Anger: Cause or Consequence of Posttraumatic Stress? A Prospective Study of Dutch Soldiers

Many studies have shown that individuals with posttraumatic stress disorder (PTSD) experience more anger over time and across situations (i.e., trait anger) than trauma‐exposed individuals without PTSD. There is a lack of prospective research, however, that considers anger levels before trauma exposure. The aim of this study was to prospectively assess the relationship between trait anger and PTSD symptoms, with several known risk factors, including baseline symptoms, neuroticism, and stressor severity in the model. Participants were 249 Dutch soldiers tested approximately 2 months before and approximately 2 months and 9 months after their deployment to Afghanistan. Trait anger and PTSD symptom severity were measured at all assessments. Structural equation modeling including cross‐lagged effects showed that higher trait anger before deployment predicted higher PTSD symptoms 2 months after deployment (β = .36), with stressor severity and baseline symptoms in the model, but not with neuroticism in the model. Trait anger at 2 months postdeployment did not predict PTSD symptom severity at 9 months, and PTSD symptom severity 2 months postdeployment did not predict subsequent trait anger scores. Findings suggest that trait anger may be a pretrauma vulnerability factor for PTSD symptoms, but does not add variance beyond the effect of neuroticism.     

Chancen und Herausforderungen der zunehmenden Digitalisierung der Lehre im Fach Anästhesiologie aus Sicht der Studierenden

Die Anaesthesiologie - Die COVID-19-Pandemie hat die medizinische Lehre weltweit verändert. Seit dem Sommersemester 2020 stehen digitale Lehrformate im Fokus, deren Einsatz zuvor in...     

Neurotoxizität von Allgemeinanästhetika im Kindesalter

Many animal experiments have shown that anesthetics can have a neurotoxic effect on immature brains because they induce apoptosis and influence neurogenesis and synaptogenesis. In animal experiments this has substantial implications for the neurocognitive functions of animals in later life. Whether these results of animal experiments can be transferred to humans is currently the subject of intensive research. In several retrospective studies no clear association between anesthesia in premature babies, newborns or infants and the occurrence of learning disorders or behavioral problems could be found. The prospective studies GAS and PANDA are designed to obtain a deeper insight and if possible to clarify this problem. Because of the high relevance of this topic and in order to achieve more clarity for this problem when dealing with parents, the scientific working group for neuroanesthesia and pediatric anesthesia of the German Society for Anesthesiology and Intensive Care Medicine (DGAI) has formulated a position document on the basis of currently available data.     

Neuroanästhesie

Anesthesiological challenges during craniotomy result from the anatomically related low compensatory capacity of the intracranial space in response to increased volume and the low ischemic tolerance of brain tissue. The anesthetic agents used should therefore not increase the intracranial volume and improve the ischemic tolerance. An acute life-threatening increase of intracranial pressure can be temporarily treated by hyperventilation until measures, such as osmotherapy and infusion of intravenous anesthetics become effective. During an operation the homeostatic parameters including blood volume, blood pressure, partial pressure of carbon dioxide and oxygen in blood, plasma glucose concentration and core body temperature have to be closely monitored and kept normal (6 Ns). Optimal implementation of anesthesia necessitates a detailed knowledge of the surgical approach and potential complications. Postoperatively, patients should be extubated as soon as possible to closely monitor cognitive function so that potential deterioration can be detected.     

Cerebrovascular autoregulation in critically ill patients during continuous hemodialysis

Purpose

In chronic renal failure, intermittent hemodialysis decreases cerebral blood flow velocity (CBFV); however, in critically ill patients with acute renal failure, the effect of continuous venovenous hemodialysis (CVVHD) on CBFV and cerebrovascular autoregulation (AR) is unknown. Therefore, a study was undertaken to investigate the potential effect of CVVHD on CBFV and AR in patients with acute renal failure.

Methods

This cohort study investigated 20 patients with acute renal failure who required CVVHD. In these patients, the CBFV and index of AR (Mx) were measured using transcranial Doppler before and during CVVHD.

Results

The median Mx values at baseline were 0.33 [interquartile range (IQR): 0.02-0.55], and during CVVHD, they were 0.20 [0.07-0.40]. The differences in Mx (CVVHD – baseline) was (median [IQR]) ?0.015 [?0.19-0.05], 95% confidence interval (CI) ?0.16 to 0.05. The Mx was > 0.3 in 11/20 patients at baseline measurement. Six of these patients recovered to Mx < 0.3 during CVVHD. The CBFV was (median [IQR]) 47 [36-59] cm·sec^?1 at baseline and 49 [36-66] cm·sec^?1 during CVVHD. The difference of CBFV was 0.0 [?4 - 2.7], 95% CI ?2.5 to 4.2.

Conclusion

Compared with patients with intermittent hemodialysis, CVVHD did not influence CBFV and AR in critically ill patients with acute renal failure, possibly due to lower extracorporeal blood flow, slower change of plasma osmolarity, and a lower fluid extraction rate. In a subgroup of patients with sepsis, the AR was impaired at baseline in more than half of the patients, and this was reversed during CVVHD. The trial was registered at ClinicalTrials.gov ID: NCT01376531.     

Liposomal nystatin in patients with invasive aspergillosis refractory to or intolerant of amphotericin B

We assessed the activity and safety of liposomal nystatin, a broad-spectrum antifungal agent, for invasive aspergillosis in patients refractory to or intolerant of amphotericin B. Thirty-three patients were enrolled, received at least one dose of the study drug, and were evaluable for safety. Twenty-six patients had confirmed probable or definite aspergillosis and were fully eligible. Most patients had a hematological malignancy (53.8%) or hematopoietic stem cell transplantation (23.0%), were neutropenic (61.5%), and were refractory to previous amphotericin B (92.3%). The median duration of previous amphotericin B treatment was 16.5 days (range, 5 to 64 days). Aspergillosis was definite in 3 cases and probable in 23 cases. Liposomal nystatin was initiated at a dose of 4 mg/kg of body weight/day. Twenty-five patients were evaluable for response: a complete response was achieved for one patient, and a partial response was achieved for six. Thus, the overall response rate is 7 of 25 (28%; 95% confidence interval, 12 to 49%). Seventeen (68.0%) of the 25 evaluable patients died during therapy or within 1 month after the end of therapy. The primary cause of death was invasive aspergillosis for nine patients and underlying malignancy for eight patients. The most frequent side effects included chills, shivering, and fever, leading to discontinuation of therapy for two patients. Grade 1 decline in renal function was seen for 10 (30.3%) patients, and hypokalemia was seen for 13 (39.4%). We conclude that liposomal nystatin can be effective for salvage therapy of invasive aspergillosis. Infusion-related adverse events have been observed frequently.     

The Class I Antigen-processing Pathway for the Membrane Protein Tyrosinase Involves Translation in the Endoplasmic Reticulum and Processing in the Cytosol

Formation of major histocompatibility complex class I–associated peptides from membrane proteins has not been thoroughly investigated. We examined the processing of an HLA-A*0201–associated epitope, YMDGTMSQV, that is derived from the membrane protein tyrosinase by posttranslational conversion of the sequence YMNGTMSQV. Only YMDGTMSQV and not YMNGTMSQV was presented by HLA-A*0201 on cells expressing full-length tyrosinase, although both peptides have similar affinities for HLA-A*0201 and are transported by TAP. In contrast, translation of YMNGTMSQV in the cytosol, as a minigene or a larger fragment of tyrosinase, led to the presentation of the unconverted YMNGTMSQV. This was not due to overexpression leading to saturation of the processing/conversion machinery, since presentation of the converted peptide, YMDGTMSQV, was low or undetectable. Thus, presentation of unconverted peptide was associated with translation in the cytosol, suggesting that processing of the full-length tyrosinase occurs after translation in the endoplasmic reticulum. Nevertheless, presentation of YMDGTMSQV in cells expressing full-length tyrosinase was TAP (transporter associated with antigen processing) and proteasome dependent. After inhibition of proteasome activity, tyrosinase species could be detected in the cytosol. We propose that processing of tyrosinase involves translation in the endoplasmic reticulum, export of full-length tyrosinase to the cytosol, and retransport of converted peptides by TAP for association with HLA-A*0201.CD8⁺ T cells recognize peptides in association with class I MHC proteins on the surface of cells. In general, these MHC class I–associated peptides are derived from intracellular proteins (1). In the classical pathway for processing of class I–associated peptides, cytosolic proteases such as the proteasome degrade proteins to generate peptides that are transported into the endoplasmic reticulum (ER)¹ by the transporter associated with antigen processing (TAP; 2–6). Upon entry into the ER, the peptides are bound to “empty” or peptide-free MHC class I molecules that are associated with TAP (7, 8) via an intermediary protein, tapasin (9). After binding peptide, the MHC class I heterotrimer dissociates from TAP and proceeds through the ER, Golgi, and exocytic pathway to the cell surface (10). The peptides in association with the MHC class I molecule are then available for recognition on the cell surface by CTLs.Because membrane and secreted proteins are normally cotranslationally translocated into the ER, they would appear to bypass the cytosolic proteases of the classical pathway. Nevertheless, a number of MHC class I–associated peptides that originate from membrane proteins have been identified, and the pathways by which they are produced have been the object of several recent studies. Peptides from the signal sequences of IP-30, HLA-E, Signal Sequence Receptor Protein–α (SSR-α), and calreticulin (11, 12), as well as peptides from more internal sequences of the HIV env (13) and Epstein-Barr virus Latent Membrane Protein 2 (LMP2) proteins (14), and a peptide epitope of uncertain location (15) are presented by HLA-A*0201 in cells that lack expression of TAP. Independence of TAP indicates that the source proteins for these peptides are produced in the ER, and that complete proteolytic processing occurs in the ER or distal vesicular compartments, and not the cytosol. Although the signal peptidase is likely to be involved in the generation of signal sequence–derived peptides, it is unlikely to account for the production of peptides from more internal sequences. In addition, none of the peptides derived from signal sequences is full-length, raising the possibility that additional proteases are involved in secondary proteolytic events. In support of this possibility, it has been shown that the production of some, but not all, of these peptides is sensitive to high concentrations of the protease inhibitor LLnL (16). In addition, several vaccinia virus constructs containing peptide epitopes embedded in a larger sequence that is in turn linked to a signal sequence can be processed for presentation in a TAP-independent manner, presumably via ER resident proteases (17–20).An alternative pathway for the processing of membrane protein–derived epitopes has been suggested by the observation that the presentation of peptides from the measles virus transmembrane (21) and the HIV env (22) proteins as well as peptides from the signal sequence of some MHC class I molecules (23, 24) and the LCMV gp33 protein (25) are dependent on TAP function. Roelse et al. (26) demonstrated that in vitro, peptides transported into the ER that are too long to bind to class I MHC molecules could be exported to the cytosol for further processing, and the products then retransported to the ER by TAP. Although a similar mechanism has not been demonstrated in vivo, partial proteolysis in the ER followed by final proteolysis in the cytosol could account for the TAP-dependent presentation of these epitopes. Alternatively, their presentation may occur after mistranslation of the source protein in the cytosol (27). This could occur either as the result of incomplete translational blockade by signal sequences on cytosolic ribosomes, or by the use of an alternate start codon internal to the signal sequence, as has been shown to occur for several class I–associated epitopes (28–34). Support for such a cytosolic mistranslation mechanism has been provided by observations with an HLA-B*3501–restricted HIV env epitope. This epitope contains a site for N-linked glycosylation that is modified during cotranslational translocation of the full-length protein into the ER (35). However, the epitope presented by HLA-B*3501 has not undergone either glycosylation or deglycosylation (22, 36). Thus, it appears that HIV env protein that gives rise to this epitope has been mistranslated in the cytosol and processed there.A final possible explanation for the TAP-dependent presentation of peptides derived from membrane proteins is that the source protein itself is exported from the ER for proteolysis in the cytosol. Recently, the reverse translocation of several apparently full-length membrane proteins from the ER to the cytosol has been reported (37–48). Visualization of these proteins has generally been possible only after inhibition by protease inhibitors, in most cases those which are effective against the proteasome (38–48). However, no evidence supporting the involvement of this pathway in the production of MHC class I–associated peptide antigens has been presented. Thus, at this point in time, the only in vivo data available for the processing of membrane proteins for class I presentation support a cytosolic mistranslation mechanism.Recently, we described an epitope from the membrane-associated protein tyrosinase that is presented by HLA-A*0201 to CTL reactive with human melanomas (49). The sequence of this peptide, YMDGTMSQV, differed from the corresponding primary sequence of the tyrosinase protein, YMNGTMSQV, by the substitution of aspartic acid for asparagine at position 3. This was shown to be due to a posttranslational conversion, and neither to spontaneous deamidation nor RNA editing. The asparagine in YMNGTMSQV is part of an N-linked glycosylation site and a mammalian enzyme, peptide-N⁴-(N acetyl-β-glucosaminyl) asparagine amidase (PNGase), has been isolated, which removes the N-linked oligosaccharide side chains from glycopeptides. This process converts the modified asparagine residues to aspartic acid (50). Our working hypothesis is that glycosylation in the ER and subsequent deglycosylation at an unknown site are responsible for the conversion of YMNGTMSQV to YMDGTMSQV. Regardless of whether this hypothesis is correct, it focused our attention on how tyrosinase is processed. Since tyrosinase is a melanosomal membrane protein, mistranslation of tyrosinase in the cytosol could lead to proteolysis of the unconverted protein, generating peptides that would be transported by TAP into the ER and converted before or after binding to HLA-A*0201. Alternatively, conversion could occur during normal cotranslational translocation into the ER and subsequent degradation either in the ER, after export of partially proteolysed fragments, or in the cytosol after reverse translocation of the source protein. In this paper, we have examined the processing and conversion of this epitope in detail.     

Mutation D30N is not preferentially selected by human immunodeficiency virus type 1 subtype C in the development of resistance to nelfinavir

Differences in baseline polymorphisms between subtypes may result in development of diverse mutational pathways during antiretroviral treatment. We compared drug resistance in patients with human immunodeficiency virus subtype C (referred to herein as "subtype-C-infected patients") versus subtype-B-infected patients following protease inhibitor (PI) therapy. Genotype, phenotype, and replication capacity (Phenosense; Virologic) were determined. We evaluated 159 subtype-C- and 65 subtype-B-infected patients failing first PI treatment. Following nelfinavir treatment, the unique nelfinavir mutation D30N was substantially less frequent in C (7%) than in B (23%; P = 0.03) while L90M was similar (P < 0.5). Significant differences were found in the rates of M36I (98 and 36%), L63P (35 and 59%), A71V (3 and 32%), V77I (0 and 36%), and I93L (91 and 32%) (0.0001 < P < 0.05) in C and B, respectively. Other mutations were L10I/V, K20R, M46I, V82A/I, I84V, N88D, and N88S. Subtype C samples with mutation D30N showed a 50% inhibitory concentration (IC(50)) change in susceptibility to nelfinavir only. Other mutations increased IC(50) correlates to all PIs. Following accumulation of mutations, replication capacity of the C virus was reduced from 43% +/- 22% to 22% +/- 15% (P = 0.04). We confirmed the selective nature of the D30N mutation in C, and the broader cross-resistance of other common protease inhibitor mutations. The rates at which these mutational pathways develop differ in C and subtype-B-infected patients failing therapy, possibly due to the differential impact of baseline polymorphisms. Because mutation D30N is not preferentially selected in nelfinavir-treated subtype-C-infected patients, as it is in those infected with subtype B, the consideration of using this drug initially to preserve future protease inhibitor options is less relevant for subtype-C-infected patients.