Digital Gangrene as a Paraneoplastic Manifestation of Peripheral T-cell Lymphoma Not Otherwise Specified Type.

BACKGROUND: Peripheral T cell lymphoma (PTCL), not otherwise specified (NOS) is a heterogenous group of predominantly nodal T cell lymphomas that generally presents with lymphadenopathy with or without extra nodal involvement. Acral vascular syndrome clinically presents as digital ischemia with Raynaud's phenomenon and acral cyanosis. Although, this condition is commonly associated with connective tissue disorder, smoking and vasculitis, its association with lymphoid malignancy is very rare. Here, we present a case report of a patient with digital gangrene of all toes and fingers as a presenting symptom of PTCL-NOS. CASE DESCRIPTION: A 62 year old male presented with digital ischemia associated with pain, low grade fever, loss of appetite and significant weight loss of 6 kilograms over a period of 3 months. On examination, he was found to have bilateral inguinal and axillary lymph nodes with gangrenous changes over toes and fingers but peripheral pulses were palpable. On evaluation he had anemia, elevated ESR and CRP. CT angiogram revealed thinned out digital arteries with multifocal areas of narrowing. Patient was screened for other causes of digital gangrene and was tested negative for ANCA, ANA, cryoglobulins and viral markers. Lymph node biopsy with IHC was suggestive of peripheral T-cell lymphoma-NOS and was started on CHOP regimen. Lymph nodes size decreased and gangrenous changes resolved. CONCLUSION: Though digital ischemia is a rare paraneoplastic presentation of lymphoma, it should be considered if there is a rapid progression of gangrene. Early initiation of chemotherapy may result in the reduction of further progression of digital gangrene and thus prevent permanent disability. In our patient, progression of gangrene was prevented even though it was an aggressive variant of T cell lymphoma.

Ustekinumab as induction and maintenance therapy for ulcerative colitis - national extended follow-up and a review of the literature.

INTRODUCTION: Ustekinumab use in ulcerative colitis had shown low adverse event and high persistence rates to 3 years via the UNIFI long-term extension study. Outcomes beyond 3 years have not been previously described. We describe the safety signals of the entire UNIFI Australian population beyond 3 years. METHODS: This retrospective multicenter observational cohort study recruited from all Australian UNIFI centers. The primary outcome was safety via adverse events. Secondary outcomes included the clinical relapse rate on ustekinumab, and the need to switch from ustekinumab to an alternate agent. RESULTS: There were 14 patients [11 male, mean age 47 (±14) years], with a median diagnosis of 10.8 (±4.5) years prior to UNIFI enrollment. Median follow-up was 298 weeks (5.7 years) (Interquartile range (IQR): 220-311 weeks). Within the long-term extension, there were three serious adverse events and one minor event. 42.9% (6/14) patients had clinical relapses, of which clinical remission was recaptured in 83.3% (5/6). 85.7% (12/14) persisted on ustekinumab in the long-term, with 7.1% (1/14) electively ceasing ustekinumab and 7.1% (1/14) changed from ustekinumab due to clinical relapse. CONCLUSION: For moderate-to-severe UC in Australia, ustekinumab maintained efficacy beyond 3 years with a high persistence rate and no new safety signals. TRIAL REGISTRATION: The trial is registered at ANZCTR (identifier: ACTRN12622001332718).

The potential of gene therapy for recessive dystrophic epidermolysis bullosa.

Epidermolysis bullosa (EB) encompasses a heterogeneous group of inherited skin fragility disorders, with mutations in genes encoding the basement membrane zone (BMZ) proteins that normally ensure dermal-epidermal integrity. Of the four main EB types, recessive dystrophic EB (RDEB), especially the severe variant, represents one of the most debilitating clinical entities, with recurrent mucocutaneous blistering and ulceration leading to chronic wounds, infections, inflammation, scarring and ultimately cutaneous squamous cell carcinoma, which leads to premature death. Improved understanding of the molecular genetics of EB over the past three decades and advances in biotechnology have led to rapid progress in developing gene and cell-based regenerative therapies for EB. In particular, RDEB is at the vanguard of advances in human clinical trials of advanced therapeutics. Furthermore, the past decade has witnessed the emergence of a real collective, global effort involving academia and industry, supported by international EB patient organizations such as the Dystrophic Epidermolysis Bullosa Research Association (DEBRA), among others, to develop clinically relevant and marketable targeted therapeutics for EB. Thus, there is an increasing need for the practising dermatologist to become familiar with the concept of gene therapy, fundamental differences between various approaches, and their human applications. This review explains the principles of different approaches of gene therapy, summarizes its journey, and discusses its current and future impact in RDEB.

Transient congenital hypothyroidism - too short to be transient.

Congenital hypothyroidism (CH) occurs due to thyroid dysgenesis, thyroid ectopy, and dyshormonogenesis. A proportion of CH is transient which might be due to iodine deficiency/excess or maternal antibody-mediated. Certain forms of dyshormonogenetic defects may cause transient hypothyroidism. Here is a report of a neonate with overt clinical and biochemical hypothyroidism, who on evaluation was found to have dyshormonogenesis with a homozygous mutation in dual oxidase 2 (DUOX2) gene. During infancy, she became euthyroid. Severe in utero deficiency of thyroid hormone, very short duration of hypothyroidism and first-reported mutation of the DUOX2 gene in the Indian subcontinent were interesting features in this infant.

Epidemiology of bloodstream infections in the paediatric population in a Malaysian general hospital over a 2-year period.

BACKGROUND: Bloodstream infection (BSI) is a major cause of morbidity and mortality. The classification of infection into community-acquired, hospital-acquired, and healthcare-associated infection provides an educated guess on the possible aetiological agents and appropriate empirical antimicrobial therapy to be instituted. This study aims to determine the aetiological agents, the antimicrobial susceptibility patterns, and the classification of infections among the paediatric population. MATERIALS & METHODS: This study was conducted in Hospital Kuala Lumpur, Malaysia from January 2016 to December 2017. A total of 303 isolates were included in this study which was obtained from 238 patients. The patients' microbiological worksheets and medical notes were reviewed to determine the antimicrobial susceptibility patterns, demographic data, classification of infection, and outcome (survival versus death). RESULTS: Most of the patients were in the age group of one to less than five years old (41%) with 58% male and 85% Malay patients. Common causes of BSI were Staphylococcus aureus (17%), followed by Klebsiella pneumoniae (15%), Acinetobacter baumanii (10%), Pseudomonas aeruginosa (10%), and Escherichia coli (6%). Sixty percent of BSI episodes were caused by gram-negative bacteria, 34% by gram-positive bacteria, and 6% by fungi. Most of the infections were classified as hospital-acquired infections (72%), followed by healthcareassociated (20%) and community-acquired infections (8%). There were 33% of methicillin-resistant Staphylococcus aureus, 53% of extended-spectrum beta-lactamase (ESBL) producing Klebsiella pneumoniae, and 33% ESBL producing Escherichia coli. The overall case fatality rate (CFR) was 27% with the highest CFR caused by Serratia marcescens (53.3%). CONCLUSIONS: The majority of paediatric bloodstream infections are hospital-acquired. Improvement in prevention strategies and revisions in antibiotic policies are important to overcome it.

Heterotopic Ossification after Knee Surgery, Arthroscopy is Not an Exception!!!!

INTRODUCTION: Reconstruction of the anterior cruciate ligament (ACL) is a common procedure. Injury is the predisposing risk factor for developing heterotopic ossification(HO). We like to report a case of HO of the knee following arthroscopic ACL reconstruction. CASE REPORT: A29-year-old patient was admitted with complaints of painful instability of the left knee after a fall from bike. MRI study confirmed a complete ACL rupture along with tear of the body and posterior horns of the medial meniscus. ACL reconstruction was carried out using ipsilateral hamstring tendon graft by knee arthroscopy. Eight months after the procedure, the patient complained of pain in the lateral side of the knee joint evidencing a slight prominence of hard consistency. The radiological study confirmed it to be a case of HO. The patient was managed conservatively. CONCLUSION: Bone is the only tissue that has an incredible property as such that it can differentiate and develop into its mature form outside its native locations. Numerous studies have suggested ways of preventing and treating this complication. One has to be aware that even these simple surgical procedures can lead on to HO.

Antiviral and immunomodulatory activity of curcumin: A case for prophylactic therapy for COVID-19.

Coronavirus disease-19 (COVID-19), a devastating respiratory illness caused by SARS-associated coronavirus-2 (SARS-CoV-2), has already affected over 64 million people and caused 1.48 million deaths, just 12 months from the first diagnosis. COVID-19 patients develop serious complications, including severe pneumonia, acute respiratory distress syndrome (ARDS), and or multiorgan failure due to exaggerated host immune response following infection. Currently, drugs that were effective against SARS-CoV are being repurposed for SARS-CoV-2. During this public health emergency, food nutraceuticals could be promising prophylactic therapeutics for COVID-19. Curcumin, a bioactive compound in turmeric, exerts diverse pharmacological activities and is widely used in foods and traditional medicines. This review presents several lines of evidence, which suggest curcumin as a promising prophylactic, therapeutic candidate for COVID-19. First, curcumin exerts antiviral activity against many types of enveloped viruses, including SARS-CoV-2, by multiple mechanisms: direct interaction with viral membrane proteins; disruption of the viral envelope; inhibition of viral proteases; induce host antiviral responses. Second, curcumin protects from lethal pneumonia and ARDS via targeting NF-κB, inflammasome, IL-6 trans signal, and HMGB1 pathways. Third, curcumin is safe and well-tolerated in both healthy and diseased human subjects. In conclusion, accumulated evidence indicates that curcumin may be a potential prophylactic therapeutic for COVID-19 in the clinic and public health settings.

A case of premature and recurrent myocardial infarction associated with ABCA.1 gene mutation.

Coronary heart disease (CHD) is the most important cause of cardiovascular death and when premature, it affects the most productive population of the community. Premature CHD usually has a specific etiology, which on diagnosis, might help in the secondary prevention in that individual. We report a case of young adult with recurrent myocardial infarction, who on evaluation had mildly reduced HDL and Protein C levels with elevated serum homocysteine. Clinical exome identified a possibly pathogenic variant of ABCA1 gene, associated with Tangier disease.

Medium term results following heart transplantation for end stage heart failure: A single center experience of 257 patients.

OBJECTIVE: End stage heart failure is a lethal disease with a dismal 5 year survival. Heart transplantation has proven to be a highly effective modality of treatment in appropriately selected group of such patients. This is a retrospective analysis of medium term outcomes of heart transplantation in the setting of a private health facility in India. The objective of this study was two fold. METHODS: The outcome of 257 heart transplants done at a single centre from October 2012 to October 2019 was analyzed. Patients with combined Heart and lung transplants and those whose complete medical records were unavailable were excluded from the study. Survival was tracked at 60 days, 90 days, one year and beyond for a maximum of 7 years. Preoperative patient risk profiles were characterized on the basis of INTERMACS category. RESULTS: There were 176 male and 81 female patients. The age range was from 8 months to 78 years with a mean of 32.9 years. Survival at 2 months was 87%, at 90 days was 83%, at one year was 81%, 2 years was 75%, at 3 years was 72% and at 5 years and beyond was 62% for the whole series. Strong predictors of 90 day mortality included INTERMACS category (odd's ratio 0.289, p = 0.000) and creatinine more than 1.5 mg/dl (odd's ratio 2.48, p = 0.056). Recipient pulmonary vascular resistance and donor organ ischemic times were not found to be statistically significant factors affecting outcome. Medium term survival was influenced by INTERMACS category (Hazard ratio > 3 for INTERMACS category 1 compared to INTERMACS 4 or 5, p < 0.0001) and creatinine > 1.5 mg/dl (Hazard ratio 2.15, p = 0.003). This effect of creatinine was related to the age of the recipient. Hazard ratio 1.4, p = 0.524 if age <30 and Hazard ratio 4.78, p = 0.006, if age was >50. CONCLUSION: Satisfactory medium term outcome is possible after heart transplantation even in resource constrained environment of a developing country.

Conferring root-knot nematode resistance via host-delivered RNAi-mediated silencing of four Mi-msp genes in Arabidopsis.

The root-knot nematode (RKN) Meloidogyne incognita is considered one of the most damaging pests among phytonematodes. The majority of nematode oesophageal gland effector genes are indispensable in facilitating M. incognita parasitization of host plants. We report the effect of host-delivered RNAi (HD-RNAi) silencing of four selected M. incognita effector genes, namely, Mi-msp3, Mi-msp5, Mi-msp18 and Mi-msp24, in Arabidopsis thaliana. Mi-msp5, Mi-msp18 and Mi-msp24, which are dorsal gland genes, were found to be maximally expressed in the adult female stage, whereas Mi-msp3, which is a sub-ventral gland gene, was maximally expressed in an earlier stage. In transgenic plants expressing dsRNA, the reduction in the number of galls on roots was 89 %, 78 %, 86 % and 89 % for the Mi-msp3, Mi-msp5, Mi-msp18 and Mi-msp24 RNAi events, respectively. Moreover, gene transcript abundance was significantly reduced in RKN females feeding on dsRNA-expressing lines by up to 60 %, 84 %, 31 % and 61 % for Mi-msp3, Mi-msp5, Mi-msp18 and Mi-msp24, respectively. Furthermore, the M. incognita reproduction factor was reduced up to 71-, 344-, 107- and 114-fold in Arabidopsis plants expressing Mi-msp3, Mi-msp5, Mi-msp18 and Mi-msp24 dsRNA constructs, respectively. This study provides a set of potential target genes to curb nematode infestation in economically important crops via the HD-RNAi approach.

Fatty liver in a two days old neonate.

Neonatal death due to inborn error of metabolism (IEM) is rare in Malaysia. We report a sudden neonate death just a few hours after being discharged from the hospital. The deceased was a two-day-old baby boy and was asymptomatic until his demise. He was fed with expressed breast milk and formula milk. Autopsy revealed fatty changes of the liver and an enlarged heart. Laboratory investigation confirmed very long chain Acyl-CoA dehydrogenase deficiency which resulted in his death. Autopsy of sudden unexpected death in neonate should include investigation for inborn error of metabolism. Fatty liver and enlarged heart could give a clue for the diagnosis.

Sudden cardiac death in a young adult man due to spontaneous coronary artery dissection.

Spontaneous coronary artery dissection is a rare event and commonly associated with pregnancy and female gender. This condition can reduce or completely obstruct the blood flow to the heart, causing a myocardial ischaemia, abnormalities in heart rhythm or sudden death. We present a case of a 28-year-old Indian male with no previous medical illness who complained sudden onset of chest pain prior to his death. Autopsy revealed a left anterior descending coronary artery dissection associated with plaque rupture. The anterior wall of left ventricle showed contraction band necrosis. There was also atheroma present in the right coronary artery which was insignificant. Histologically, dissection was associated with atherosclerosis. There was no evidence of vasculitis. The cause of death was given as coronary artery dissection due to coronary artery atherosclerosis.

Cellulitis in human brucellosis: An atypical presentation.

INTRODUCTION: Brucellosis is a zoonotic disease with variable clinical manifestations and atypical presentation in humans. Human brucellosis cases are not seen often in Malaysia. CASE REPORT: This is a case report of 19 years old gentleman who presented with fever, lower limb redness, pain and swelling. He was initially treated as cellulitis. However, based on the recovery of Brucella melitensis from his blood culture, he was later diagnosed to have brucellosis. He had a history of consumption of fresh goat's milk and uncooked meat which could have been the possible modes of transmission. Brucella serology IgM and IgG were both positive, and anti-Brucella immunocapture agglutination test (BrucellaCapt) was also positive with a titer of 1:2560. He was treated with six weeks of oral doxycycline 100 mg twice daily and oral rifampin 450 mg twice daily. DISCUSSION: This is a case of human brucellosis with atypical cutaneous involvement.

Association of the drug of abuse in road traffic collision death in Hospital Kuala Lumpur.

INTRODUCTION: The role of pathologist not only confined in performing post mortem but also can assist in prevention. The aim of this study to determine the prevalence and association of drug of abuse (DoA) in road traffic collision (RTC) at Hospital Kuala Lumpur. METHODS: This is a retrospective study of post mortem cases at Hospital Kuala Lumpur from 2014 to 2016. Deaths from RTC were included while decomposed and homicide cases were excluded. We performed Spearman Correlation statistical test to relate RTC and positive DoA results. RESULTS: A total of 523 RTC cases were identified in which either blood or urine or both samples were taken for toxicology. 93 cases were positive for both DoA and therapeutic drugs. A total of 37 cases were positive for DoA. Alcohol was present in 5 out of 37 DoA positive cases. Most of the cases seen among 16 to 45 years old (69%) and predominantly in males (93.1%). 29 out of 37 were motorcyclist and the rest were pillion rider and pedestrian. Spearman Correlation statistical test showed a negative relationship between RTC and positive DoA results. DISCUSSION AND CONCLUSION: Majority of the DoA cases in RTC were identified in the younger age group and among the motorcyclist. Spearman Correlation statistical test showed that more cases of DoA died in natural or suicidal manner compared to RTC. However, this doesn't reflect the true association of DoA in RTC. This is because of mainly two factors which the delayed effect of DoA that gives negative toxicology test and also the influence of other road users on DoA.

Host-mediated RNAi of a Notch-like receptor gene in Meloidogyne incognita induces nematode resistance.

GLP-1 (abnormal germline proliferation) is a Notch-like receptor protein that plays an essential role in pharyngeal development. In this study, an orthologue of Caenorhabditis elegans glp-1 was identified in Meloidogyne incognita. A computational analysis revealed that the orthologue contained almost all the domains present in the C. elegans gene: specifically, the LIN-12/Notch repeat, the ankyrin repeat, a transmembrane domain and different ligand-binding motifs were present in orthologue, but the epidermal growth factor-like motif was not observed. An expression analysis showed differential expression of glp-1 throughout the life cycle of M. incognita, with relatively higher expression in the egg stage. To evaluate the silencing efficacy of Mi-glp-1, transgenic Arabidopsis plants carrying double-stranded RNA constructs of glp-1 were generated, and infection of these plants with M. incognita resulted in a 47-50% reduction in the numbers of galls, females and egg masses. Females obtained from the transgenic RNAi lines exhibited 40-60% reductions in the transcript levels of the targeted glp-1 gene compared with females isolated from the control plants. Second-generation juveniles (J2s), which were descendants of the infected females from the transgenic lines, showed aberrant phenotypes. These J2s exhibited a significant decrease in the overall distance from the stylet to the metacorpus region, and this effect was accompanied by disruption around the metacorporeal bulb of the pharynx. The present study suggests a role for this gene in organ (pharynx) development during embryogenesis in M. incognita and its potential use as a target in the management of nematode infestations in plants.

Type I Cryoglobulinemic Nephritis in a Patient of Monoclonal Gammopathy of Renal Significance.

Monoclonal gammopathy of renal significance is a recently described entity in which a small B-cell clone not meeting the criteria for the diagnosis of multiple myeloma produces renal disease usually through deposition of a secreted monoclonal immunoglobulin. Here, we describe a case of Type I cryoglobulinemic glomerulonephritis diagnosed on a kidney biopsy and caused by a monoclonal IgM produced by a small bone marrow clone. The patient made a complete renal recovery after chemotherapy to suppress the clone.

Metrics of lung tissue heterogeneity depend on BMI but not age.

Altered parenchymal microstructure and complexity have been observed in older age. How to distinguish between healthy, expected changes and early signs of pathology remains poorly understood. An objective quantitative analysis of computed tomography imaging was conducted to compare mean lung density, tissue density distributions, and tissue heterogeneity in 16 subjects, 8 aged >60 yr who were gender and body mass index matched with 8 subjects aged <30 yr. Subjects had never been smokers, with no prior respiratory disease, and no radiologically identified abnormalities on computed tomography. Volume-controlled breath hold imaging acquired at 80% vital capacity (end inspiration) and 55% vital capacity (end expiration) were used for analysis. Mean lung density was not different between the age groups at end inspiration ( P = 0.806) but was larger in the younger group at end expiration (0.26 ± 0.033 vs. 0.22 ± 0.026, P = 0.008), as is expected due to increased air trapping in the older population. However, gravitational gradients of tissue density did not differ with age; the only difference in distribution of tissue density between the two age groups was a lower density in the apices of the older group at end expiration. The heterogeneity of the lung tissue assessed using two metrics showed significant differences between end inspiration and end expiration, no dependence on age, and a significant relationship with body mass index at both lung volumes when heterogeneity was calculated using quadtree decomposition but only at end expiration when using a fractal dimension. NEW & NOTEWORTHY Changes to lung tissue heterogeneity can be a normal part of aging but can also be an early indicator of disease. We use novel techniques, which have previously not been used on thoracic computed tomography imaging, to quantify lung tissue heterogeneity in young and old healthy subjects. Our results show no dependence on age but a significant correlation with body mass index.

Adult extracorporeal membrane oxygenation: an international survey of transfusion and anticoagulation techniques.

BACKGROUND AND OBJECTIVES: Extracorporeal membrane oxygenation (ECMO) is a method of life support for either isolated cardiac failure or respiratory failure, with or without cardiac failure. When used for hemodynamic support, the ECMO circuit presents a non-endothelialized, artificial surface to blood inciting an inflammatory response which activates haemostatic pathways. Anticoagulation may complicate a pre-existing coagulopathy and/or inadequate surgical hemostasis of varying severity. There is no standardized method to achieve and monitor anticoagulation or guide transfusion therapy during ECMO. We tested the hypothesis that institutions across the world conduct similar management of anticoagulation and transfusion during adult ECMO support. METHODS: This is a descriptive, self-reporting cross-sectional survey of anticoagulation and transfusion practice for patients age 18 or older on ECMO. This 38 multiple-choice question survey was sent to 166 institutions, internationally, utilizing adult ECMO. About 32·4% (54) of institutions responded. Responses were anonymously collected. Descriptive analyses were calculated. RESULTS: Our findings indicate there appears to be a significant practice variation among institutions regarding anticoagulation and transfusion during adult ECMO support. DISCUSSION: The lack of standard practices among institutions may reflect a paucity of data regarding optimal anticoagulation and transfusion for patients requiring ECMO. Standardized protocols for anticoagulation and transfusion may help increase quality of care for and reduce morbidity, mortality and cost to patients and healthcare centres. Further study is required for standardized, high quality care.