Adenosine A2AR in viral immune evasion and therapy: unveiling new avenues for treating COVID-19 and AIDS.

Adenosine is a neuro- and immunomodulator that functions via G protein-coupled cell surface receptors. Several microbes, including viruses, use the adenosine signaling pathway to escape from host defense systems. Since the recent research developments in its role in health and disease, adenosine and its signaling pathway have attracted attention for targeting to treat many diseases. The therapeutic role of adenosine has been extensively studied for neurological, cardiovascular, and inflammatory disorders and bacterial pathophysiology, but published data on the role of adenosine in viral infections are lacking. Therefore, the purpose of this review article was to explain in detail the therapeutic role of adenosine signaling against viral infections, particularly COVID-19 and HIV. Several therapeutic approaches targeting A2AR-mediated pathways are in development and have shown encouraging results in decreasing the intensity of inflammatory reaction. The hypoxia-adenosinergic mechanism provides protection from inflammation-mediated tissue injury during COVID-19. A2AR expression increased remarkably in CD39 + and CD8 + T cells harvested from HIV patients in comparison to healthy subjects. A combined in vitro treatment performed by blocking PD-1 and CD39/adenosine signaling produced a synergistic outcome in restoring the CD8 + T cells funstion in HIV patients. We suggest that A2AR is an ideal target for pharmacological interventions against viral infections because it reduces inflammation, prevents disease progression, and ultimately improves patient survival.

Adenosine A2A receptor as a potential target for improving cancer immunotherapy.

The adenosine nucleoside performs a wide range of actions on various human tissues by activating four cell surface receptors. Adenosine A2A receptors (A2ARs) are widely expressed in the striatum, olfactory bulb, platelets, leukocytes, spleen, and thymus. They promote vasodilatation, platelet antiaggregatory effect, protection from ischemic damage, and regulation of sensorimotor neurons in basal ganglia. Adenosine signaling plays a vital part in modulating in vivo pathophysiological responses. A2ARs are potent negative regulators of the antitumor and proinflammatory actions of activated T cells. This axis offers several therapeutic targets, the most important of which are A2ARs, HIF-1α, and CD39/CD73. Downregulation of this axis increases the effectiveness of modern immunotherapeutic approaches against cancer, such as αCTLA-4/αPD-1. These discoveries have led to a promising novel role of antagonists of A2AR in blocking angiogenesis in immunotherapy of cancer. A small molecule, AZD4635, strongly inhibits A2AR, lowering cancer volume and increasing anticancer immunity. Deletion of A2AR with CRISPR/Cas9 in both human and murine CAR T cells produces a substantial increase in the efficiency of these cells. This review asserts that inhibition of the adenosinergic pathway can boost antitumor immunity, and this axis should be a target for future immunotherapeutic strategies.

Berardinelli Seip Syndrome: A rare case report.

Berardinelli Seip Congenital Lipodystrophy (BSCL) or Congenital Generalized Lipodystrophy (CGL) is one of the four subgroups of lipodystrophy syndrome which is characterized by varying degrees of loss of adipose mass in the body. It is an extremely rare autosomal recessive disorder and commonly reported clinical presentations include muscular hypertrophy, gigantism, hepatomegaly, impaired glucose tolerance, acanthosis nigricans, hypertriglyceridaemia, cardiomyopathy, intellectual impairment, bone cysts and phlebomegaly. We present a case of a 4.5 years old male child born to consanguineous parents, presented with pneumonia. There was history of recurrent diarrhea and chest infection in the past. He had acromegaly like features, hirsutism, firm hepatomegaly, a well defined bone cyst in proximal right femur, pancytopenias with normal bone marrow biopsy report, hypertriglyceridemia and selective IgA deficiency. This is the first case of BSCL, reported in Pakistan with a bone cyst and IgA deficiency. Such patients need to be identified and monitored for complications like diabetes mellitus and hypertrophic cardiomyopathy.

From Molecular Pathology of COVID 19 to Nigella Sativum as a Treatment Option: Scientific Based Evidence of Its Myth or Reality.

COVID-19 virus is a causative agent of viral pandemic in human beings which specifically targets respiratory system of humans and causes viral pneumonia. This unusual viral pneumonia is rapidly spreading to all parts of the world, currently affecting about 105 million people with 2.3 million deaths. Current review described history, genomic characteristics, replication, and pathogenesis of COVID-19 with special emphasis on Nigella sativum (N. sativum) as a treatment option. N. sativum seeds are historically and religiously used over the centuries, both for prevention and treatment of different diseases. This review summarizes the potential role of N. sativum seeds against COVID-19 infection at levels of in silico, cell lines and animal models.

Targeting Adenosine Receptors in Neurological Diseases.

Adenosine plays a significant role in neurotransmission process by controlling the blood pressure, while adenosine triphosphate (ATP) acts as a neuromodulator and neurotransmitter and by activation of P2 receptors, regulates the contractility of the heart. Adenosine signaling is essential in the process of regeneration by regulating proliferation, differentiation, and apoptosis of stem cells. In this review, we have selected neurological disorders (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and epilepsy) with clinical trials using antagonists and epigenetic tools targeting adenosine receptor as a therapeutic approach in the treatment of these disorders. Promising results have been reported from many clinical trials. It has been found that higher expression levels of A2A and P2X7 receptors in neurological disorders further complicate the disease condition. Therefore, modulations of these receptors by using antagonists of these receptors or SAM (S-adenosylmethionine) therapy as an epigenetic tool could be useful in reversing the complications of these disorders. Finally, we suggest that modulation of adenosine receptors in neurological disorders can increase the regenerative phase by increasing the rate of proliferation and differentiation in the damaged tissues.

Clinical profile of subacute sclerosing panencephalitis.

OBJECTIVE: To describe the clinical manifestations of subacute sclerosing panencephalitis in children. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: This study was conducted in the Department of Neurology at The Children's Hospital and the Institute of Child Health, Lahore, from April 2005 to April 2007. METHODOLOGY: Fifty patients were diagnosed as subacute sclerosing panencephalitis during the study period. Their diagnosis was based on a detailed history, clinical examination, presence of antimeasles antibodies in Cerebrospinal Fluid (CSF) and typical electroencephalogram (EEG). The findings were described as average, mean and percentages. RESULTS: Fifty patients were included in this study. The average age of the patients was 8 years. Thirty-eight (76%) were males and 12 (24%) were females. The average duration of symptoms before presentation was 66.72 days. History of measles infection was present in 31 patients (62%) and measles vaccination in 43 patients (86%). Motor regression was present in all (100%) patients and cognition decline in 43 patients (86%). Seizures were focal (10%), generalized tonicclonic (16%) and myoclonic (74%). Burst-suppression pattern Electroencephalogram (EEG) and the antimeasles antibody in CSF were positive in 100% of patients. CONCLUSION: SSPE is an indicator of high incidence of measles infection among the paediatric population even among vaccinated children. Males are more common sufferers. SSPE can present with different types of seizures, cognition decline and motor regression being supported by suggestive EEG and presence of anti-measles antibodies in CSF.

Spectrum of Joint Deformities in Children with Juvenile Idiopathic Arthritis.

OBJECTIVE: To determine the frequency and types of joint deformities in children with juvenile idiopathic arthritis and their association with clinical parameters and rheumatoid factor. STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: Rheumatology Outpatient Clinic, the Children's Hospital and the Institute of Child Health, Lahore, from September 2014 to February 2015. METHODOLOGY: All patients of both genders of less than 16 years of age, who fulfilled the International League of Association for Rheumatology (ILAR) criteria for Juvenile Idiopathic Arthritis (JIA), were enrolled in this study. Their demographic data, duration of disease at the time of presentation, types of JIA, various joint deformities and rheumatoid factor (RF) were documented. Statistical analysis of data was done on SPSS version 16. Chi-square test was applied to determine the association of clinical deformity with age of patients, disease duration at presentation, types of JIA and RF. RESULTS: Out of 70 patients enrolled during the study period, 51.4% were boys with mean age at presentation being 9.44 ±3.89 years (2-7 years) and median duration of disease being 24 months (interquartile range 42 months). Forty patients (57.1%) had joint deformities. Most common joints involved were hand (50%), wrist (50%), and knee (35.7%). The common types of joint deformities were boutonniere deformity (28.6%), ulnar deviation of wrist (28.6%), fixed flexion deformity of wrist (22.9%), and knee (31.4%). The most common type of JIA was polyarthritis RF negative with or without deformity. There was a strong association of deformities with older age of patients at presentation (p=0.036), longer duration of disease at presentation (p=0.028), polyarthritis (RF seronegative / seropositive) (p=0.013), and seropositivity (p=0.04). CONCLUSION: More than 50% patients with JIA have joint deformities. Joint deformities are more likely to be seen in children with long-standing disease, those with polyarthritis JIA and seropositive patients.

Tuberculous Dactylitis with Concomitant Thyroid Involvement: A Rare Presentation of Childhood Tuberculosis.

Extrapulmonary tuberculosis rarely presents as thyroid involvement along with other manifestations, and poses a diagnostic challenge on account of paucibacillary nature of disease. In general, the diagnosis of tuberculosis is based on epidemiological risk factors, clinical features, imaging studies, in addition to a positive skin testing or Interferon Gamma Release Assay (IGRA). A 14-year boy presented with history of fever and weight loss for one year. On examination, he had painful swelling of fingers and toes along with a painless thyroid nodule and squint. Hand X-ray showed lytic-sclerotic lesions in phalanges. MRI of brian showed multiple ring enhancing lesions and radionuclide thyroid scan showed multinodular goitre. Histology showed epithelioid cell granulomas (thyroid and bone) and tuberculomas of brain confirmed tuberculosis. He responded well to four-drug anti-tuberculous therapy and his fever, squint, thyroid nodule, and dactylitis disappeared. Tuberculosis of thyroid, a rare phenomenon, can be diagnosed and treated well; if clinical index of suspicion is kept high, particularly in tuberculosis prevalent areas.

Psittacosis: Rare Respiratory Problem in Children.

Psittacosis is a rare disease particularly in children with usual presentation of respiratory and constitutional symptoms. The cases may remain undiagnosed or diagnosis may be delayed because of lack of awareness among the paediatricians and physicians. Early diagnosis is very important as this is potentially curable and preventable disease. An interesting case of psittacosis is being reported here, which has been treated successfully with azithromycin.

Effectiveness of nebulized N-acetylcysteine solution in children with acute bronchiolitis.

OBJECTIVE: To evaluate the effectiveness of nebulized mucolytic therapy (N-acetylcysteine) in treatment of children with acute bronchiolitis. STUDY DESIGN: Prospective randomized, controlled study. PLACE AND DURATION OF STUDY: Paediatric Medical Unit of the Children's Hospital and the Institute of Child Health, Lahore, from November 2011 to April 2012. METHODOLOGY: All the patients aged 2 months to 24 months, with the diagnosis of acute viral bronchiolitis were enrolled in the study. A predesigned proforma was completed after taking parental consent. All eligible patients were randomly assigned to one of the two groups: group-1 received N-acetylcysteine in nebulized form, and group-2 received salbutamol as a nebulized aerosol. Both groups were then compared regarding their clinical improvement and duration of stay in the hospital. The data obtained was analyzed on the statistical software SPSS version 16. Descriptive statistics were obtained by frequencies and percentages. Chi-square test was applied to find p-value. RESULTS: A total of 100 patients met the inclusion criteria. The mean age was 3 months. On the first day of treatment, the mean clinical severity score at baseline were 5.38 ± 2.62 in group-1 and 4.68 ± 2.2 in group-2. At day 3 and 5, it was 2.9 ± 1.48 and 3.30 ± 1.77 in group-1 and 0.88 ± 1.08 and 1.90 ± 1.32 in group-2 respectively. The clinical severity score after N-acetylcysteine inhalation therapy was better in group-1 on the third but more so on fifth day after hospital admission. The mean duration of hospitalization was 4.67 ± 2.2 days for the whole population and it differed between the 2 groups: 4.36 ± 1.66 days in group-1 versus 4.98 ± 2.6 days in group-2. CONCLUSION: On the basis of improvement in clinical severity score and early discharge from the hospital, N-acetylcysteine was found to be an effective therapy in acute bronchiolitis.

Caffey's disease in an infant.

Caffey's disease is a self limited disorder of infantile age group. It is synonymous with 'infantile cortical hyperostosis' and 'Caffey's-Silver syndrome'.It is characterized by fever, irritability, bone pain and characteristic bony changes. It has no definite etiology. This report describes a 4 months old infant presenting with fever, irritability and soft tissue swellings. Investigations led to the diagnosis of Caffey's disease. Symptomatic treatment was given to good clinical response.