A Pragmatic Scoring Tool to Predict Hydroxyurea Response Among ß-Thalassemia Major Patients in Pakistan.

Despite high prevalence and incidence of ß-thalassemia in Pakistan, there is very limited work on the use of hydroxyurea (HU) in thalassemia patients in the country. This is the first insight regarding genetic profiling of BCL11A and HU responses in Pakistani ß-thalassemia. It correlates single-nucleotide polymorphisms on BCL11A (rs4671393, rs766432) and HBG2 (XmnI), age at first transfusion, and ß-globin mutations with HU response in ß-thalassemia major (BTM). Of 272 patients treated with HU, 98 were complete responders, 55 partial responders, and 119 nonresponders. Our analysis shows that HU response was significantly associated with patients having IVSI-1 or CD 30 mutation (P<0.001), age at first transfusion >1 year (P<0.001), and with the presence of XmnI polymorphism (P<0.001). The single-nucleotide polymorphisms of BCL11A were more prevalent among responders, but could not show significant association with HU response (P>0.05). Cumulative effect of all 5 predicting factors through simple binary scoring indicates that the likelihood of HU response increases with the number of primary and secondary genetic modifiers (P<0.001). Predictors scoring is a pragmatic tool to foresee HU response in patients with BTM. The authors recommend a score of ≥2 for starting HU therapy in Pakistani patients with BTM.

Seizure symptoms and ambulatory EEG findings: incidence of epileptiform discharges.

AIMS: Ambulatory video-EEG monitoring has been utilized as a cost-effective alternative to inpatient video-EEG monitoring for non-surgical diagnostic evaluation of symptoms suggestive of epileptic seizures. We aimed to assess incidence of epileptiform discharges in ambulatory video-EEG recordings according to seizure symptom history obtained during clinical evaluation. METHODS: This was a retrospective cohort study. We queried seizure symptoms from 9,221 consecutive ambulatory video-EEG studies in 35 states over one calendar year. We assessed incidence of epileptiform discharges for each symptom, including symptoms that conformed to a category heading, even if not included in the ILAE 2017 symptom list. We report incidences, odds ratios, and corresponding p values using Fisher's exact test and univariate logistic regression. We applied multivariable logistic regression to generate odds ratios for the six symptom categories that are controlled for the presence of other symptoms. RESULTS: History that included motor symptoms (OR=1.53) or automatisms (OR=1.42) was associated with increased occurrence of epileptiform discharges, whereas history of sensory symptoms (OR=0.76) predicted lack of epileptiform discharges. Patient-reported symptoms that were associated with increased occurrence of epileptiform discharges included lip-smacking, moaning, verbal automatism, aggression, eye-blinking, déjà vu, muscle pain, urinary incontinence, choking and jerking. On the other hand, auditory hallucination memory deficits, lightheadedness, syncope, giddiness, fibromyalgia and chronic pain predicted absence of epileptiform discharges. The majority of epileptiform discharges consisted only of interictal sharp waves or spikes. CONCLUSIONS: Our study shows that the use of ILAE 2017 symptom categories may help guide ambulatory video-EEG studies.

A Spectrum of Hematological Disorders in Children with Pancytopenia Based on Bone Marrow Examination in a Tertiary Care Hospital.

Introduction Pancytopenia is a common presentation in the pediatric population. It is a manifestation of various diseases, and its etiology can be explained on the basis of bone marrow examination. The study aims to determine the etiological factors leading to pancytopenia via bone marrow examination in pediatric patients presenting in our hospital. Materials and methods This retrospective cross-sectional study was conducted in the Department of Pathology at a public sector tertiary care hospital. Data were recorded by convenience sampling from the patients' database from January 2015 to April 2018. Patients aged 2 months to 15 years who had pancytopenia on peripheral blood smear and were admitted for bone marrow examination were included in the study. Patients who were beyond these age limits, diagnosed cases of aplastic anemia and leukemia, and those with a recent history of blood transfusion were excluded from the study. The analysis was done via the Statistical Package for Social Sciences (SPSS) v.23.0 (IBM SPSS Statistics, Armonk, NY, USA), and descriptive statistics were applied. Results Of 115 cases, 58 (50.4%) were males and 57 (49.6%) were females. Megaloblastic anemia was present in 32 (27.8%) patients, and it was the most common cause of pancytopenia. Non-malignant disorders were seen in 95 cases (82.6%) and malignant disorders were seen in 20 (17.4%) cases. Conclusion Megaloblastic anemia is the most common cause, and acute lymphoblastic leukemia is the most common malignant cause of pancytopenia in children. There was no significant gender predilection among causes of pancytopenia.

Stoichioproteomics reveal oxygen usage bias, key proteins and pathways in glioma.

BACKGROUND: The five-year survival rate and therapeutic effect of malignant glioma is low. Identification of key/associated proteins and pathways in glioma is necessary for developing effective diagnosis and targeted therapy of glioma. In addition, Glioma involves hypoxia-specific microenvironment, whether hypoxia restriction influences the stoichioproteomic characteristics of expressed proteins is unknown. METHODS: In this study, we analyzed the most comprehensive immunohistochemical data from 12 human glioma samples and 4 normal cell types of cerebral cortex, identified differentially expressed proteins (DEPs), and researched the oxygen contents of DEPs, highly and lowly expressed proteins. Further we located key genes on human genome to determine their locations and enriched them for key functional pathways. RESULTS: Our results showed that although no difference was detected on whole proteome, the average oxygen content of highly expressed proteins is 6.65% higher than that of lowly expressed proteins in glioma. A total of 1480 differentially expressed proteins were identified in glioma, including 226 up regulated proteins and 1254 down regulated proteins. The average oxygen content of up regulated proteins is 2.56% higher than that of down regulated proteins in glioma. The localization of differentially expressed genes on human genome showed that most genes were on chromosome 1 and least on Y. The up regulated proteins were significantly enriched in pathways including cell cycle, pathways in cancer, oocyte meiosis, DNA replication etc. Functional dissection of the up regulated proteins with high oxygen contents showed that 51.28% of the proteins were involved in cell cycle and cyclins. CONCLUSIONS: Element signature of oxygen limitation could not be detected in glioma, just as what happened in plants and microbes. Unsaved use of oxygen by the highly expressed proteins and DEPs were adapted to the fast division of glioma cells. This study can help to reveal the molecular mechanism of glioma, and provide a new approach for studies of cancer-related biomacromolecules. In addition, this study lays a foundation for application of stoichioproteomics in precision medicine.

The Landscape of Protein Tyrosine Phosphatase (Shp2) and Cancer.

Role of Shp2: The dysregulation of cell signaling cascades associated with the cell differentiation and growth, due to the deletion, insertion or point mutation in specific amino acids which alters the intrinsic conformation of the protein, can ultimately lead to a fatal cancer disease. The protein tyrosine phosphatase has been recognized as a key regulator of extracellular stimuli such as cytokine receptor and receptor tyrosine kinase signaling. In the last era, the PTPN11 gene (encode a Shp2 protein) and its association with acute myeloid, juvenile myelomonocytic, and B-cell acute lymphoblastic leukemia, Noonan syndrome, and myelodysplastic have been recognized as the cause of such deadly disease due to the occurrence of germline mutations in the interface of PTP and SH2 domain. Conclusion: The current study was designed to focus on the allosteric regulation (autoinhibition) of the of Shp2 protein. Subsequently, it will cover the last 10-year recap of Shp2 protein, their role in cancer, and regulation in numerous ways (allosteric regulation).

Potential New Cysteine Sparing Mutation in the NOTCH3 Gene in a Patient with Nonfamilial CADASIL-like Disease.

BACKGROUND: Several different mutations have been reported in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We present a unique case with transversion not involving cysteine on neurogenic locus notch homolog protein 3 gene. CASE DESCRIPTION: We present a case of 65-year-old woman with new ischemic stroke resulting in right hemiparesis. She has previously suffered minor strokes at age 56, 58, and 60 years and migraine headaches between age 10 and 50 years. Magnetic resonance imaging demonstrated multifocal chronic ischemic infarctions with encephalomalacia in the left posterior parietal, parieto-occipital regions and the pons. An analysis of the protein sequence of notch 3 gene did not demonstrate any alterations characteristics of CADASIL disease. There was a deoxyribonucleic acid variant with transversion of alanine with tyrosine and change of histidine with leucine on notch 3 gene. None of the family members had any clinical manifestations suggestive of CADASIL. CONCLUSION: We report the first report of deoxyribonucleic acid variation in notch 3 gene associated with clinical features of CADASIL without any familial component.

Unusual atypical language lateralization.

Determining the language-dominant hemisphere is essential for planning epilepsy surgery. A 60-year-old right-handed woman with epilepsy since age 16 failed a partial right anterior lobectomy at age 21. Later, a brain MRI found extensive right-sided cortical dysplasia and periventricular heterotopia. Subsequently, prolonged video-EEG monitoring localized her seizures to the right temporoparietal region. Functional MRI was inconclusive in lateralizing her language, prompting a Wada test, which strongly lateralized language to the right. This unique case of atypical language representation in a right-handed individual with an extensive right-hemispheric congenital malformation and seizure focus illustrates the important thorough presurgical language assessment.

A simple technique to control anastomotic suture line bleeding.

We present a simple and practical method of eliminating anastomotic suture line bleeding that we believe is a safer method than the traditional approach of taking extra stitches around the suture line.

Pioglitazone improves myocardial blood flow and glucose utilization in nondiabetic patients with combined hyperlipidemia: a randomized, double-blind, placebo-controlled study.

OBJECTIVES: This study's aim was to examine whether treatment with pioglitazone, added to conventional lipid-lowering therapy, would improve myocardial glucose utilization (MGU) and blood flow (MBF) in nondiabetic patients with familial combined hyperlipidemia (FCHL). BACKGROUND: Thiazolidinediones were found to improve insulin sensitivity and MGU in type 2 diabetes and MBF in Mexican Americans with insulin resistance. Familial combined hyperlipidemia is a complex genetic disorder conferring a high risk of premature coronary artery disease, characterized by high serum cholesterol and/or triglyceride, low high-density lipoprotein (HDL) cholesterol, and insulin resistance. METHODS: We undertook a randomized, double-blind, placebo-controlled study in 26 patients with FCHL, treated with pioglitazone or matching placebo 30 mg daily for 4 weeks, followed by 45 mg daily for 12 weeks. Positron emission tomography was used to measure MBF at rest and during adenosine-induced hyperemia and MGU during euglycemic hyperinsulinemic clamp at baseline and after treatment. RESULTS: Whereas no change was observed in the placebo group after treatment, patients receiving pioglitazone showed a significant increase in whole body glucose disposal (3.93 +/- 1.59 mg/kg/min to 5.24 +/- 1.65 mg/kg/min; p = 0.004) and MGU (0.62 +/- 0.26 micromol/g/min to 0.81 +/- 0.14 micromol/g/min; p = 0.0007), accompanied by a significant improvement in resting MBF (1.11 +/- 0.20 ml/min/g to 1.25 +/- 0.21 ml/min/g; p = 0.008). Furthermore, in the pioglitazone group HDL cholesterol (+28%; p = 0.003) and adiponectin (+156.2%; p = 0.0001) were increased and plasma insulin (-35%; p = 0.017) was reduced. CONCLUSIONS: In patients with FCHL treated with conventional lipid-lowering therapy, the addition of pioglitazone led to significant improvements in MGU and MBF, with a favorable effect on blood lipid and metabolic parameters. (A study to investigate the effect of pioglitazone on whole body and myocardial glucose uptake and myocardial blood flow/coronary vasodilator reserve in patients with familial combined hyperlipidaemia; http://www.controlled-trials.com/mrct/trial/230761/ISRCTN78563659; ISRCTN78563659).

Pre- and post-synaptic sympathetic function in human hibernating myocardium.

PURPOSE: Impaired pre-synaptic noradrenaline uptake-1 mechanism has been reported in a swine model of hibernating myocardium (HM). To ascertain whether adrenergic neuroeffector abnormalities are present in human HM, we combined functional measurements in vivo using cardiovascular magnetic resonance (CMR) and positron emission tomography (PET) to assess pre- and post-synaptic sympathetic function. METHODS: Twelve patients with coronary artery disease and chronic left ventricular (LV) dysfunction underwent CMR at baseline and 6 months after bypass for assessment of regional and global LV function and identification of segments with reversible dysfunction. Before surgery, myocardial noradrenaline uptake-1 ([(11)C]meta-hydroxy-ephedrine; HED) and beta-adrenoceptor (beta-AR) density ([(11)C]CGP-12177) were measured with PET. Patient PET data were compared with those in 18 healthy controls. RESULTS: The volume of distribution (V(d)) of HED in HM (47.95+/-28.05 ml/g) and infarcted myocardium (42.69+/-25.76 ml/g) was significantly reduced compared with controls (66.09+/-14.48 ml/g). The V(d) of HED in normal myocardium (49.93+/-20.48 ml/g) of patients was also lower than that in controls and the difference was close to statistical significance (p=0.06). Myocardial beta-AR density was significantly lower in HM (5.49+/-2.35 pmol/g), infarcted (4.82+/-2.61 pmol/g) and normal (5.86+/-1.81 pmol/g) segments of patients compared with healthy controls (8.61+/-1.32 pmol/g). CONCLUSION: Noradrenaline uptake-1 mechanism and beta-AR density are reduced in the myocardium of patients with chronic LV dysfunction and evidence of HM. The increased sympathetic activity to the heart in these patients is a generalised rather than regional phenomenon which is likely to contribute to the remodelling process of the whole LV rather than playing a causative role in HM.