Defect In Synthesis Research Articles

Synthesis and crystal and defect structures of polycrystalline Cu2SrSnS4 and Cu1.9SrSnS4 powders

The polycrystalline samples of Cu2 – δSrSnS4 with a trigonal structure were prepared by solid-phase ampoule synthesis with a long annealing time (1944 h), and their crystal lattice parameters were refined and Raman spectra were obtained. For the first time, the effect of defect structure on the lifetimes of photogenerated current carriers in the polycrystalline powders was examined by combining time-resolved microwave photoconductivity and cathodoluminescence methods. A significant increase in the lifetimes during the conversion of Cu2SrSnS4 into Cu1.9SrSnS4 was found, which was probably due to changes in the defect structure.

Constitutive Expression of a Cytotoxic Anticancer Protein in Tumor-Colonizing Bacteria.

Bacterial cancer therapy is a promising next-generation modality to treat cancer that often uses tumor-colonizing bacteria to deliver cytotoxic anticancer proteins. However, the expression of cytotoxic anticancer proteins in bacteria that accumulate in the nontumoral reticuloendothelial system (RES), mainly the liver and spleen, is considered detrimental. This study examined the fate of the Escherichia coli strain MG1655 and an attenuated strain of Salmonella enterica serovar Gallinarum (S. Gallinarum) with defective ppGpp synthesis after intravenous injection into tumor-bearing mice (~108 colony forming units/animal). Approximately 10% of the injected bacteria were detected initially in the RES, whereas approximately 0.01% were in tumor tissues. The bacteria in the tumor tissue proliferated vigorously to up to 109 colony forming units/g tissue, whereas those in the RES died off. RNA analysis revealed that tumor-associated E. coli activated rrnB operon genes encoding the rRNA building block of ribosome needed most during the exponential stage of growth, whereas those in the RES expressed substantially decreased levels of this gene and were cleared soon presumably by innate immune systems. Based on this finding, we engineered ΔppGpp S. Gallinarum to express constitutively a recombinant immunotoxin comprising TGFα and the Pseudomonas exotoxin A (PE38) using a constitutive exponential phase promoter, the ribosomal RNA promoter rrnB P1. The construct exerted anticancer effects on mice grafted with mouse colon (CT26) or breast (4T1) tumor cells without any notable adverse effects, suggesting that constitutive expression of cytotoxic anticancer protein from rrnB P1 occurred only in tumor tissue.

Product Validation and Stability Testing of Pharmacy Compounded Cholic Acid Capsules for Dutch Patients with Rare Bile Acid Synthesis Defects

Bile acid synthesis defects (BASDs) comprise a group of rare diseases that can be severely disabling. Bile acid supplementation with 5 to 15 mg/kg cholic acid (CA) has been hypothesized to decrease endogenous bile acid production, stimulate bile secretion, and improve bile flow and micellar solubilization, thereby improving the biochemical profile and potentially slowing down disease progression. Currently, CA treatment is unavailable in the Netherlands, and CA capsules were compounded by the Amsterdam UMC Pharmacy from CA raw material. This study aims to determine the pharmaceutical quality and stability of the pharmacy compounded CA capsules. Pharmaceutical quality tests were performed on 25 mg and 250 mg CA capsules according to general monographs of the European Pharmacopoeia 10th ed. For the stability study, the capsules were stored under long-term conditions (25 °C ± 2 °C/60% ± 5% RH) and accelerated conditions (40 °C ± 2 °C/75% ± 5% RH). Samples were analyzed at 0, 3, 6, 9 and 12 months. The findings demonstrate that the pharmacy compounded CA capsules within a range of 25-250 mg that complied with the European regulations in regard to product quality and safety. The pharmacy compounded CA capsules are suitable for use in patients with BASD, as clinically indicated. With its simple formulation, pharmacies are provided a guidance on product validation and stability testing when commercial CA capsules are unavailable.

Intraputaminal Gene Delivery in Two Patients with Aromatic L-Amino Acid Decarboxylase Deficiency.

Aromatic l-amino acid decarboxylase deficiency (AADCD) is a rare, early-onset, dyskinetic encephalopathy mostly reflecting a defective synthesis of brain dopamine and serotonin. Intracerebral gene delivery (GD) provided a significant improvement among AADCD patients (mean age, ≤6 years). We describe the clinical, biological, and imaging evolution of two AADCD patients ages >10 years after GD. Eladocagene exuparvovec, a recombinant adeno-associated virus containing the human complimentary DNA encoding the AADC enzyme, was administered into bilateral putamen by stereotactic surgery. Eighteen months after GD, patients showed improvement in motor, cognitive and behavioral function, and in quality of life. Cerebral l-6-[18F] fluoro-3, 4-dihydroxyphenylalanine uptake was increased at 1 month, persisting at 1 year compared to baseline. Two patients with a severe form of AADCD had an objective motor and non-motor benefit from eladocagene exuparvovec injection even when treated after the age of 10 years, as in the seminal study.

Multiple congenital anomalies-hypotonia-seizures syndrome 3 secondary to phosphatidylinositol glycan class T mutation: a neonatal case report

Multiple congenital anomalies-hypotonia-seizures syndrome 3 (MCAHS3) is caused by genetic defects in glycosyl-phosphatidylinositol transamidase complex synthesis due to mutations in the PIGT gene. The disease encompasses dysmorphism, cardiac, genito-urinary and skeletal anomalies, developmental delay and epilepsy in variable severity. Only 39 such cases have been reported till date in literature. We reported the first Indian case with neonatal presentation and overall the sixth case of MCAHS3 to present in neonatal age. The pro-band was a male baby born to non-consanguineous parents. He had perinatal depression, craniofacial dysmorphism, epileptic encephalopathy, left radio-ulnar congenital fractures and respiratory failure managed with multiple anti-epileptics, invasive ventilation and limb splinting. Clinical exome sequencing revealed an autosomal recessive homozygous PIGT gene mutation on exon 6 of chromosome 20 with a variant nomenclature of C.709G>C with heterozygous parents confirming MCAHS3. This report expands the range of information available on MCAHS3. It highlights the need to elaborately investigate dysmorphic newborns with severe hypotonia along with the described neurological symptoms, so as to pin point this potentially diagnosable entity.

Beneficial in vitro effect of N-acetylcysteine and coenzyme Q10 on DNA damage in neurodegenerative Niemann-Pick type C 1 disease: preliminary results.

Niemann-Pick type C1 (NP-C1) is a lysosomal storage disease (LSD) caused by mutations in NPC1 gene that lead to defective synthesis of the respective lysosomal transporter protein and cholesterol accumulation in late endosomes/lysosomes (LE/L) compartments, as well as glycosphingolipids GM2 and GM3 in the central nervous system (CNS). Clinical presentation varies according to the age of onset and includes visceral and neurological symptoms, such as hepatosplenomegaly and psychiatric disorders. Studies have been associating the pathophysiology of NP-C1 with oxidative damage to lipids and proteins, as well as evaluating the benefits of adjuvant therapy with antioxidants for this disease. In this work, we evaluated the DNA damage in fibroblasts culture from patients with NP-C1 treated with miglustat, as well as the in vitro effect of the antioxidant compounds N-acetylcysteine (NAC) and Coenzyme Q10 (CoQ10), using the alkaline comet assay. Our preliminary results demonstrate that NP-C1 patients have increased DNA damage compared to healthy individuals and that the treatments with antioxidants can mitigate it. DNA damage may be due to an increase in reactive species since it has been described that NP-C1 patients have increased peripheral markers of damage to other biomolecules. Our study suggests that NP-C1 patients could benefit from the use of adjuvant therapy with NAC and CoQ10, which should be better evaluated in a future clinical trial.

Regulatory and structural mechanisms of PvrA-mediated regulation of the PQS quorum-sensing system and PHA biosynthesis in Pseudomonas aeruginosa.

Pseudomonas aeruginosa is capable of causing acute and chronic infections in various host tissues, which depends on its abilities to effectively utilize host-derived nutrients and produce protein virulence factors and toxic compounds. However, the regulatory mechanisms that direct metabolic intermediates towards production of toxic compounds are poorly understood. We previously identified a regulatory protein PvrA that controls genes involved in fatty acid catabolism by binding to palmitoyl-coenzyme A (CoA). In this study, transcriptomic analyses revealed that PvrA activates the Pseudomonas quinolone signal (PQS) synthesis genes, while suppressing genes for production of polyhydroxyalkanoates (PHAs). When palmitic acid was the sole carbon source, mutation of pvrA reduced production of pyocyanin and rhamnolipids due to defective PQS synthesis, but increased PHA production. We further solved the co-crystal structure of PvrA with palmitoyl-CoA and identified palmitoyl-CoA-binding residues. By using pvrA mutants, we verified the roles of the key palmitoyl-CoA-binding residues in gene regulation in response to palmitic acid. Since the PQS signal molecules, rhamnolipids and PHA synthesis pathways are interconnected by common metabolic intermediates, our results revealed a regulatory mechanism that directs carbon flux from carbon/energy storage to virulence factor production, which might be crucial for the pathogenesis.

A study to assess the Effectiveness of Structured Teaching Program on knowledge regarding Iron Deficiency Anemia among Adolescent girls of Swami Dayananda Saraswati Inter College at Ayodhya, Uttar Pradesh

Abstract: Introduction-Iron is an important micronutrient which is Very Important for various functions in human body. It is essential for cellular growth and differentiation, oxygen binding, transport and storage, enzymatic reactions, immune function, cognitive function, mental and physical growth etc. So, deficiency of iron due to either physiological or pathological reason can affect mental and physical growth resulting in decreased learning capacity and work productivity. Iron Deficiency Anemia is characterized by a defect in haemoglobin synthesis, resulting in hypochromic and microcytic red blood cells. Iron deficiency can result either due to less nutritional supply, increased demand or blood loss due to any reason. Anemia is a serious global public health problem that particularly affects young children, Adolescent and pregnant women. Although IDA occurs at all ages and involves both sexes, adolescent girls are more prone to it. The World Health Organization (WHO) defined adolescents as the population of 10-19 years of age.

Higher frequency of TMEM199-CDG in the southern mediterranean area is associated with c.92G>C (p.Arg31Pro) mutation

Congenital disorders of glycosylation (CDG) are genetic multisystem diseases, characterized by defective glycoconjugate synthesis. A small number of CDG with isolated liver damage have been described, such as TMEM199-CDG, a non-encephalopathic liver disorder with Wilson disease-like phenotype. Only eight patients with TMEM199-CDG have been described including seven Europeans (originating from Greece and Italy) and one Chinese. Three patients from southern Italy (Campania) shared the same known missense mutation pathogenetic variant NM_152464.3:c. 92G > C (p.Arg31Pro), also found in a Greek patient.Here we report a new patient from southern Italy (Sicily), with a homozygous c.92G > C p.(Arg31Pro) variant in TMEM199. The patient's phenotype is characterized by mild non-progressive hepatopathy with a normal hepatic echo structure. A persistent increase in serum transaminases, total and low-density lipoprotein cholesterol and low serum ceruloplasmin and copper levels and normal urinary copper excretion were observed. Matrix-assisted laser desorption/ionization mass spectrometry analyses showed abnormal N- and O- protein glycosylation, indicative of a Golgi processing defect and supporting the function of TMEM199 in maintaining Golgi homeostasis. TMEM199-CDG is an ultra-rare CDG relatively frequent in the southern Mediterranean area (7 in 9 patients, 77%). It is mainly associated with the c.92G > C (p.Arg31Pro) pathogenetic allele globally reported in 4 out of 7 families (57%), including one from Greece and three unrelated families from southern Italy. The almost uniform clinical phenotype described in patients with TMEM199-CDG appears to reflect a higher prevalence of the same variant in patients from the southern Mediterranean area.

Analysis of C-Peptide Levels Among Gynaecological Malignancies Patients Underwent Chemotherapy with Carboplatin Regiment

C-peptide is part of the, which its amounts were equal to endogenous insulin secreted by pancreatic β cells. Carboplatin is one of the chemotherapy regimens that are widely used to treat gynecological malignancies. Carboplatin may cause the damage of β-islets of Langerhans, which may cause defects in insulin synthesis leading to secondary diabetes mellitus or other types of diabetes mellitus. The purpose of this study was to determine the differences in C-peptide, (which reflects endogenous insulin levels) levels in patients with gynecologic malignancy who underwent carboplatin chemotherapy. This study was a comparative observational study with a cross-sectional design. There was a total of 42 subjects who met the inclusion criteria. Subjects with gynecological malignancy post-carboplatin chemotherapy regimens had lower serum C-peptide levels in group II compared to group I. Serum C-peptide levels can further be used to monitor side effects of carboplatin and can be used as a test to diagnose the other types of diabetes mellitus especially before starting the fourth cycle

The role of von Willebrand factor in hemostasis pathology

Von Willebrand factor (VWF) is a multimeric plasma glycoprotein present in endothelial cells, megakaryocytes, platelets, and connective tissue. It mediates platelet adhesion in small arteries. VWF also binds and protects coagulation factor VIII from degradation. Moreover, VWF is involved in inflammatory response, linking hemostasis and inflammation. VWF multimers and platelets attached to damaged or activated endothelium mediate leukocyte recruitment, facilitating local inflammatory response. At shear rates above 5000 s–1, VWF molecules are capable of hydrodynamic activation that changes their conformation from globular to fibrillar. Therefore, VWF plays a key role in cellular hemostasis at high shear rates. Acquired and inherited disfunction, defective synthesis or increased proteolysis of VWF multimers lead to bleeding, as in von Willebrand disease or Heyde syndrome. Pathological activation of VWF may lead to the development of thrombotic complications of coronary artery disease. COVID-19, especially severe form, is characterized by prothrombotic shift in pulmonary vascular bed. Following endothelial damage, VWF plasma level rises and ADAMTS-13 activity decreases. In patients with COVID-19, a change in the VWF/ADAMTS-13 ratio is associated with an increase in the risk of thromboembolic complications. Therefore, assessment of hydrodynamic activation of VWF under flow conditions may be valuable in fundamental research and laboratory diagnostics.

BACH1 regulates erythrophagocytosis and iron-recycling in β-thalassemia.

Macrophages play essential roles in erythrophagocytosis and iron recycling. β-thalassemia is characterized by a genetic defect in hemoglobin synthesis, which increases the rate of iron recycling. We previously showed that reduced expression of the BTB and CNC homolog 1 (BACH1) gene leads to increased phagocytosis of abnormal RBCs by activated monocytes. However, the mechanisms underlying this abnormal RBC clearance remained unclear. Herein, the spleen and bone marrow cells of β-thalassemic mice were examined for erythrophagocytosis CD markers and iron-recycling genes. Higher expression levels of CD47 and CD163 on RBCs and macrophages, respectively, were observed in β-thalassemic mice than in wild-type cells. The decreased expression of BACH1 caused an increase in Nrf2, Spic, Slc40a1, and HMOX1 expression in splenic red pulp macrophages of thalassemic mice. To investigate BACH1 regulation, a macrophage cell line was transfected with BACH1-siRNA. Decreased BACH1 expression caused an increase in CD163 expression; however, the expression levels were lower when the cells were cultured in media supplemented with β-thalassemia/HbE patient plasma. Additionally, the iron recycling-related genes SPIC, SLC40A1, and HMOX1 were significantly upregulated in BACH1-suppressed macrophages. Our findings provide insights into BACH1 regulation, which plays an important role in erythrophagocytosis and iron recycling in thalassemic macrophages.

Persistence of foetal testicular features in patients with defective androgen signalling.

Congenital defects of androgen synthesis or action in 46, XY individuals can result in impaired virilisation, despite the apparent testicular development. In a recent case report of a young adult with complete androgen insensitivity syndrome (CAIS), tumorous gonadal tissue was shown to express HSD17B3 in Sertoli cells (SCs) and not in Leydig cells (LCs). This expression pattern differs from the typical adult human testis and resembles foetal mouse testis, suggesting an underlying testicular development and function defect. Here, we investigate the effect of altered androgen signalling in gonads from five 46, XY individuals with defects in androgen synthesis or action. Gonadal tissue sections from four patients with CAIS, one with CYP17A1 deficiency, and one control were immunostained for LC developmental and steroidogenic markers. The expression of some of these markers during development was investigated by reanalysing previously published single-cell RNA sequencing (scRNA-seq) data from normal human testicular tissues. All gonadal tissues from the patients show exclusive expression of HSD17B3 in SCs and expression of the foetal/immature LC marker DLK1 in a subset of LCs, suggesting an androgen-dependent differentiation defect of adult SCs and LCs. Furthermore, reanalysis of scRNA-seq data reveals an expression of HSD17B3 in foetal and neonatal SCs that is downregulated in adult SCs. Androgen signalling may affect the differentiation of adult but possibly not foetal SCs or LCs and may induce a shift of testosterone production from the tubular compartment in the foetal phase to the interstitial compartment in the adult phase.

β-Thalassemia in childhood: Current state of health in a high-income country.

β-thalassemia is an haemoglobinopathy characterized by a defective synthesis of the β-globin chain. To assess the current state of health of paediatric patients with β-thalassemia, data from the French national registry regarding children born between 2005 and 2020 with β-thalassemia intermedia (TI) or major (TM) were collected. A total of 237 patients (median age 7.1 years at last visit) were analysed, of whom 156 (65.8%) were born in France and 162 (68.4%) had a TM phenotype. The probability of survival for children with TM born in France was 98.3% at 15 years. Fifty-four (22.8%) children received a haematopoietic stem cell transplant with a success rate of 88.8%. Hepatic and cardiac iron overload monitoring in non-transplanted patients showed moderate overload in 15.7% (18/115) and 7.1% (7/99) of cases, respectively, while clinical complications were found in only 4 patients with TM (hepatic in 3 cases). At last visit, mean ferritinemia was 1293 ng/ml (±759). Overall, less than 10% of children underwent splenectomy. No significant impact of the disease on growth or academic achievement was observed. Deferasirox was the main first-line chelator, prescribed in 78.2% of cases, with side effects reported in 11.7% of instances.

Simple-Virilizing Congenital Adrenal Hyperplasia – A Rare Case Report

Abstract Simple-virilizing congenital adrenal hyperplasia (SV-CAH) is an inherited condition which transmission is autosomal recessive due to complete or partial enzyme deficiency which leads to defective cortisol synthesis. It involves five enzyme-linked steps. Insufficiency of any enzyme leads to different types of CAH. It can be classified into classic and nonclassic. Classic has two subtypes – salt wasting and simple-virilizing type. This case report of a 3½-year-old boy showing an increase in growth of genitals and increase in pigmentation of the skin. A probable diagnosis of virilizing CAH or precocious puberty was made. On laboratory investigation, there was a decrease in the level of cortisol and grossly raised level of 17-hydroxyprogesterone. This condition was diagnosed with SV-CAH after confirmation with laboratory parameters. The patient was managed accordingly. The aim of the treatment was to correct the level of cortisol and maintain balance of electrolytes. Hence, the patient was treated with hydrocortisone and fludrocortisone and discharged with advice to continue the same treatment.

Uso de placa de polimetilmetacrilato (PMMA) no tratamento de craniosquise associada à meningocele em uma bezerra girolando: relato de caso

Abstract Most genetic diseases affect purebred animals and are inherited as recessive genes. Cranioschisis refers to dysraphism, which occurs in the midline of the skull due to failure to close the cranial symphysis, which can lead to herniation of the meninges filled with cerebrospinal fluid (meningocele), where there is usually a projection of the meningeal tissue. Diagnosis is performed based on clinical examination, characteristic anatomopathological data, and complementary imaging tests. The surgical approach for correction of cranioschisis is the only described as a therapeutic solution and is indicated in cases in which the cranial synthesis defect does not allow for brain protrusion and there is only the occurrence of meningocele, in addition to the absence of severe signs of neurological alteration. This paper reports a case of the use of polymethylmethacrylate (PMMA) plaque to treat cranioschisis associated with meningocele in a Girolando heifer. The surgical opening of the frontonasal sacculation allowed draining a total liquid content of 488 mL, inspection, and suture of the envelope membrane. APMMA plaque, molded to the bone surface and anchored in the adjacent soft tissue, was used to cover the evidenced frontonasal bone opening. Despite the unfavorable prognosis of the disease, the cranioplasty surgery for the treatment of cranioschisis associated with meningocele using PMMA plaque obtained satisfactory results relative to the quality and maintenance of this animal’s life, evaluated at 19 months postoperatively.

Relationship between serum ferritin and parathyroid function in adult male patients with transfusion dependent thalassemia

Background: Thalassemia is a genetic disorder of defective hemoglobin synthesis. In transfusion dependent thalassemia (TDT), iron overload is caused by repeated blood transfusion for a long time. This increased iron is deposited in body tissue and may lead to endocrine dysfunction. Objective: To evaluate the relationship between serum ferritin and parathyroid dysfunction in adult male patients with TDT. Methods: It was a cross sectional study which was conducted from March 2018 to February 2019 in the Department of Physiology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka. For this study, 35 TDT male patients aged 18 to 40 year, were considered as study group and 35 age and sex matched apparently healthy subjects were considered as control group. The outpatient department of Hematology and Transfusion Medicine was the point of collection of study group. Parathyroid function was assessed by plasma intact para thyroid hormone (iPTH), serum total calcium and serum inorganic phosphate. Plasma iPTH and serum ferritin levels were estimated by Electrochemiluminescence Immunoassay method using automated analyzer. Serum total calcium and serum inorganic phosphate levels were estimated by colorimetric method using automated analyzer. Independent sample t test and Pearson’s correlation coefficient (r) test were applied for statistical analysis using SPSS version 16. Results: In this study, serum ferritin level was significantly (p <0.001) higher in patients with TDT than that of healthy control. Correlation analysis showed negative correlation of serum ferritin with plasma iPTH and serum corrected calcium and positive correlation with serum inorganic phosphate in patients with TDT. Among them correlation with serum corrected calcium and inorganic phosphate were statistically significant (p <0.05). Conclusion: This study concluded that TDT may be associated with elevated iron status which is inversely related with parathyroid function. J Bangladesh Soc Physiol. 2022, June; 17(1): 1-5

Evaluation of Hepatic Enzymes in major β-thalassemic Patients using Deferasirox

Abstract β-thalassemia major is a genetic disease that causes sever defect in normal hemoglobin synthesis. The patients with β-thalassemia major need periodic blood transfusions that can result in accumulation of body iron, so treatment with iron chelating agent is required. Complications of this iron overload affecting many vital organs, including the liver. The aim of this work was to evaluate liver enzymes in β -thalassemia major patients with deferasirox versus without it. Two groups of β-thalassemia major patients were involved in this study named group A; 40 β-thalassemia patients of blood transfusion dependent without deferasirox, group B; 40 β-thalassemia patients of blood transfusion dependent on deferasirox. In addition to group C, 40 normal subjects as a control group. Samples of serum were obtained from all participants to be tested for alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase and ferritin. The biochemical data of the patients on blood transfusion without deferasirox showed significant increases in the mean serum levels of aminotransferases and ferritin in comparison with control. Whereas the patients on blood transfusion with deferasirox exhibit significant increases in the means serum levels of alkaline phosphatase activity and ferritin in comparison with control. Iron overload may cause liver injury, shown by significant increases of; ALT and AST activities and elevated ferritin level in serum of transfusion dependent patients of β-thalassemia major. Administration of deferasirox for β-thalassemia major patients causes elevation of serum ALP activity and ferritin level.

The Role of Serum Lactate Dehydrogenase in Etiological Diagnosis of Macrocytic Anemia

Background: Macrocytic anemia is common and is characterized by decreased hemoglobin levels with elevated Mean Corpuscular Volume (MCV), due to a range of diseases and divided into Megaloblastic and Non-megaloblastic anemia. Serum vitamin B12 and folic acid tests are usually performed but they are limited by their low sensitivity and specificity. To confirm diagnosis of macrocytic anemia bone marrow examination is required but it is invasive procedure. Vitamin B12 and/or B9 deficiency leads to a defect in DNA synthesis leading to ineffective erythropoiesis and intramedullary hemolysis in patients of megaloblastic anemia, this leads to increased serum LDH (Lactate Dehydrogenase) and unconjugated bilirubin. Aims of study: This study was carried out to evaluate the role of serum LDH in the distinction between megaloblastic and non-megaloblastic anemia, and to study the correlation between serum LDH and MCV Patient and Methods: The study included 60 patients with non-regenerative macrocytic anemia (We exclude patients with regenerative macrocytic anemia because elevated reticulocytes leads us to hymolysis anemia or bleeding and it’s not a diagnostic problem(. Complete blood count, biochemical investigation, peripheral blood examination, reticulocyte count, bone marrow examination was performed in all cases Results: The most common cause of macrocytic anemia was Megaloblastic anemia (65%). The other causes were primary bone marrow disorders (35%). There was a significant difference in the mean values of serum LDH and MCV between two groups ( megaloblastic and non-megaloblastic anemia). When LDH>2076.5 IU/L, there is more probability of having megaloblastic anemia than non-megaloblastic anemia but when LDH>2076.5 and MCV>109.45 with bilirubin> 1.2mg/dl will must more probably not have non-megaloblastic anemia (the specificity was 100%), all three parameters combined together can be used as screening test to distinguish between the 2 groups of macrocytic anemia (megaloblastic and non-megaloblastic) without necessity of bone marrow aspiration in patients of non- regenerative macrocytic anemia. Present study had also shown that there were a positive relationship between serum LDH and MCV (r=+0.613).

Amyotrophic Lateral Sclerosis, FUS and Protein Synthesis Defects.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that mainly affects the motor system. It is a very heterogeneous disorder, so far more than 40 genes have been described as responsible for ALS. The cause of motor neuron degeneration is not yet fully understood, but there is consensus in the literature that it is the result of a complex interplay of several pathogenic processes, which include alterations in nucleocytoplasmic transport, defects in transcription and splicing, altered formation and/or disassembly of stress granules and impaired proteostasis. These defects result in protein aggregation, impaired DNA repair, mitochondrial dysfunction and oxidative stress, neuroinflammation, impaired axonal transport, impaired vesicular transport, excitotoxicity, as well as impaired calcium influx. We argue here that all the above functions ultimately lead to defects in protein synthesis. Fused in Sarcoma (FUS) is one of the genes associated with ALS. It causes ALS type 6 when mutated and is found mislocalized to the cytoplasm in the motor neurons of sporadic ALS patients (without FUS mutations). In addition, FUS plays a role in all cellular functions that are impaired in degenerating motor neurons. Moreover, ALS patients with FUS mutations present the first symptoms significantly earlier than in other forms of the disease. Therefore, the aim of this review is to further discuss ALS6, detail the cellular functions of FUS, and suggest that the localization of FUS, as well as protein synthesis rates, could be hallmarks of the ALS phenotype and thus good therapeutic targets.