3D-QSAR Studies, Molecular Docking, Molecular Dynamic Simulation, and ADMET Proprieties of Novel Pteridinone Derivatives as PLK1 Inhibitors for the Treatment of Prostate Cancer.

Overexpression of polo-like kinase 1 (PLK1) has been found in many different types of cancers. With its essential role in cell proliferation, PLK1 has been determined to be a broad-spectrum anti-cancer target. In this study, 3D-QSAR, molecular docking, and molecular dynamics (MD) simulations were applied on a series of novel pteridinone derivatives as PLK1 inhibitors to discover anti-cancer drug candidates. In this work, three models­CoMFA (Q² = 0.67, R² = 0.992), CoMSIA/SHE (Q² = 0.69, R² = 0.974), and CoMSIA/SEAH (Q² = 0.66, R² = 0.975)­of pteridinone derivatives were established. The three models that were established gave Rpred2 = 0.683, Rpred 2= 0.758, and Rpred 2= 0.767, respectively. Thus, the predictive abilities of the three proposed models were successfully evaluated. The relations between the different champs and activities were well-demonstrated by the contour chart of the CoMFA and CoMSIA/SEAH models. The results of molecular docking indicated that residues R136, R57, Y133, L69, L82, and Y139 were the active sites of the PLK1 protein (PDB code: 2RKU), in which the more active ligands can inhibit the enzyme of PLK1. The results of the molecular dynamic MD simulation diagram were obtained to reinforce the previous molecular docking results, which showed that both inhibitors remained stable in the active sites of the PLK1 protein (PDB code: 2RKU) for 50 ns. Finally, a check of the ADME-Tox properties of the two most active molecules showed that molecular N° 28 could represent a good drug candidate for the therapy of prostate cancer diseases.

Classifying Single Channel Epileptic EEG data based on Sparse Representation using Shallow Autoencoder.

Patient independent epileptic seizure detection algorithm for scalp electroencephalogram (EEG) data is pro- posed in this paper. Principal motivation of this work is to integrate neural and conventional machine learning methods to develop a classification system which can advance the current wearable health systems in terms of computational complexity and accuracy. Being based on processing a single channel EEG processing, the approach is suitable for usage with small wireless sensors. A shallow autoencoder model is utilized for sparse representation of the EEG signal followed by k-nearest neighbor (kNN) classifier to categorize the data as epileptic or non-epileptic. Using a single EEG channel an optimum sparsity level is explored in the encoded sample. Attaining an accuracy, sensitivity and specificity of 98.85%, 99.29% and 98.86% respectively, for CHB-MIT scalp EEG database, proposed classification method outperforms state of- the-art seizure detection methodologies. Experiments has shown that this performance was possible by using a sparsity level of 4 in the auto-encoder. Furthermore, use of shallow learning instead of deep learning approach for generation of sparse but effective representation is computationally lighter than many other feature extraction and preprocessing methods.

Elusive tuberculous meningitis with rare neurological complication of longitudinally extensive transverse myelitis: a case report.

INTRODUCTION: Longitudinally extensive transverse myelitis (LETM) is inflammation of the spinal cord that spans three or more spinal segments. LETM is a rare occurrence on its own and has seldom been reported with tuberculous meningitis (TBM), the rarest and deadliest of tuberculous manifestations. TBM is usually seen in children, the immunocompromised, or those with a previous history of tuberculosis infection. CASE PRESENTATION: A 24-year-old healthy male with no co-morbidities or history of tuberculosis presented with fever and headache for the past 3 months. The patient's Kernig's and Brudzinski's signs were both negative, with bilateral abnormal plantar reflexes. The neurological level of injury was T8 and the patient was classified as AIS grade A. His CSF analysis showed a lymphocytic picture. However, both GeneXpert and Ziehl-Neelsen staining came back negative for Mycobacterium tuberculosis. MRI scans of the brain and thoracic spine revealed enhancing nodules and ring lesions in the brain and spinal cord, along with the rare complication of LETM, extending from T2 to T9. DISCUSSION: Although Mycobacterium tuberculosis was never isolated, the patient started recovering as soon as antituberculous therapy was initiated. Hence, more emphasis needs to be placed on radiological imaging in the management of rare medical emergencies like tuberculous meningitis, especially in areas where tuberculosis is rampant and endemic, rather than waiting for a positive culture. This case report also demonstrates the growing evidence that transverse myelitis and/or LETM is associated with TBM.

Behcet's Disease Presenting With Life Threatening Manifestation Of Cerebral Venous Thrombosis.

Behcet's disease (BD) presents as uncommon inflammatory disorder involving multiple systems, identified by longstanding relapsing path. Its chief manifestations are oral and genital ulcers together with involvement of the eyes, skin and joints. Neurological and vascular complications are significant. We report a case of a twenty-four years old young male who presented with headache, fever, and vomiting along with decreased vision; and repeated oral and genital ulcers. Diagnosis of BD complicated with cerebral venous thrombosis (CVT) was made. He was treated with corticosteroids, immunosuppression therapy and colchicine along with anticoagulation therapy. He responded well to the given treatment. Cerebral venous thrombosis complications in with BD can lead to serious consequences. Early recognition and treatment may lessen poor outcomes.

An Unusual Presentation of Opioid Induced Cerebral Infarction.

Opioid induced cerebral infarction is one of the most dreadful complications encountered in clinical practice. A30-year known hypertensive male presented to the emergency department of Shalamar Hospital, Lahore, Pakistan, with altered state of consciousness. He had been in his usual state of health a day before the presentation. On examination he was afebrile, his GCS was 3/15 having pinpoint pupils with absent doll's eye movements. His blood pressure was 90/60 mmHg, pulse rate was 62/minute, and respiratory rate was 10/minute. His right plantar was upgoing. He was resuscitated in emergency and was placed on ventilator due to hypoxemia. Computed tomography (CT) of brain revealed bilateral internal capsule hypolucencies and bilateral frontal lobe infarction. His urinary toxicological screening revealed extremely high concentrations of opioids and benzodiazepine. Patient made an uneventful recovery with antidote and supportive care.

Association of common carotid intimal medial thickness (CCA-IMT) with risk factors of atherosclerosis in patients with type 2 diabetes mellitus.

OBJECTIVE: To determine the association of Common Carotid Intimal Medial Thickness (CCA-IMT) with risk factors of atherosclerosis in patients with type 2 diabetes mellitus. METHODS: This is an observational study carried out in 200 type 2 diabetic patients. Age, gender, duration of diabetes, history of ischaemic heart disease, hypertension and smoking was recorded. Body mass index, glycosylated haemoglobin (HbA1c), total cholesterol, triglyceride and high density (HDL) cholesterol were determined in all the patients. CCA-IMT determination was done by Carotid Doppler Ultrasonography. RESULTS: There were 120 (60%) males and 80 females (40%). Ages ranged from 28 to 79, mean 59.5 +/- 9.07 years. IMT on right side ranged from 0.4 mm to 2.4 mm, mean 0.88 mm and on left side mean IMT was 0.93 mm, range 0.5 mm to 2.5 mm. Duration of DM and BMI were correlated with IMT on both the sides (p < .05), statistically inverse correlation was seen with HDL cholesterol (p < .05). No significant correlation was seen with other variables. CONCLUSION: Duration of DM, BMI and HDL cholesterol were associated with CCA-IMT in patients with type 2 DM. No significant association was seen with other risk factors.

Epidural abscess and meningitis, a complication of spinal anesthesia in a bacteraemic patient.

Meningitis can be caused in experimental performing a lumbar puncture (LP) after bacteraemia. Several authors have speculated bacteraemic patient without having meningitis LP might actually cause meningitis. We meningitis and epidural abscess after spinal bacteraemic patient. A 57-year-old male, known admitted for below knee amputation, with infection and gangrene of the left foot. Intravenous were started and a below knee amputation date of admission under spinal anaesthesia. started having backache, fever and became operatively. A cerebrospinal fluid examination meningitis. Patient had seizures and developed failure. Cerebrospinal fluid smear showed the ie, Streptococcus agalactiae that grew on blood wound culture, sent at the time of admission. Resonance Imaging of LS spine showed an and was managed successfully with antibiotics.

Circadian pattern of onset of ischaemic and haemorrhagic strokes, and their relation to sleep/wake cycle.

OBJECTIVE: To determine whether there is a circadian pattern of onset of ischaemic and haemorrhagic strokes, and their relation to sleep/wake cycle. METHODS: A descriptive study with prospective data was conducted at the Combined Military Hospital Lahore from Jan 2004 to Dec 2007. Eight hundred patients above 26 years of age who had their first ever stroke were included in the study. Strokes were classified into cerebral infarction (CIF), intra-cerebral bleed (ICB) and subarachnoid haemorrhage (SAH). Diagnosis was confirmed either by CT or MRI scan of brain. RESULTS: Out of 800 patients, 80% were males and 20% were females. There were 438 (55%) cases of CIF, 329 (41%) of ICB and 33 (4%) of SAH. The age of the patients ranged from 26 to 84 years. Of all stroke cases, 592 (74%) occurred when the patients were awake and 208 (26%) occurred during sleep (p < 0.001). ICB cases showed significant variation with respect to wake/sleep cycle (p < 0.001). In CIF and SAH cases there was insignificant association with wake/sleep state of the patient, (p < 0.180 and 0.792 respectively). Of all strokes 22.5% occurred between 4 am - 8 am, followed by 20.7% between 4 pm - 8 pm, 20.1% between 8 am - 12 noon, 19.5% between 12 noon to 4 PM, 12.7% between 12 midnight and 4 am while 4.3% cases occurred between 8 pm and 12 midnight. The maximum number of CIF (28.5%) occurred between 4 am- 8 am, maximum ICB (29.8%) between 8 am to 12 noon and maximum SAH (30.3%) between 4 pm - 8 pm. The CIF and SAH cases showed smaller peaks between 4 pm to 8 pm and 8 am to 12 noon respectively. The lowest number of ICB cases (4.9%) were around mid night. Significant circadian variation was found in CIF and ICB patients (p < 0.001), however it was insignificant for SAH cases (p = 0.391). CONCLUSION: The findings of this study confirm the presence of circadian variation among cases of ischaemic stroke and intra cerebral bleed while no circadian variation was found in subarachnoid haemorrhage. CIF, ICB and SAH predominantly occur in early morning hours, late morning hours and in late afternoon to early evening respectively. Only intracerebral bleed was affected by wake/sleep state.