Weight Difference Between Double Parathyroid Adenomas Is the Cause of False-positive IOPTH Test After Resection of the First Lesion

Background  

Some patients with double parathyroid adenoma show a greater than 50% decline in intraoperative parathyroid hormone (IOPTH) after resection of the first lesion. The present study was designed to test the hypothesis that significant adenoma weight differences may explain this inappropriate decline of IOPTH.     

Inflammatory Myofibroblastic Tumor of the Temporal Bone: A Histologically Nonmalignant Lesion with Fatal Outcome

Introduction: Inflammatory myofibroblastic tumor (IMFT) of the temporal bone is an unusual but distinct clinicopathologic entity. Case Report: We report the case of a 75-year-old patient with an IMFT located in the temporal bone. Symptoms included VI, X, XI, and XII cranial nerves palsies. Computed tomography and magnetic resonance images are described. The lesion was locally aggressive and outcome was fatal. IMFT was identified by analysis of postmortem specimen with histopathologic and immunohistochemical confirmation. Discussion: IMFT can be locally destructive lesions. Involvement of the skull base and cervical spine is indistinguishable from an aggressive infection or a malignant tumor and can be fatal as in our case report. The difficulties in establishing clinicopathologic diagnosis, radiological imaging characteristics, and treatment are discussed.     

A multicentre randomized pilot trial on the effectiveness of different levels of cooling in comatose survivors of out-of-hospital cardiac arrest: the FROST-I trial

Purpose

To obtain initial data on the effect of different levels of targeted temperature management (TTM) in out-of-hospital cardiac arrest (OHCA).

Methods

We designed a multicentre pilot trial with 1:1:1 randomization to either 32 °C (n?=?52), 33 °C (n?=?49) or 34 °C (n?=?49), via endovascular cooling devices during a 24-h period in comatose survivors of witnessed OHCA and initial shockable rhythm. The primary endpoint was the percentage of subjects surviving with good neurologic outcome defined by a modified Rankin Scale (mRS) score of?≤?3, blindly assessed at 90 days.

Results

At baseline, different proportions of patients who had received defibrillation administered by a bystander were assigned to groups of 32 °C (13.5%), 33 °C (34.7%) and 34 °C (28.6%; p?=?0.03). The percentage of patients with an mRS?≤?3 at 90 days (primary endpoint) was 65.3, 65.9 and 65.9% in patients assigned to 32, 33 and 34 °C, respectively, non-significant (NS). The multivariate Cox proportional hazards model identified two variables significantly related to the primary outcome: male gender and defibrillation by a bystander. Among the 43 patients who died before 90 days, 28 died following withdrawal of life-sustaining therapy, as follows: 7/16 (43.8%), 10/13 (76.9%) and 11/14 (78.6%) of patients assigned to 32, 33 and 34 °C, respectively (trend test p?=?0.04). All levels of cooling were well tolerated.

Conclusions

There were no statistically significant differences in neurological outcomes among the different levels of TTM. However, future research should explore the efficacy of TTM at 32 °C.

Clinical trial registration

ClinicalTrials.gov unique identifier: NCT02035839 (http://clinicaltrials.gov).

     

Structural basis for the recruitment and activation of the Legionella phospholipase VipD by the host GTPase Rab5

A challenge for microbial pathogens is to assure that their translocated effector proteins target only the correct host cell compartment during infection. The Legionella pneumophila effector vacuolar protein sorting inhibitor protein D (VipD) localizes to early endosomal membranes and alters their lipid and protein composition, thereby protecting the pathogen from endosomal fusion. This process requires the phospholipase A1 (PLA₁) activity of VipD that is triggered specifically on VipD binding to the host cell GTPase Rab5, a key regulator of endosomes. Here, we present the crystal structure of VipD in complex with constitutively active Rab5 and reveal the molecular mechanism underlying PLA₁ activation. An active site-obstructing loop that originates from the C-terminal domain of VipD is repositioned on Rab5 binding, thereby exposing the catalytic pocket within the N-terminal PLA₁ domain. Substitution of amino acid residues located within the VipD–Rab5 interface prevented Rab5 binding and PLA₁ activation and caused a failure of VipD mutant proteins to target to Rab5-enriched endosomal structures within cells. Experimental and computational analyses confirmed an extended VipD-binding interface on Rab5, explaining why this L. pneumophila effector can compete with cellular ligands for Rab5 binding. Together, our data explain how the catalytic activity of a microbial effector can be precisely linked to its subcellular localization.Microbial pathogens have evolved numerous ways to subvert and exploit normal host cell processes and to cause disease. Intravacuolar pathogens use specialized translocation devices such as type IV secretion systems (T4SS) to deliver virulence proteins, so-called effectors, across the bacterial and host cell membrane into the cytosol of the infected cell (1–3). Many of the translocated effectors studied to date alter cellular events such as vesicle trafficking, apoptosis, autophagy, protein ubiquitylation, or protein synthesis, among others, thereby creating conditions that support intracellular survival and replication of the microbe (4, 5). Bacteria with a nonfunctional T4SS are often avirulent and degraded along the endolysosomal pathway, thus underscoring the importance of translocated effectors for microbial pathogenesis.Although T4SS-mediated effector translocation may be a convenient way for pathogens to manipulate host cells from within the safety of their membrane-enclosed compartment, it also creates a challenging dilemma: how can the bacteria ensure that their translocated effectors reach the correct host cell target for manipulation, and how can they prevent them from indiscriminately affecting bystander organelles or proteins that may otherwise be beneficial for intracellular survival and replication of the microbe? It is reasonable to expect that regulatory mechanisms have evolved that restrain the catalytic activity of effectors. Although detailed insight into these processes is scarce, an emerging theme among effectors is that their enzymatic activity is functionally coupled to their interaction with a particular host factor. For example, SseJ from Salmonella enterica serovar Typhimurium displays glycerophospholipid-cholesterol acyltransferase activity only on binding to the active GTPases RhoA, RhoB, or RhoC (6–8). Likewise, Pseudomonas aeruginosa ExoU requires mono- or poly-ubiquitinated proteins for the activation of its phospholipase A2 (PLA₂) domain (9), whereas Yersinia YpkA exhibits kinase activity only in the presence of host cell actin (10). Exactly how binding to host ligands results in the activation of these translocated effectors remains unclear because no structural information for these protein complexes is available.VipD is a T4SS-translocated substrate of Legionella pneumophila, the causative agent of a potentially fatal pneumonia known as Legionnaires'' disease, and another example of an effector whose catalytic activity depends on the presence of a host factor (11–14). Following uptake by human alveolar macrophages, L. pneumophila translocates VipD together with more than 250 other effector proteins through its Dot/Icm T4SS into the host cell cytoplasm (15). These effectors act on numerous host processes to mediate evasion of the endolysosomal compartment and to establish a Legionella-containing vacuole (LCV) that supports bacterial growth (16). Although the precise biological role of most L. pneumophila effectors remains unclear, we recently showed that VipD is important for endosomal avoidance by LCVs. The protein localizes to endosomes presumably by binding to the small GTPases Rab5 or Rab22, key regulators of endosomal function (13, 14). Rab GTPase binding to the C-terminal domain of VipD triggers robust phospholipase A1 (PLA₁) activity within the N-terminal domain, resulting in the removal of phosphatidylinositol 3-phosphate [PI(3)P] and potentially other lipids from endosomal membranes (14). Without PI(3)P, endosomal markers such as early endosomal antigen 1 (EEA1) are lost from these membranes, most likely rendering the endosomal compartment fusion incompetent (17). L. pneumophila mutants lacking vipD are attenuated in avoiding endosomal fusion, and their LCVs acquire the endosomal marker Rab5 more frequently than LCVs containing the parental strain producing VipD (14). Thus, by coupling PLA₁ activity to Rab5 binding, the catalytic activity of VipD is directed specifically against the endosomal compartment without visibly affecting neighboring cell organelles.VipD was originally identified in a screen for L. pneumophila effectors that interfere with the vacuolar sorting pathway in yeast (11). The N-terminal half of VipD possesses high homology to patatin, a lipid acyl hydrolase present in the potato tuber (12, 13). Analogous to other patatin-like proteins, VipD harbors a conserved serine lipase motif Gly-x-Ser-x-Gly (x = any amino acid) as part of a Ser-Asp catalytic dyad that, together with two consecutive glycine residues (Asp-Gly-Gly motif), is expected to stabilize the oxyanion intermediate during the acyl chain cleavage (13). Mutation of these conserved catalytic residues in VipD results in loss of PLA₁ activity (14), confirming their role in substrate hydrolysis.The recently reported crystal structure of VipD confirmed the predicted bimodular organization (13) and, in addition, revealed a surface loop, called “lid” in other phospholipases, that shields the entry to the catalytic site. The inhibitory lid may explain why purified recombinant VipD alone exhibits little or no PLA₁ activity in vitro. However, given that binding of Rab5 or Rab22 to VipD activates the PLA₁ activity within the N-terminal region (14), we wondered if and how this binding event causes the inhibitory lid to be removed to render the active site substrate accessible.Using an integrative approach involving X-ray crystallography, molecular dynamics, biochemistry, and cellular imaging, we now deciphered at a molecular level the mechanism that stimulates the intrinsic PLA₁ activity of VipD and determined the underlying specificity for the VipD–Rab5 interaction and endosomal targeting.     

Whole‐Exome Sequencing Identifies a Variant of the Mitochondrial MT‐ND1 Gene Associated with Epileptic Encephalopathy: West Syndrome Evolving to Lennox–Gastaut Syndrome

We describe a West syndrome (WS) patient with unidentified etiology that evolved to Lennox–Gastaut syndrome. The mitochondrial respiratory chain of the patient showed a simple complex I deficiency in fibroblasts. Whole‐exome sequencing (WES) uncovered two heterozygous mutations in NDUFV2 gene that were reassigned to a pseudogene. With the WES data, it was possible to obtain whole mitochondrial DNA sequencing and to identify a heteroplasmic variant in the MT‐ND1 (MTND1) gene (m.3946G>A, p.E214K). The expression of the gene in patient fibroblasts was not affected but the protein level was significantly reduced, suggesting that protein stability was affected by this mutation. The lower protein level also affected assembly of complex I and supercomplexes (I/III₂/IV and I/III₂), leading to complex I deficiency. While ATP levels at steady state under stress conditions were not affected, the amount of ROS produced by complex I was significantly increased.     

Is cardiorespiratory fitness independently associated with the biochemical profile in overweight/obese adults with primary hypertension? The EXERDIET-HTA study

Abstract

Cardiorespiratory fitness (CRF) is positively associated with enhanced cardiovascular health. This cross-sectional study aimed to determine associations between CRF and the biochemical profile of overweight/obese adults diagnosed with primary hypertension (HTN). Does cardiorespiratory fitness (exposure) positively affect the biochemical profile (outcome) in overweight/obese individuals suffering from HTN? Assessment with anthropometric, ambulatory blood pressure monitoring (24?h), CRF (peak oxygen uptake, V?O_2peak) and biochemical analysis was performed on 214 participants (138 men, 76 women). A series of linear and logistic regression analyses were conducted. Participants were divided into CRF tertiles (classified as low, moderate and high CRF). The CRF was independently and inversely associated with aspartate aminotransferase (AST; β?=??0.328, p?p?相似文献   

Validity of the modified shuttle walk test to assess cardiorespiratory fitness after exercise intervention in overweight/obese adults with primary hypertension

The study aimed to assess whether the Modified Shuttle Walk Test (MSWT) can detect changes in cardiorespiratory fitness (CRF) in overweight/obese people with hypertension (HTN) after an exercise intervention evaluating the equation presented in the previous research by Jurio-Iriarte et al. Participants (N= 248) performed a peak cardiorespiratory exercise test (CPET) and MSWT before and after 16-weeks of different types of aerobic exercise intervention. The formula of Jurio-Iriarte et al. was used to predict peak oxygen uptake (V?O_2peak). The correlation between measured and predicted V?O_2peak was strong (r= 0.76, P< 0.001) with a standard error of estimate (SEE) of 4.9 mL·kg^?1·min^?1; SEE%= 17%. The intraclass correlation coefficient indicates a moderate level of association and agreement (ICC= 0.69; 95% CI 0.34–0.82; P< 0.001) between the measured and predicted V?O_2peak. When analyzing obese participants alone (N= 128), MSWT equation was more accurate compared to the whole sample (ICC= 0.76; 95% CI 0.52–0.87). The relationship between the change of measured and predicted V?O_2peak at follow-up was weak (r= 0.42, P< 0.001) with a 31% SEE, and a low level of association and agreement (ICC= 0.31; 95% CI 0.06–0.49; P< 0.001). In conclusion, although MSWT does not accurately predict CRF in people with HTN after exercise intervention and questions its validity, the new equation may have practical application to estimate V?O_2peak for obese people with HTN when CPET is not available.

Abbreviations: AC: Attention Control; BM: Body Mass; BP: Blood Pressure; CI: Confidence Interval; CRF: Cardiorespiratory Fitness; CPET: Cardiopulmonary Exercise Test; HTN: Primary Hypertension; HR: Heart Rate; HV-HIIT: High-Volume and High-Intensity Interval Training; ICC: Intraclass Correlation Coefficient; LV-HIIT: Low-Volume and High-Intensity Interval Training; MICT: Moderate-intensity continuous training; MSWT: Modified Shuttle Walk Test; SD: Standard Deviation; SEE: Standard Error of Estimate; V?O_2peak: Peak Oxygen Uptake.     

Neuropilin-1: A feasible link between liver pathologies and COVID-19

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has a tremendous impact on the health of millions of people worldwide. Unfortunately, those suffering from previous pathological conditions are more vulnerable and tend to develop more severe disease upon infection with the new SARS-CoV-2. This coronavirus interacts with the angiotensin-converting enzyme 2 receptor to invade the cells. Recently, another receptor, neuropilin-1 (NRP-1), has been reported to amplify the viral infection. Interestingly, NRP-1 is expressed in nonparenchymal liver cells and is related to and upregulated in a wide variety of liver-related pathologies. It has been observed that SARS-CoV-2 infection promotes liver injury through several pathways that may be influenced by the previous pathological status of the patient and liver expression of NRP-1. Moreover, coronavirus disease 2019 causes an inflammatory cascade called cytokine storm in patients with severe disease. This cytokine storm may influence liver sinusoidal-cell phenotype, facilitating viral invasion. In this review, the shreds of evidence linking NRP-1 with liver pathologies such as hepatocellular carcinoma, liver fibrosis, nonalcoholic fatty liver disease and inflammatory disorders are discussed in the context of SARS-CoV-2 infection. In addition, the involvement of the infection-related cytokine storm in NRP-1 overexpression and the subsequent increased risk of SARS-CoV-2 infection are also analyzed. This review aims to shed some light on the involvement of liver NRP-1 during SARS-CoV-2 infection and emphasizes the possible involvement this receptor with the observed liver damage.