Biochemical and functional characterization of the p.A165T missense variant of mitochondrial amidoxime-reducing component 1.

Recent genome-wide association studies have identified a missense variant p.A165T in mitochondrial amidoxime-reducing component 1 (mARC1) that is strongly associated with protection from all-cause cirrhosis and improved prognosis in nonalcoholic steatohepatitis (NASH). The precise mechanism of this protective effect is unknown. Substitution of alanine 165 with threonine is predicted to affect mARC1 protein stability and to have deleterious effects on its function. To investigate the mechanism, we have generated a knock-in mutant mARC1 A165T and a catalytically dead mutant C273A (as a control) in human hepatoma HepG2 cells, enabling characterization of protein subcellular distribution, stability, and biochemical functions of the mARC1 mutant protein expressed from its endogenous locus. Compared to wild-type (WT) mARC1, we found that the A165T mutant exhibits significant mislocalization outside of its traditional location anchored in the mitochondrial outer membrane and reduces protein stability, resulting in lower basal levels. We evaluated the involvement of the ubiquitin proteasome system in mARC1 A165T degradation and observed increased ubiquitination and faster degradation of the A165T variant. In addition, we have shown that HepG2 cells carrying the MTARC1 p.A165T variant exhibit lower N-reductive activity on exogenously-added amidoxime substrates in vitro. The data from these biochemical and functional assays suggest a mechanism by which the MTARC1 p.A165T variant abrogates enzyme function which may contribute to its protective effect in liver disease.

Does the Timing of Surgical Intervention Impact Outcomes in Necrotizing Enterocolitis?

OBJECTIVES: The optimal time for intervention in surgical necrotizing enterocolitis (sNEC) remains to be elucidated. Surgical management varies between peritoneal drain (PD), laparotomy (LAP), and PD with subsequent LAP (PD + LAP). We propose that some infants with surgical NEC benefit from late (>48 h) operative intervention to allow for resuscitation. METHODS: A retrospective comparison of clinical information in infants with sNEC from 2012 to 2022 was performed. Early intervention was defined as less than 48 hours from time of NEC diagnosis to surgical intervention. RESULTS: 118 infants were identified, 92 underwent early intervention (62 LAP; 22 PD; 8 PD + LAP) and 26 underwent late intervention (20 LAP; 2 PD; 4 PD + LAP). Infants with early intervention were diagnosed younger (DOL 8 [6, 15] vs 20 [11, 26]; P=< .05) with more pneumoperitoneum (76% vs 23%; P=< .05). The early intervention group had a higher mortality (35% vs 15%; P=< .05). When excluding infants with pneumoperitoneum, the early intervention group had a higher mortality rate (10/22 (45%), 4/26 (15%); P < .05) and had more bowel resected (29 ± 17 cm vs 9 ± 8 cm; P < .05), with the same number of patients scoring above 3 on the MD7 criteria. CONCLUSION: Infants with NEC who underwent early surgical intervention had a higher mortality and more bowel resected. While this study has a provocative finding, it is severely limited by the non-specific 48-hour cut off. However, our data suggests that a period of medical optimization may improve outcomes in infants with sNEC and thus more in-depth studies are needed.

Food Insecurity and Family Dynamics: A Systematic Review.

BACKGROUND: Undernutrition is related to numerous childhood outcomes. However, little research has investigated the relationship between food insecurity and family dynamics. This systematic review seeks to validate the evidence for a relationship between these 2 factors. METHODS: A systematic literature review was conducted in Embase, PubMed, and Scopus. Inclusion criteria include peer-reviewed research articles published during or after 1996 in English, using standardized measures of family function and food insecurity. Exclusion criteria include measurement of parent or child characteristics without assessing household or family characteristics or demographics. Two reviewers independently voted using Covidence, and Alpha agreement was determined at each phase. RESULTS: A total of 15 studies were included for data extraction after the initial search being completed in April 2022. All included studies were found to be appropriate in numerous categories for quality assessment. Primary findings from these studies show a potential relationship exists between food insecurity and family dynamics. DISCUSSION: The findings in this review suggest that effects of food insecurity expand to various aspects of healthy family functioning. Unhealthy family dynamics in childhood can also expose children to trauma and lead to increased physical and mental health disorders in the future.

A man with concomitant polycythaemia vera and chronic myeloid leukemia: the dynamics of the two disorders.

The co-occurrence of JAK2 V617F mutation with BCR-ABL reciprocal translocation is uncommon. We report a 60-year-old man who initially presented with phenotype of polycythemia vera (PV), which evolved into chronic myeloid leukemia and back to PV once treatment with imatinib was commenced. JAK2 V617F mutation and BCR-ABL fusion transcripts were detected in the initial sample. However, JAK2 V617F alleles diminished when BCR-ABL mRNA burden increased and reappeared once the patient was commenced on imatinib. The dynamic interaction between JAK2 V617F and BCR-ABL implies that two independent clones exist with the JAK2 V617F clone only achieving clonal dominance when BCR-ABL positive clones are suppressed by imatinib.

Chediak-Higashi syndrome: a case report.

A 5-month-old Chinese male infant was referred to the University Hospital, Kuala Lumpur for persistent fever, generalised rash and abdominal distension. Clinically he was suspected to have haemophagocytic lymphohistiocytosis. Haematological findings including the presence of several abnormal giant granules in neutrophils and single large azurophilic granules in many lymphocytes and monocytes in the peripheral blood established the diagnosis of Chediak-Higashi syndrome. The patient responded to allogeneic bone marrow transplant. This paper discusses the characteristic features, clinical course and management of this rare disorder. We suggest that peripheral blood film examination for the abnormal giant granules in granulocytes is an essential investigation in all young children with frequent recurrent infections or who are suspected to have virus-associated haemophagocytic syndrome or familial haemophagocytic lymphohistiocytosis.

Adult allogeneic bone marrow transplantation: initial experience in the University Hospital, Kuala Lumpur.

Prior to 1993, bone marrow transplantation for adult patients was not available in Malaysia. Adult allogeneic bone marrow transplantation commenced in Malaysia when the first transplant was conducted at the University Hospital, Kuala Lumpur on 2 November 1993. Up till July 1995, 10 adult bone marrow transplants had been conducted at the University Hospital. Five patients had acute myeloid leukaemia in first remission, 4 had chronic myeloid leukaemia and 1 had acute lymphoblastic leukaemia in first partial remission. The age range of patients at the time of transplant is 16-40 years (mean 25.5 years). All patients engrafted successfully and the survival for the first 100 days post-transplant is 90%. One patient demonstrated haematological relapse post-transplant but achieved remission with donor buffy-coat infusion. The mean drug cost incurred was RM28,269 for the first 100 days. Locally available adult allogeneic bone marrow transplantation is safe, affordable and has comparable results with reputable overseas transplant centres.

Efficiency of blood usage for elective surgery in the University Hospital Kuala Lumpur.

Provision of quality care, service and blood products to patients while containing costs and the amount of blood used should be the aim of every blood bank. Therefore a prospective audit was carried out over three months to determine how efficiently blood was being used in elective surgery in the University Hospital, Kuala Lumpur. Every case with blood crossmatched was monitored to determine the amount transfused and the posttransfusion haemoglobin level. Overcrossmatching of varying degrees was noted in almost all surgical procedures and overtransfusion in 45.5% of patients transfused. The rate of case postponement was 18.1%. These indicate inefficient utilization of blood and other resources. The transfusion index (TI) and range of units transfused were calculated for each procedure. They can be used as indicators of blood requirement and potential severity of hemorrhage. Suggestions to improve efficiency of blood utilization include the introduction and ongoing monitoring of guidelines on crossmatching and transfusion based on the data obtained here, by the hospital blood transfusion committee; the "group, screen and hold" practice for surgical procedures with high crossmatch transfusion ratios, low transfusion indices and a small range of units transfused could also be adopted.

Antiphospholipid antibodies and stroke in the young--a study of three cases.

Cerebral infarction in the young is likely to be non-atheromatous. While in previous studies no cause has been found in 40% to 50% of patients, an increasing role for haemorheological factors is becoming apparent. Among these, an association between antiphospholipid antibodies (aPLs) and ischaemic cerebrovascular disease is now well-recognised. This entity has not been previously reported in Malaysian patients. In a study of 80 patients with stroke below the age of 50 years who were seen at the University Hospital, Kuala Lumpur, between January 1982 and May 1992, 3 patients with ischaemic cerebral infarction were found to have aPLs. aPLs was detected using ELISA method for anticardiolipin antibodies (aCLs), and presence of lupus anticoagulant (LA) was established by kaolin clotting time, thromboplastin inhibition test and platelet neutralisation procedure. Only 1 patient had active systemic lupus erythematous. Cerebrovascular events were recurrent in one of the 2 non-lupus patients. aPL-related stroke should be considered in young patients who have cerebral ischaemia occurring without obvious cause. More cases are likely to emerge in Malaysia with active screening.

Biphenotypic hybrid acute leukaemia detected by two colour flow cytometry.

Immunophenotypic studies using immunofluorescent flow cytometry were performed on the blast cells of 36 patients with acute leukaemia using a panel of eight monoclonal antibodies. Six patients had blasts which co-expressed markers for lymphoid and myeloid differentiation, and which were therefore defined as biphenotypic hybrid acute leukaemia. Of the six, three patients were in the paediatric age group (below 12 years old) while the other three were more than 12 years old. Peripheral blood counts were variable; however, bone marrow infiltration was extensive (blasts > or = 75% in all). At the time of study, remission was achieved in only two patients. The authors' data show that biphenotypic hybrid acute leukaemia is not rare in Malaysia. This represents a subgroup of acute leukaemia identifiable by immunophenotyping but not by the French-American-British classification based on morphological and basic cytochemical studies alone. The recognition of this subgroup is important for both practical and theoretical reasons. There are implications for treatment of the individual patient because treatment directed at a single lineage may not be effective. The two colour flow cytometry proved to be a useful tool for diagnosis and classification of acute leukaemia.

Multiple myeloma in the University Hospital: a retrospective study of biodata, clinical, laboratory and radiological profiles, 1980-1987.

A retrospective study of 37 cases of multiple myeloma admitted from 1980 to 1987 to the University Hospital Kuala Lumpur, Malaysia, was carried out to analyse the biodata, clinical presentation, laboratory and radiological profiles. The cases were selected after they had satisfied preset diagnostic criteria. The mean age was 60 years. There was no sex or ethnic preponderance. The most common symptom was bone pain. Pallor was detected in 73% of the patients. Haemoglobin was less than 120 g/L in 95%, and ESR was greater than 100 mm/hr in 70% of cases. Bone marrow and trephine biopsies were diagnostically important. Hypercalcaemia occurred in seven cases out of which three were IgA myelomas. Either serum creatinine or blood urea was raised in nearly 50% of cases. The most common heavy chain paraprotein was IgG while Kappa light chain was the commoner light chain type. 86% of cases had osteolytic lesions. These findings are, in general, similar to those of larger studies on multiple myeloma.

Evaluation of the Contraves Autolyzer 801.

The Contraves Autolyzer 801 is a 20 parameter cell counter that operates on the principle of impedance. This evaluation study found that the within-batch precision for 5 of its parameters--WBC, RBC, Hb, Hct and Plt--had coefficients of variation below 5%, while the counts for red cell parameters were reproducible for up to 3 days. The analyser exhibited good linearity for all the parameters. When compared with 2 other counters--the Coulter S-Plus and the Coulter M350, some degree of proportional and constant bias due to unsuitable calibration were detected in the WBC, Hct and Plt parameters. Otherwise it showed generally good correlation in all the parameters and also with the manual PCV method. Carry over was negligible in the red cell parameters. The Contraves Autolyzer 801 is easy to operate and readily accepted by operators.

Myelodysplastic syndrome: a review from University Hospital, Kuala Lumpur.

Twenty patients with Myelodysplastic Syndrome (MDS) were diagnosed in University Hospital, Kuala Lumpur over a 5 year period. They were subclassified using the French American British (FAB) criteria. 90% of the patients were above 40 years old and the sex ratio was about equal. The predominant presenting symptom was anaemia and there was paucity of physical signs at presentation. Patients with 'aggressive' subtypes of MDS i.e. refractory anaemia with excess blasts (RAEB), refractory anaemia with excess blasts in transformation (RAEB(-)+) and chronic myelomonocytic leukaemia (CMML) had more frequent thrombocytopenia and neutropenia and their marrow pictures frequently had dysmegakaryopoiesis and dysgranulopoiesis as compared to more the "benign" subtypes i.e. refractory anaemia (RA) and refractory leukaemic anaemia with ringed sideroblasts (RARS). Four patients had leukaemic transformation and all of them came from the 'aggressive' subtypes. The current views on treatment of MDS are discussed.

Treatment of childhood acute lymphoblastic leukemia in Malaysia, 1976-1982.

One hundred four children with acute lymphoblastic leukaemia were diagnosed at the University Hospital, Kuala Lumpur, Malaysia, between 1976 and 1982; 87 were evaluable with respect to treatment. They were divided into good prognosis (GP) and bad prognosis (BP) groups based on their initial total white cell count, their treatment differing only during the maintenance phase. Remission was achieved in 82 patients (94%) of whom ten (12%) subsequently died in remission from infection. Twenty-eight (34%) relapsed while on treatment and three while off therapy. Eleven patients ceased treatment after 3 yr of continuous complete remission (CCR). Three of these later relapsed, two within the first year. Survival in CCR was significantly better in the GP group up to 30 months, after which the difference diminished. There was no difference in survival between boys and girls. The overall disease-free survival at 3 yr and 5 yr was 40% and 25%, respectively, with a median follow-up period of 20 months (range 4-69 months). The reasons for the relatively low survival rates as compared with those in developed countries are discussed.