Positive-sense RNA viruses modify intracellular calcium stores, endoplasmic reticulum and Golgi apparatus (Golgi) to generate membranous replication organelles known as viral factories. Viral factories provide a conducive and substantial enclave for essential virus replication via concentrating necessary cellular factors and viral proteins in proximity. Here, we identified the vital role of a broad-spectrum antiviral, peruvoside in limiting the formation of viral factories. Mechanistically, we revealed the pleiotropic cellular effect of Src and PLC kinase signaling via cyclin-dependent kinase 1 signaling leads to Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1) phosphorylation and Golgi vesiculation by peruvoside treatment. The ramification of GBF1 phosphorylation fosters GBF1 deprivation consequentially activating downstream antiviral signaling by dampening viral factories formation. Further investigation showed signaling of ERK1/2 pathway via cyclin-dependent kinase 1 activation leading to GBF1 phosphorylation at Threonine 1337 (T1337). We also showed 100% of protection in peruvoside-treated mouse model with a significant reduction in viral titre and without measurable cytotoxicity in serum. These findings highlight the importance of dissecting the broad-spectrum antiviral therapeutics mechanism and pave the way for consideration of peruvoside, host-directed antivirals for positive-sense RNA virus-mediated disease, in the interim where no vaccine is available.

Aged ; Aged, 80 and over ; Betacoronavirus ; genetics ; Coronavirus Infections ; epidemiology ; therapy ; DNA, Viral ; analysis ; Disease Management ; Female ; Humans ; Male ; Pandemics ; Pneumonia, Viral ; epidemiology ; therapy ; Singapore

Purpose: The study aimed to investigate the utility of ultrasonographic (US) findings in predicting the subsequent radiographic parameters of developmental dysplasia of the hips. Methods: In this 12-year retrospective cohort study, all new-born infants with a positive clinical examination or risk factors were included. They were scheduled for hip ultrasonography in the first 3 months, and subsequent radiographs at 1 year of life. The US images were evaluated using the Graf classification, Harcke’s dynamic screening method, and Terjesen’s femoral head coverage method. The radiographic images were evaluated using the acetabular index and femoral head position. The overall US or radiographic findings were considered abnormal if they were classified as abnormal for any of their respective parameters. The overall US and radiographic parameters were correlated. Results: A total of 160 patients were included. The overall US and radiographic parameters showed no statistically significant difference (P=0.050). The sensitivity, specificity, and accuracy of the overall US parameters were 57.1%, 84.9%, and 81.3%, respectively. All three individual US parameters showed no statistically significant differences, with the overall radiographic findings and acetabular index (P>0.05). However, they showed a statistically significant difference, with the position of the femoral head (P<0.001), with the US parameters having an excellent negative predictive value of 100% for identifying an abnormal femoral head position. Conclusion The current study suggests that US findings evaluated in the first 3 months of life showed no statistically significant difference with radiographic findings evaluated at 1 year of life. The US parameters showed an excellent negative predictive value for abnormal femoral head position on radiographs.

PURPOSE: The current study aimed to evaluate the results of ultrasound screening for developmental dysplasia of the hips (DDH) done at various weeks of life, to determine the earliest time that ultrasound screening can be performed reliably. METHODS: In this 17-year cohort study, all neonates who underwent ultrasound screening prior to the 12th week of life with subsequent follow-up radiography done at 1 year of life were included. The ultrasound images were evaluated according to the Graf classification, Harcke’s dynamic ultrasound screening method, and Terjesen’s femoral head coverage method. The radiographic images were evaluated according to the acetabular index and the femoral head position. The accuracy and correlation between the ultrasound findings from various weeks of life with the radiographic findings at 1 year of life were evaluated. RESULTS: A total of 348 neonates were included in the study, of whom 92 had abnormal ultrasound findings and 42 had abnormal radiographic findings at 1 year. Significant differences were identified between the findings of ultrasound screening examinations performed prior to the fourth week of life (day 21 and before) and the radiographic findings at 1 year of life (P<0.05). In contrast, no significant differences were identified when ultrasound screening was performed between the fourth and 12th weeks of life (day 22 and beyond) (P>0.05). The accuracy of ultrasound screening was 79.2% or higher when performed during or after the fourth week of life (day 22 and beyond). CONCLUSION: The earliest that ultrasound screening for DDH can be performed reliably is during the fourth week of life (day 22 and beyond).
Acetabulum ; Classification ; Cohort Studies ; Follow-Up Studies ; Head ; Hip Dislocation ; Hip ; Humans ; Infant, Newborn ; Mass Screening ; Methods ; Radiography ; Ultrasonography

Adult ; Aged ; Cervical Vertebrae ; surgery ; Decompression, Surgical ; instrumentation ; methods ; Diskectomy ; instrumentation ; methods ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Outcome Assessment (Health Care) ; Prospective Studies ; Spinal Fusion ; instrumentation ; methods

Adult ; Aged ; Aged, 80 and over ; Amputation ; methods ; Cohort Studies ; Diabetic Foot ; surgery ; Female ; Humans ; Male ; Middle Aged ; Prospective Studies ; Treatment Outcome ; Young Adult

INTRODUCTIONThis study aims to evaluate the predictive factors affecting the clinical outcome of Below Knee Amputations (BKA) performed in diabetic foot patients admitted to National University Hospital (NUH) Multi-Disciplinary Diabetic Foot Team.

MATERIALS AND METHODSThis is a prospective cohort study of 151 patients admitted to the Department of Orthopaedic Surgery, NUH, for Diabetic Foot Problems (DFP) from January 2006 to January 2010. All had undergone BKA performed by NUH Multi-Disciplinary Diabetic Foot Team. Statistical analyses (univariate and multivariate analysis with logistic regression) were carried out using SPSS version 18.0, for factors such as demographic data, diabetic duration and control, clinical findings and investigations, indications for surgery, preoperative investigations and evaluation, microbiological cultures, and these were compared to the clinical outcome of the patient. A good clinical outcome is defined as one not requiring proximal re-amputation and whose stump healed well within 6 months. The ability to ambulate with successful use of a prosthesis after 1 year was documented. Statistical significance was set at P <0.050.

RESULTSMean age of study population was 55.2 years with a male to female ratio of about 3:2. Mean follow up duration was 36 months. Of BKAs, 73.5% gave a good outcome. Univariate analysis showed that smoking, previous limb surgery secondary to diabetes, high Total White Count (TW), Erythrocyte Sedimentation Rate (ESR), C-Reactive Protein (CRP), Urea, Creatinine (Cr), Neutrophils, absence of posterior tibial and popliteal pulses, low Ankle Brachial Index (ABI) and Toe Brachial Index (TBI) were associated with poor clinical outcome. Multivariate analysis showed that high CRP, ESR, Neutrophils, absence of popliteal pulse and low ABI were associated with poor clinical outcome. Of patients, 50.3% attained mobility with prosthesis after 1 year. Mortality rate was 21.2% within 6 months of operation, with sepsis being the most significant cause of death.

CONCLUSIONSuccess rate of BKA was 73.5%, with mortality rate being 21.2% within 6 months. In this cohort, 50.3% were able to attain eventual mobility with prosthesis after 1 year. Sepsis was the most significant cause of death. Markers of infection such as high CRP, ESR, neutrophils; and indicators of poor vascularity such as absence of popliteal pulse and low ABI were significantly associated with poor clinical outcome.

Adult ; Aged ; Aged, 80 and over ; Amputation ; methods ; Diabetic Foot ; surgery ; Female ; Humans ; Knee ; Male ; Middle Aged ; Prospective Studies ; Treatment Outcome

Apart from clinical, histological and biochemical indices, genomics are now being employed to unravel the pathogenetic mechanisms in the disease progression of IgA nephritis (IgAN). The results of angiotensin converting enzyme (ACE) gene polymorphism have been controversial. Those patients with the DD genotype seem to have a poorer prognosis. However, with high dose angiotensin receptor blocker (ARB) therapy, the ACE gene polymorphism status of a patient may no longer be a matter for concern as those with the DD genotype would also respond favourably to high dose ARB therapy. Association studies with gene sequencing and haplotypes have suggested that multiple genes are involved in the pathogenesis of IgAN. Some workers have reported a synergistic effect in the combined analysis of AGT-M235T and ACE I/D polymorphism. With the use of deoxyribo nucleic acid (DNA) microarray, tens of thousands of gene expressions genome-wide can be examined together simultaneously. A locus of familial IgAN has been described with strong evidence of linkage to IgAN1 on chromosome 6q22-23. Two other loci were reported at 4q26-31 and 17q12-22. DNA microarray techniques could also help in the identification of specific pathogenic genes that are up- or down-regulated and this may allow genome wide analyses of these genes and their role in the pathogenesis and progression of IgAN. Recently, using genome-wide association studies (GWAS) more loci for disease susceptibility for IgAN have been identified at 17p13, 8p23, 22q12, 1q32 and 6p21.
Angiotensin Receptor Antagonists ; administration & dosage ; Disease Progression ; Dose-Response Relationship, Drug ; Genomics ; methods ; Glomerulonephritis, IGA ; drug therapy ; genetics ; pathology ; Haplotypes ; Humans ; Molecular Sequence Data ; Polymorphism, Single Nucleotide