Marginal impaction in complex posterior wall acetabular fractures: role of allograft and mid-term results

European Journal of Orthopaedic Surgery & Traumatology - To evaluate the functional and radiological outcome of complex posterior wall acetabular fractures with marginal impaction treated with...     

Taenia solium taeniosis/cysticercosis in Asia: epidemiology,impact and issues

Several reports of patients with cysticercosis from many countries in Asia such as India, China, Indonesia, Thailand, Korea, Taiwan and Nepal are a clear indicator of the wide prevalence of Taenia solium cysticercosis and taeniosis in these and other Asian countries. However, epidemiological data from community based studies are sparse and available only for a few countries in Asia. Cysticercosis is the cause of epilepsy in up to 50% of Indian patients presenting with partial seizures. It is also a major cause of epilepsy in Bali (Indonesia), Vietnam and possibly China and Nepal. Seroprevalence studies indicate high rates of exposure to the parasite in several countries (Vietnam, China, Korea and Bali (Indonesia)) with rates ranging from 0.02 to 12.6%. Rates of taeniosis, as determined by stool examination for ova, have also been reported to range between 0.1 and 6% in the community in India, Vietnam, China, and Bali (Indonesia). An astonishingly high rate of taeniosis of 50% was reported from an area in Nepal populated by pig rearing farmers. In addition to poor sanitation, unhealthy pig rearing practices, low hygienic standards, unusual customs such as consumption of raw pork is an additional factor contributing to the spread of the disease in some communities of Asia. Undoubtedly, cysticercosis is a major public health problem in several Asian countries effecting several million people by not only causing neurological morbidity but also imposing economic hardship on impoverished populations. However, there are wide variations in the prevalence rates in different regions and different socio-economic groups in the same country. It is important to press for the recognition of cysticercosis as one of the major public health problems in Asia that needs to be tackled vigorously by the governments and public health authorities of the region.     

Does Parsonnet scoring model predict mortality following adult cardiac surgery in India?

Aims and Objectives:

To validate the Parsonnet scoring model to predict mortality following adult cardiac surgery in Indian scenario.

Materials and Methods:

A total of 889 consecutive patients undergoing adult cardiac surgery between January 2010 and April 2011 were included in the study. The Parsonnet score was determined for each patient and its predictive ability for in-hospital mortality was evaluated. The validation of Parsonnet score was performed for the total data and separately for the sub-groups coronary artery bypass grafting (CABG), valve surgery and combined procedures (CABG with valve surgery). The model calibration was performed using Hosmer–Lemeshow goodness of fit test and receiver operating characteristics (ROC) analysis for discrimination. Independent predictors of mortality were assessed from the variables used in the Parsonnet score by multivariate regression analysis.

Results:

The overall mortality was 6.3% (56 patients), 7.1% (34 patients) for CABG, 4.3% (16 patients) for valve surgery and 16.2% (6 patients) for combined procedures. The Hosmer–Lemeshow statistic was <0.05 for the total data and also within the sub-groups suggesting that the predicted outcome using Parsonnet score did not match the observed outcome. The area under the ROC curve for the total data was 0.699 (95% confidence interval 0.62–0.77) and when tested separately, it was 0.73 (0.64–0.81) for CABG, 0.79 (0.63–0.92) for valve surgery (good discriminatory ability) and only 0.55 (0.26–0.83) for combined procedures. The independent predictors of mortality determined for the total data were low ejection fraction (odds ratio [OR] - 1.7), preoperative intra-aortic balloon pump (OR - 10.7), combined procedures (OR - 5.1), dialysis dependency (OR - 23.4), and re-operation (OR - 9.4).

Conclusions:

The Parsonnet score yielded a good predictive value for valve surgeries, moderate predictive value for the total data and for CABG and poor predictive value for combined procedures.     

Reactive nitrogen species regulate autophagy through ATM-AMPK-TSC2–mediated suppression of mTORC1

Reactive intermediates such as reactive nitrogen species play essential roles in the cell as signaling molecules but, in excess, constitute a major source of cellular damage. We found that nitrosative stress induced by steady-state nitric oxide (NO) caused rapid activation of an ATM damage-response pathway leading to downstream signaling by this stress kinase to LKB1 and AMPK kinases, and activation of the TSC tumor suppressor. As a result, in an ATM-, LKB1-, TSC-dependent fashion, mTORC1 was repressed, as evidenced by decreased phosphorylation of S6K, 4E-BP1, and ULK1, direct targets of the mTORC1 kinase. Decreased ULK1 phosphorylation by mTORC1 at S757 and activation of AMPK to phosphorylate ULK1 at S317 in response to nitrosative stress resulted in increased autophagy: the LC3-II/LC3-I ratio increased as did GFP-LC3 puncta and acidic vesicles; p62 levels decreased in a lysosome-dependent manner, confirming an NO-induced increase in autophagic flux. Induction of autophagy by NO correlated with loss of cell viability, suggesting that, in this setting, autophagy was functioning primarily as a cytotoxic response to excess nitrosative stress. These data identify a nitrosative-stress signaling pathway that engages ATM and the LKB1 and TSC2 tumor suppressors to repress mTORC1 and regulate autophagy. As cancer cells are particularly sensitive to nitrosative stress, these data open another path for therapies capitalizing on the ability of reactive nitrogen species to induce autophagy-mediated cell death.Autophagy is a self-digestion process by which a eukaryotic cell degrades and recycles aggregate-prone proteins, macromolecules, and organelles. During autophagy, cytoplasmic contents are sequestered in double-membrane bound vesicles called autophagosomes and delivered to lysosomes for degradation, thereby allowing cells to eliminate and recycle the contents (1–3). Autophagy participates in both prosurvival (recycling of cellular building blocks) and prodeath (excess catalysis) pathways. A comprehensive understanding of signaling pathways that regulate autophagy holds great promise for new therapeutic opportunities by opening the possibility to compromise prosurvival autophagic pathways that enable tumor cells to evade therapy, or by promoting prodeath autophagic pathways to kill cancer cells.The classical pathway regulating autophagy in mammalian cells involves the serine/threonine kinase, mammalian target of rapamycin (mTOR). Active mTOR kinase in the mTORC1 complex phosphorylates and inhibits ULK1, a key proautophagy adapter involved in nucleation of the autophagophore membrane. Inactivation of mTORC1, either pharmacologically with rapamycin or via activation of the tuberous sclerosis complex (TSC) tumor suppressor, leads to downstream dephosphorylation events, including loss of ULK1 phosphorylation at S757. The TSC1/2 heterodimer is itself regulated by upstream kinases, including the AMP-activated protein kinase (AMPK), which regulates several metabolic processes and activates the TSC to repress mTORC1 under conditions of energy stress (4–6). AMPK also directly regulates autophagy by phosphorylating and activating ULK1 at S317 (7).Nitric oxide (NO) is a pleiotropic regulator, critical to numerous biological processes extending from its role as a chemical messenger and antibacterial agent to an integral component of the cardiovascular system and immune response to pathogens (8). NO has also been documented to play both promotional and inhibitory roles in cancer etiology. NO is produced endogenously by tumor cells of various histogenetic origins and has been associated with tumor proliferation and resistance to anticancer drugs. Although cancer cells may maintain endogenous NO at elevated levels that facilitate tumor growth, this strategy carries a survival liability, as high levels of NO can cause cytostasis or cytotoxicity (9). Thus, cancer cells may be more sensitive to NO-induced nitrosative stress, which could potentially provide a therapeutic avenue for modulating nitrosative stress to induce cell death. However, understanding at the molecular level regarding how NO participates in regulation of either prosurvival or prodeath autophagic pathways is limited.Recently, a novel signaling pathway involving activation of ATM to suppress mTORC1 in response to oxidative damage was identified (10). In the study reported here, we demonstrate that NO engages this pathway to suppress mTORC1 and promote autophagy. In response to nitrosative stress induced by steady-state exposure to NO, ATM is activated, signaling to AMPK via LKB1 to activate the TSC tumor suppressor and suppress mTORC1. Concomitant with suppression of mTORC1, autophagy is induced, accompanied by loss of cell viability. Our data provide strong evidence that NO regulates autophagy, with implications both for understanding the physiological role of NO-induced signaling and the development of therapies that can modulate nitrosative stress to kill cancer cells.     

Synaptophysin Positive Glomus Tumor of Trachea Simulating Typical Carcinoid: A Potential trap

Glomus tumors (GTs) are uncommon benign tumors, accounting for <2% of all soft tissue tumors and usually occur within the dermis or subcutis of distal extremities. Primary tracheal GT is rare, and to date less than 40 tracheal GTs have been reported. Tracheal GT usually present as a polypoidal mass. They express smooth muscle markers, and are negative for cytokeratin (CK) and neuroendocrine markers on immunohistochemistry (IHC). We here report a case of tracheal GT showing diffuse strong aberrant immunoexpression for synaptophysin, initially construed as carcinoid. Focal synaptophysin expression has been described in few gastric GTs, and a nasal GT. Diligent histomorphological examination and careful selection of IHC panel helps in clinching the diagnosis. Complete resection is the standard treatment of modality.     

PET/CTA detection of muscle inflammation related to cholesterol crystal emboli without arterial obstruction

Background

PET/CTA was used to evaluate the effect of cholesterol crystal emboli (CCE) on muscle injury. Cholesterol crystals (CCs) released during plaque rupture travel downstream and lodge in muscle triggering inflammation and tissue injury.

Methods

Thigh muscles in three groups of rabbits (n = 22) were studied after intra-arterial injection of CCs, Group I (n = 10); polystyrene microspheres, Group II (n = 5); or normal saline, Group III (n = 7). After 48 hours, muscle inflammation and injury were measured by fluorodeoxy-glucose uptake using PET/CTA, serum tissue factor (TF), and creatinine phosphokinase (CPK). Macrophages were stained with RAM11 and CCs with Bodipy.

Results

SUVmax of thigh muscles was greater for Group I vs Group II and III (0.40 ± 0.16 vs 0.21 ± 0.11, P = .038 and 0.23 ± 0.06, P = .036). CPK levels rose significantly in Group I vs Group II and III (6.7 ± 6.0 vs 0.6 ± 0.4, P = .007 and 0.9 ± 0.4 mg·dL^?1, P = .023). No arterial thrombosis was detected by CTA or histology of embolized arteries and TF did not rise significantly. There were extensive macrophage infiltrates surrounding muscle necrosis in Group I only.

Conclusions

Cholesterol crystal emboli triggered muscle inflammation and necrosis with an intact circulation. PET/CTA may help in the early detection of inflammation caused by CCs.

     

Cardiovascular risks associated with Janus kinase inhibitors: peering outside the black box

Clinical Rheumatology - Considerable controversy related to the cardiovascular safety of Janus kinase inhibitors (JAKinibs) has arisen following the results of the ORAL Surveillance trial. In this...     

Pleural effusion in Takayasu arteritis: think infection rather than disease activity!

Clinical Rheumatology -     

Rheumatologists’ perspective on coronavirus disease 19 (COVID-19) and potential therapeutic targets

Clinical Rheumatology - The ongoing pandemic coronavirus disease 19 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a matter of global concern....