain abscess.

A case of a known psychiatric patient who presented with rapid neurological deterioration is reported. Neuroimaging revealed a gas-producing brain abscess in left parietal lobe with a contiguous focus of infection in the adjacent bone and scalp initiated by obsessive scalp scratching. On complete surgical excision of abscess, followed by culture-based antibiotic therapy, a good neurological recovery was achieved with minimal residual deficits at follow-up.

Craniocerebral aspergillosis of sinonasal origin in immunocompetent patients: clinical spectrum and outcome in 25 cases.

OBJECTIVE: Craniocerebral aspergillosis of sinonasal origin has been reported mainly in immunocompromised patients with high mortality, and it has been described very infrequently in immunocompetent hosts. This retrospective study focuses on clinical outcome in relation to anatomic locations of invasive aspergillosis of sinonasal origin in immunocompetent patients with emphasis on our preliminary experience with use of preoperative orally administered itraconazole. METHODS: Medical records of patients treated in two tertiary care hospitals from 1991 to 2003 were reviewed retrospectively. All patients had radiological evidence of disease in the paranasal sinuses with or without intracranial extension. The study cohort was divided into three types on the basis of area of involvement revealed by computed tomographic or magnetic resonance imaging scans of brain. All patients underwent surgical intervention and treatment with antifungal therapy. Preoperative orally administered itraconazole therapy was used in four patients on the basis of neuroradiological features. Clinical outcome was assessed with the Glasgow Outcome Scale, and univariate analysis of prognostic factors was performed with 95% confidence interval (P = 0.05). RESULTS: Mean patient age was 36.5 years (range, 14-74 yr) with a male preponderance (male-to-female ratio, 23:2). Nasal stuffiness (n = 13), headaches (n = 10), proptosis (n = 9), and nasal discharges (n = 7) were major presenting clinical features. Radiological data were obtained by computed tomographic (n = 25) and magnetic resonance imaging (n = 20) scans of the brain, and diagnoses were established by histopathological analysis (n = 20) or/and fungal cultures (n = 15). Preoperative orally administered itraconazole was given in four patients with intracerebral aspergillosis. Overall mortality was 28% and was highest in patients with Type 1 aspergillosis (66.7%). Type 3 aspergillosis and use of preoperative itraconazole remained statistically significant prognostic factors. CONCLUSION: Craniocerebral aspergillosis in immunocompetent hosts has three patterns of presentation that seem to correlate with clinical outcomes. Intracerebral aspergillosis (Type 1) is associated with the worst clinical outcome. Patients with orbital and cranial base aspergillosis (Type 3) had good recovery. Intracranial extradural aspergillosis (Type 2) remained intermediate on the Glasgow Outcome Scale. Preoperative orally administered itraconazole therapy may improve clinical outcome in patients with intracerebral aspergillosis. Prospective clinical studies are required to make firm clinical therapeutic recommendations.

An audit of head trauma care and mortality.

OBJECTIVE: To analyze the factors contributing to deaths from head trauma by using standardized assessment parameters and to provide a peer-review of head injury deaths with focus on identifying deficiencies and analyzing contributory factors. DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: The study was carried out at the Emergency, Aga Khan University Hospital during January 1998 to December 1999. SUBJECTS AND METHOD: One hundred and three patients above the age of 15 years presenting alive to the Aga Khan University Hospital (AKUH) emergency with head injury were included in this study. Identified deaths data was reviewed by the Hospital Trauma Peer Review Committee and consensus arrived at for categorization of deaths. The potential deficiencies in care were identified and final recommendations made. The data was computed on CDC Trauma Registry (V 3.0) and SPSS (V 8.0). RESULTS: Mean age was 31.9 years (n=103) with predominant male population (4:1). Severe head injury (GCS<8) accounted for 21.3 % (n=22) of all cases with a total number of deaths being 12.6 % (n=13). Deaths were categorized preventable in 3 cases with non-preventable and potentially preventable in 4 and 6 cases respectively. Road traffic accidents were the predominant mechanism (n=8) in all deaths (n=13). The time interval in relation to mortality was biphasic, most deaths occurring either within 24 hours or between 3-7 days of injury. Inappropriate pre-hospital treatment, pre-hospital delays and inappropriate mode of transportation without inter-hospital communication were the process-related defects in pre-hospital care with major determinant of deaths outside AKUH (n=5). Prolonged emergency stay, delayed intensive care availability were the process-related deficiencies whereas inappropriate initial resuscitation, inappropriate initial head injury management were provider-related deficiencies in in-hospital care. CONCLUSION: Transfer of inappropriately managed patients, lapses in inter-hospital communications, delayed transfers were identified as the major pre-hospital factors whereas lack of ICU beds, portable ventilators in emergency room, delays in CT scan facilities were the deficiencies in the hospital services. Opportunities for improvement in head trauma care are needed to focus on initial resuscitation and appropriate surgical management.

Chance-type flexion-distraction fracture of lumbar spine.

A case of a twenty years old male who had been hit by a van at the lower back, presented two weeks later with complete paraplegia and double incontinence is presented. Radiological imaging revealed shearing of spine with fracture line slicing through the second lumbar (L2) vertebra going across all the three vertebral columns with complete retrolisthesis of upper fragment. He was managed conservatively with immobilization and rehabilitation.

Extradural Granulocytic sarcoma causing acute paraparesis.

A case of 9 years old female presenting with rapidly progressive paraparesis during remission phase of acute myeloblastic leukemia is reported. Radiological imaging revealed an extradural mass in the upper dorsal spine producing significant cord compression. The patient showed a dramatic neurological recovery after spinal cord decompression and subsequently treated with appropriate chemotherapy and local radiotherapy.

Discovery of thiophene-2-carboxylic acids as potent inhibitors of HCV NS5B polymerase and HCV subgenomic RNA replication. Part 1: Sulfonamides.

The discovery of a novel class of HCV NS5B polymerase inhibitors, 3-arylsulfonylamino-5-phenyl-thiophene-2-carboxylic acids is described. SAR studies have yielded several potent inhibitors of HCV polymerase as well as of HCV subgenomic RNA replication in Huh-7 cells.

Discovery of thiophene-2-carboxylic acids as potent inhibitors of HCV NS5B polymerase and HCV subgenomic RNA replication. Part 2: tertiary amides.

Further SAR studies on the thiophene-2-carboxylic acids are reported. These studies led to the identification of a series of tertiary amides that show inhibition of both HCV NS5B polymerase in vitro and HCV subgenomic RNA replication in Huh-7 cells. Structural insights about the bioactive conformation of this class of molecules were deduced from a combination of modeling and transferred NOE (trNOE) studies.