Inclusion body myositis in the rheumatology clinic

Inclusion body myositis is a rare sporadic inflammatory‐degenerative myopathy of the elderly. Despite being the commonest type of acquired myopathy after the age of 50, misdiagnosis is extremely common. The most frequent hurdle in identifying new cases is the wrong diagnosis of polymyositis or motor neuron disease. Novel insights into pathogenic mechanisms have heralded the quest for newer therapeutics as well as drug repurposing in this otherwise progressive disorder.     

Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca2+-permeable AMPA receptors

Gene knockout (KO) does not always result in phenotypic changes, possibly due to mechanisms of functional compensation. We have studied mice lacking cGMP-dependent kinase II (cGKII), which phosphorylates GluA1, a subunit of AMPA receptors (AMPARs), and promotes hippocampal long-term potentiation (LTP) through AMPAR trafficking. Acute cGKII inhibition significantly reduces LTP, whereas cGKII KO mice show no LTP impairment. Significantly, the closely related kinase, cGKI, does not compensate for cGKII KO. Here, we describe a previously unidentified pathway in the KO hippocampus that provides functional compensation for the LTP impairment observed when cGKII is acutely inhibited. We found that in cultured cGKII KO hippocampal neurons, cGKII-dependent phosphorylation of inositol 1,4,5-trisphosphate receptors was decreased, reducing cytoplasmic Ca²⁺ signals. This led to a reduction of calcineurin activity, thereby stabilizing GluA1 phosphorylation and promoting synaptic expression of Ca²⁺-permeable AMPARs, which in turn induced a previously unidentified form of LTP as a compensatory response in the KO hippocampus. Calcineurin-dependent Ca²⁺-permeable AMPAR expression observed here is also used during activity-dependent homeostatic synaptic plasticity. Thus, a homeostatic mechanism used during activity reduction provides functional compensation for gene KO in the cGKII KO hippocampus.Some gene deletions yield no phenotypic changes because of functional compensation by closely related or duplicate genes (1). However, such duplicate gene activity may not be the main compensatory mechanism in mouse (2), although this possibility is still controversial (3). A second mechanism of compensation is provided by alternative metabolic pathways or regulatory networks (4). Although such compensatory mechanisms have been extensively studied, especially in yeast and nematode (1), the roles of metabolic and network compensatory pathways are not well understood in mouse.Long-term potentiation (LTP) and long-term depression (LTD) are long-lasting forms of synaptic plasticity that are thought to be the cellular basis for learning and memory and proper formation of neural circuits during development (5). NMDA receptor (NMDAR)-mediated synaptic plasticity is a generally agreed postsynaptic mechanism in the hippocampus (5). In particular, synaptic Ca²⁺ influx through NMDARs is critical for LTP and LTD through control of various protein kinases and phosphatases (6). LTP is in part dependent upon the activation of protein kinases, which phosphorylate target proteins (6). Several kinases are activated during the induction of LTP, including cAMP-dependent protein kinase (PKA) and cGMP-dependent protein kinases (cGKs) (6). In contrast, LTD results from activation of phosphatases that dephosphorylate target proteins (6), and calcineurin, a Ca²⁺/calmodulin-dependent protein phosphatase, is important for LTD expression (7). AMPA receptors (AMPARs) are postsynaptic glutamate receptors that mediate rapid excitatory transmission in the central nervous system (8). During LTP, activated kinases phosphorylate AMPARs, leading to synaptic trafficking of the receptors to increase synapse activity (5). For LTD, activation of postsynaptic phosphatases induces internalization of AMPARs from the synaptic membrane, thereby reducing synaptic strength (5). Therefore, both protein kinases and phosphatases control synaptic trafficking of AMPARs, underlying LTP and LTD.AMPARs are tetrameric ligand-gated ion channels that consist of a combinatorial assembly of four subunits (GluA1–4) (9). Studies of GluA1 knockout (KO) mice show that GluA1 is critical for LTP in the CA1 region of the hippocampus (10). GluA1 homomers, like all GluA2-lacking/GluA1-containing receptors, are sensitive to polyamine block and are Ca²⁺-permeable, whereas GluA2-containing AMPARs are Ca²⁺-impermeable (9). Moreover, GluA1 is the major subunit that is trafficked from recycling endosomes to the synaptic membrane in response to neuronal activity (11). Phosphorylation of GluA1 within its intracellular carboxyl-terminal domain (CTD) can regulate AMPAR membrane trafficking (12). Several CTD phosphorylations regulate trafficking (6). In particular, PKA and cGKII both phosphorylate serine 845 of GluA1, increasing the level of extrasynaptic receptors (13, 14). Therefore, activation of PKA and cGKII during LTP induction increases GluA1 phosphorylation, which enhances AMPAR activity at synapses. On the other hand, calcineurin dephosphorylates serine 845 of GluA1, which enables GluA1-containing AMPARs to be endocytosed from the plasma membrane during LTD (15, 16). This removes synaptic AMPARs, leading to reduction of receptor function during LTD. Taken together, the activity-dependent trafficking of synaptic GluA1 is regulated by the status of phosphorylation in the CTD, which provides a critical mechanism underlying LTP and LTD.Several studies have shown that acute inhibition of cGKII impairs hippocampal LTP (13, 17, 18). However, cGKII KO animals show apparently normal LTP in the hippocampus (19), suggesting that a form of functional compensation takes place in the KO hippocampus. Here, we show that cGKII KO reduces Ca²⁺ signals by decreasing cGKII-dependent phosphorylation of inositol 1,4,5-trisphosphate receptors (IP3Rs), which in turn lowers calcineurin activity in hippocampal neurons, which stabilizes phosphorylation of GluA1 in homomeric, Ca²⁺-permeable AMPARs (CPARs). This elevates CPARs at the synapse as a previously unidentified compensatory mechanism for hippocampal LTP in cGKII-deficient animals that is alternative to the form of LTP expressed in WT.     

Lower esophageal sphincter pressures in patients of bronchial asthma and its correlation with spirometric parameters: a case-control study

Objectives: The cause–effect relationship between bronchial asthma and gastro-esophageal reflux (GER) is known, but studies have not been able to confirm the improvement of lung function with anti-acid therapy. Hypotensive lower esophageal sphincter (LES) may lead to both acid and non-acid reflux, resulting in asthma symptoms and decreased lung function. The objectives of our study were, firstly, to compare basal LES pressure between adult patients of asthma and normal controls and, secondly, to correlate the basal LES pressure with spirometric parameters in these patients. Methods: Thirty patients, aged between 18 and 65 years, diagnosed as cases of bronchial asthma and 27 healthy controls were included in the study. All the participants were subjected to esophageal manometry after overnight fasting and basal LES pressures were recorded. Then, spirometry was done 2?h after meal and pre- and post-bronchodilator FEV₁, FVC, PEFR were obtained for the asthma group. Results and conclusions: There is significant difference between basal LES pressure in patients of bronchial asthma and control population (8.70?±?2.67?mmHg versus 16.64?±?5.52, p?<?0.0001). 66.67% of the asthma patients have reduced LES pressures (<10?mmHg). The correlation coefficient between basal LES pressure and prebronchodilator FEV₁% predicted is 0.596 (p?<?0.0001, 95% CI 0.3002–0.7872). Obstructive airway impairment in adult patients of bronchial asthma is associated with hypotensive LES. GER, due to hypotensive LES may contribute to deterioration of spirometric parameters in asthma patients.     

Axial spondyloarthritis may protect against poor outcomes in COVID-19: propensity score matched analysis of 9766 patients from a nationwide multi-centric research network

Clinical Rheumatology - The outcomes of COVID-19 in patients with axial spondyloarthritis (ax-SpA) have not been explored in detail. Tumour necrosis factor inhibitors (TNFi) are commonly used for...     

The untapped potential of Instagram to facilitate rheumatology academia

Clinical Rheumatology - Instagram allows for graphical and visual information exchange. This paper aims to explore the current landscape of rheumatology on Instagram and analyse the accounts...     

Evaluation of the Universal Immunization Program and Challenges in Coverage of Migrant Children in Haridwar,Uttarakhand, India

Background:

Studies show that immunization among migrant children is poor. India has a dropout rate of 17.7% between Bacillus Calmette-Guιrin (BCG) and measles (District Level Household Survey (DLHS)-3). Haridwar district had the highest dropout rate of 27.4% from BCG to diphtheria, pertussis, and tetanus (DPT) 3 (DLHS-3) in Uttarakhand. We evaluated the Universal Immunization Programme (UIP) among migrants in Haridwar in two blocks.

Materials and Methods:

We developed input, process, and output indicators on infrastructure, human resources, and service delivery. A facility, session site and cross-sectional survey of 180 children were done and proportions for various indicators were estimated. We determined factors associated with not taking vaccination using multivariate analysis.

Results:

We surveyed 11 cold chain centers, 25 subcenters, 14 sessions, and interviewed 180 mothers. Dropouts were supposed to be tracked using vaccination card counterfoils and tracking registers. The dropout rate from BCG to DPT3 was 30%. Lack of knowledge (adjusted odds ratio (AOR) 6.6,95% confidence interval (CI) 2.6–16.7), mother not being decision maker (AOR 4.0,95%CI 1.7–9.2), lack of contact by Accredited Social Health Activist (ASHA; AOR 3.0,95%CI 1.1–7.7), not being given four post-vaccination messages (AOR 7.7, 95% CI 2.9–20.2), and longer duration of stay in Haridwar (AOR 3.0 95% 1.9–7.6) were risk factors for nonimmunization. The reasons stated by mothers included lack of awareness of session site location (67%) and belief that child should only be vaccinated in their resident district (43%).

Conclusions:

There was low immunization coverage among migrants within adequate supervision, poor cold chain maintenance, and improper tracking of dropouts. Mobile immunization teams, prelisting of migrant children, and change in incentives of ASHAs for child tracking were needed. A monitoring plan for sessions and cold chain needed enforcement.     

Effect of vaginally administered (Ala)-magainin II amide on the morphology of implantation stage endometrium in the rhesus monkey (Macaca mulatta)

Intravaginal administration of an anti-microbial agent, (Ala^8,13,18)-magainin II amide, during blastocyst implantation inhibits pregnancy establishment in a dose-related manner in the rhesus monkey (Macaca mulatta). In the present study, mated female rhesus monkeys were vaginally inserted with tampons containing vehicle (Group 1; N = 5) and test agent (magainin, 0.5 mg/animal; Group 2; N = 6) on cycle day 20. Endometrial tissue samples were collected on Cycle Day 24 from all monkeys and processed for morphometric and ultrastructural analysis. Concentrations of estradiol-17β, progesterone, and chorionic gonadotrophin in peripheral circulation were determined, which revealed that two monkeys in Group 1 were pregnant while no animals were pregnant in Group 2. Endometrial morphology, however, revealed histologic evidence of pregnancy in three out of the six magainin-treated animals. It appears that intra-vaginal administration of magainin II amide had a marginal effect on the implantation stage endometrium and the initiation of the implantation process in the rhesus monkey.     

Gastrointestinal problems at high altitude.

Gastrointestinal (GI) problems at high altitude are commonplace. The manifestations differ considerably in short-term visitors, long-term residents and native highlanders. Ethnic food habits and social norms also play a role in causing GI dysfuntion. Symptoms like nausea and vomiting are common manifestations of acute mountain sickness and are seen in 81.4% short-term visitors like mountaineers. Anorexia is almost universal and has a mutifactorial causation including effect of hormones like leptin and cholecystokinin and also due to hypoxia itself. Dyspepsia and flatulence are other common symptoms. Diarrhoea, often related to poor hygiene and sanitation is also frequently seen especially among the short-term visitors. Peptic ulceration and upper gastro-intestinal haemorrhage are reported to be common in native highlanders in the' Peruvian Andes (9.6/10000 population per year) and also from Ladakh in India. A hig h incidence o f gastriccarcinoma is also reported, especially from Bolivia (138.2 cases per 10000 population per year). Megacolon and sigmoid volvulus are common lower GI disorders at high altitude. The latter accounted for 79% of all intestinal obstructions at a Bolivian hospital. Thrombosis of the portosystemic vascultature and splenic hematomas has been reported from India. Malnutrition is multifactorial and mainly due to hypoxia. Fat malabsorption is probably significant only at altitudes > 5000m. Neonatal hyperbilirubinemia was found to be four times more common in babies born at high altitude in Colorado than at sea level. Gall stones disease is common in Peruvian highlands. A high seroprevalence of antibodies to H pylori (95%) has been found in Ladakh but its correlation to the prevalence of upper gastro-intestinal disease has not been proven.     

Inositol hexakisphosphate kinase-2 determines cellular energy dynamics by regulating creatine kinase-B

Inositol hexakisphosphate kinases (IP6Ks) regulate various biological processes. IP6Ks convert IP6 to pyrophosphates such as diphosphoinositol pentakisphosphate (IP7) and bis-diphosphoinositol tetrakisphosphate (IP8). IP7 is produced in mammals by a family of inositol hexakisphosphate kinases, IP6K1, IP6K2, and IP6K3, which have distinct biological functions. The inositol hexakisphosphate kinase 2 (IP6K2) controls cellular apoptosis. To explore roles for IP6K2 in brain function, we elucidated its protein interactome in mouse brain revealing a robust association of IP6K2 with creatine kinase-B (CK-B), a key enzyme in energy homeostasis. Cerebella of IP6K2-deleted mice (IP6K2-knockout [KO]) produced less phosphocreatine and ATP and generated higher levels of reactive oxygen species and protein oxidative damage. In IP6K2-KO mice, mitochondrial dysfunction was associated with impaired expression of the cytochrome-c1 subunit of complex III of the electron transport chain. We reversed some of these effects by combined treatment with N-acetylcysteine and phosphocreatine. These findings establish a role for IP6K2–CK-B interaction in energy homeostasis associated with neuroprotection.

Inositol pyrophosphates are versatile messenger molecules that mediate a variety of cellular functions, including cell growth, apoptosis, endocytosis, and cell differentiation. The most extensively studied inositol pyrophosphate, diphosphoinositol pentakisphosphate (IP7), displays a 5′-diphosphate (1, 2). IP7 is generated in mammals by a family of inositol hexakisphosphate kinases (IP6Ks) (3, 4). IP6Ks exists in three isoforms: IP6K1, IP6K2, and IP6K3. Inositol hexakisphosphate kinase-2 (IP6K2) sensitizes cells to apoptosis (5, 6). Mice with targeted deletion of IP6K2 display an increased incidence of aero-digestive tract carcinoma (7). Cell survival associated with heat shock protein 90 also involves IP6K2 (8, 9).We previously reported a major role for IP6K2 in the disposition of cerebellar granule cells as well as Purkinje cell morphology and motor coordination. The influence of IP6K2 upon cerebellar disposition involved protein 4.1N, both of which were highly expressed in cerebellar granule cells (10).To further assess the functions of IP6K2 in the brain, we explored its binding partners using coimmunoprecipitation and tandem liquid chromatography mass spectrometry (LC-MS/MS). Here, we report that IP6K2 robustly interacts with creatine kinase-B (CK-B), which regulates energy homeostasis of cells and exists in two forms, brain type (CK-B) and muscle type (CK-M). CK catalyzes the reversible transfer of the phosphate group of phosphocreatine to ADP to yield ATP (11, 12). A functional interplay between mitochondrial and cytosolic isoforms of CK regulates cellular energy homeostasis. Cytosolic CK rephosphorylates locally produced free ADP and increases creatine globally, while the mitochondrial enzyme catalyzes the conversion of creatine to phosphocreatine utilizing mitochondrial ATP (13–15).Here, we show that IP6K2 loss leads to decreased CK-B expression, reduced ATP levels, and diminished mitochondrial activity associated with increased oxidative stress. About 80 to 90% of ATP is generated in the mitochondria by oxidative phosphorylation, and diminished ATP levels are the immediate effect of mitochondrial dysfunction. Loss of IP6K2 and CK-B reflects the suppression of the mitochondrial cytochrome c1 expression, a component of complex III of the mitochondrial electron transport chain. In the present study, we report a physiologic association of CK-B and IP6K2, whose disruption impacts mitochondrial functions.Dendritic morphogenesis was reduced in IP6K2-deficient neurons and was rescued by restoring normal levels of ATP. These observations reveal an essential role of IP6K2 in the energy production of the brain. Our findings indicate that IP6K2 is a key regulator of mitochondrial homeostasis which promotes neuroprotection.     

The Role of Asymmetric Dimethylarginine (ADMA) in Endothelial Dysfunction and Cardiovascular Disease

Endothelium plays a crucial role in the maintenance of vascular tone and structure. Endothelial dysfunction is known to precede overt coronary artery disease. A number of cardiovascular risk factors, as well as metabolic diseases and systemic or local inflammation cause endothelial dysfunction. Nitric oxide (NO) is one of the major endothelium derived vaso-active substances whose role is of prime importance in maintaining endothelial homeostasis. Low levels of NO are associated with impaired endothelial function. Asymmetric dimethylarginine (ADMA), an analogue of L-arginine, is a naturally occurring product of metabolism found in human circulation. Elevated levels of ADMA inhibit NO synthesis and therefore impair endothelial function and thus promote atherosclerosis. ADMA levels are increased in people with hypercholesterolemia, atherosclerosis, hypertension, chronic heart failure, diabetes mellitus and chronic renal failure. A number of studies have reported ADMA as a novel risk marker of cardiovascular disease. Increased levels of ADMA have been shown to be the strongest risk predictor, beyond traditional risk factors, of cardiovascular events and all-cause and cardiovascular mortality in people with coronary artery disease. Interventions such as treatment with L-arginine have been shown to improve endothelium-mediated vasodilatation in people with high ADMA levels. However the clinical utility of modifying circulating ADMA levels remains uncertain.