Rationale
Clarification of alcohol’s effect on stress response during threat is critical to understand motivation for alcohol use and related alcohol-use disorders. Evaluation of stress response ...dampening (SRD) effects of alcohol has been limited by nonsystematic use of varied experimental methods and measures.
Objectives
This experiment parametrically varied alcohol dose and shock threat intensity among social drinkers to examine their effects on startle potentiation, a physiological measure of the affective component of the stress response.
Methods
Ninety-six participants were assigned to one of four beverage groups: placebo and target blood alcohol concentration (BAC) groups of 0.04%, 0.075%, and 0.11%. Participants viewed colored cues presented in shock and no-shock blocks. Distinct colored cues predicted imminent low, moderate, or high intensity electric shock administration. Startle potentiation during shock threat relative to no-shock cues indexed affective response.
Results
High threat increased startle potentiation relative to moderate/low intensity threat. Startle potentiation decreased as BAC increased. Threat intensity moderated this BAC effect with the strongest BAC effect observed during high threat. Analysis of individual difference moderators revealed reduced effect of BAC among heavier, more problematic drinkers.
Conclusions
Clear alcohol SRD effects were observed. These SRD effects were greatest at higher BACs and during more potent threat. Failure to account for these factors may partially explain inconsistent findings in past laboratory SRD research. Furthermore, they suggest greater reinforcement from alcohol at higher doses and among individuals with greater stress. Moderation of SRD effects by alcohol consumption and problems point to possible important risk factors.
Hypoxia stabilizes the transcription factor HIF-1α, which promotes the transcription of many genes essential to adapt to reduced oxygen levels. Besides proline hydroxylation, expression of HIF-1α is ...also regulated by a range of other posttranslational modifications including phosphorylation by cAMP-dependent protein kinase A (PKA), which stabilizes HIF-1α. We recently demonstrated that MAGED2 is required for cAMP generation under hypoxia and proposed that this regulation may explain the transient nature of antenatal Bartter syndrome (aBS) due to
mutations. Consequently, we sought to determine whether hypoxic induction of HIF-1α requires also MAGED2. In HEK293 and HeLa cells, MAGED2 knock-down impaired maximal induction of HIF-1α under physical hypoxia as evidenced by time-course experiments, which showed a signification reduction of HIF-1α upon MAGED2 depletion. Similarly, using cobalt chloride to induce HIF-1α, MAGED2 depletion impaired its appropriate induction. Given the known effect of the cAMP/PKA pathway on the hypoxic induction of HIF-1α, we sought to rescue impaired HIF-1α induction with isoproterenol and forskolin acting upstream and downstream of Gαs, respectively. Importantly, while forskolin induced HIF-1α above control levels in MAGED2-depleted cells, isoproterenol had no effect. To further delineate which PKA subtype is involved, we analyzed the effect of two PKA inhibitors and identified that PKA type II regulates HIF-1α. Interestingly, MAGED2 mRNA and protein were also increased under hypoxia by a cAMP mimetic. Moreover, MAGED2 protein expression also required HIF-1α. Thus, our data provide evidence for reciprocal regulation of MAGED2 and HIF-1α under hypoxia, revealing therefore a new regulatory mechanism that may further explain the transient nature of aBS caused by MAGED2 mutations.
To evaluate the association of body temperature with mortality in septic patients admitted to the ICU from the ward. In addition, we intend to investigate whether the timing of antibiotic ...administration was different between febrile and afebrile patients and whether this difference contributed to mortality. This is a retrospective cohort study that included sepsis patients admitted to the ICU from the ward between July 2017 and July 2019. Antibiotic administration was defined as the initiation of antimicrobial treatment or the expansion of the antimicrobial spectrum within 48 h prior to admission to the ICU. Regarding vital signs, the most altered vital sign in the 48 h prior to admission to the ICU was considered. Two hundred and eight patients were included in the final analysis. Antibiotic administration occurred earlier in patients with fever than in patients without fever. Antibiotic administration occurred before admission to the ICU in 27 (90.0%) patients with fever and in 101 (64.7%) patients without fever (p = 0.006). The mortality rate in the ICU was 88 in 176 (50.0%; 95% CI 42.5-57.5%) patients without fever and 7 in 32 (21.9%; 95% CI 6.7-37.0%) patients with fever (p = 0.004). In the multivariate analysis, absence of fever significantly increased the risk of ICU mortality (OR 3.462; 95% CI 1.293-9.272). We found an inverse association between body temperature and mortality in patients with sepsis admitted to the ICU from the ward. Although antibiotic administration was earlier in patients with fever and precocity was associated with reduced mortality, the time of antibiotic administration did not fully explain the lower mortality in these patients.
Background/Aims: Rheumatoid arthritis is a chronic autoimmune disease hallmarked by inflammation in synovial joints. Treatment is hampered by the lack of a cure and current disease-modifying drugs ...are associated with potentially severe toxicities. Methods: We investigated arthritis severity by measuring joint swelling and pro-inflammatory cytokine production in a murine experimental model of inflammatory arthritis (antigen-induced arthritis). We analyzed acid sphingomyelinase knock-out mice and wild-type littermates, as well as mice treated with the pharmacological acid sphingomyelinase inhibitor amitriptyline. Results: Genetic ablation or pharmacological inhibition of acid sphingomyelinase reduced joint swelling and levels of pro-inflammatory cytokines in the arthritic joint. Conclusion: We identified acid sphingomyelinase as a novel druggable target in rheumatoid arthritis. Functional inhibitors of acid sphingomyelinase have been clinically used for decades, are well tolerated and suitable for long-term treatment. They would be immediately available for clinical development as a novel rheumatoid arthritis therapy.
Congenital anomalies of the kidney and urinary tract (CAKUT) are among the most frequent organ malformations. They are a relevant cause of chronic renal failure in children. Apart from isolated forms ...of CAKUT, more than 500 syndromes have been described that are characterized by combined defects of the kidney and other organ systems. Familial aggregation of renal malformations in approximately 10% of patients suggests that genetic events might be involved. Modifying effects due to missense mutations in additional developmental genes seem to enhance the phenotypic variability in affected families. In these families, genetic counseling can be difficult. In contrast, in patients with defined autosomal dominant disease, genetic counseling is of high clinical relevance, also with respect to additional extrarenal symptoms.
Due to the development of numerous genetic knock-out mouse models, the identification of specific renal developmental genes and the application of novel sequencing techniques of the human genome, our understanding of kidney organogenesis has largely improved during very recent years.
This review will focus on important genetic factors that influence nephrogenesis and highlight important human disorders that are associated with anomalies of kidneys, proximal and distal urinary tract.
The clinical diagnosis of pneumonia is usually based on crackles at auscultation, but it is not yet clear what kind of crackles are the characteristic features of pneumonia in children. Lung sound ...monitoring can be used as a "longtime stethoscope". Therefore, it was the aim of this pilot study to use a lung sound monitor system to detect crackles and to differentiate between fine and coarse crackles in children with acute pneumonia. The change of crackles during the course of the disease shall be investigated in a follow-up study.
Crackles were recorded overnight from 22:00 to 06:00 h in 30 children with radiographically confirmed pneumonia. The data for a total of 28 800 recorded 30-s epochs were audiovisually analysed for fine and coarse crackles.
Fine crackles and coarse crackles were recognised in every patient with pneumonia, but the number of epochs with and without crackles varied widely among the different patients: fine crackles were detected in 40±22% (mean±sd), coarse crackles in 76±20%. The predominant localisation of crackles as recorded during overnight monitoring was in accordance with the radiographic infiltrates and the classical auscultation in most patients. The distribution of crackles was fairly equal throughout the night. However, there were time periods without any crackle in the single patients so that the diagnosis of pneumonia might be missed at sporadic auscultation.
Nocturnal monitoring can be beneficial to reliably detect fine and coarse crackles in children with pneumonia.
X-linked Alport syndrome (AS) caused by hemizygous disease-causing variants in
COL4A5
primarily affects males. Females with a heterozygous state show a diverse phenotypic spectrum ranging from ...microscopic hematuria to end-stage kidney disease (ESKD) and extrarenal manifestations. In other X-linked diseases, skewed X-inactivation leads to preferential silencing of one X-chromosome and thus can determine the phenotype in females. We aimed to show a correlation between X-inactivation in blood and urine-derived renal cells and clinical phenotype of females with a heterozygous disease-causing variant in
COL4A5
compared to healthy controls. A total of 56 females with a heterozygous disease-causing
COL4A5
variant and a mean age of 31.6 ± 18.3 SD years were included in this study. A total of 94% had hematuria, 62% proteinuria >200 mg/day, yet only 7% had decreased eGFR. Using human androgen receptor assay X-inactivation was examined in blood cells of all 56 individuals, in urine-derived cells of 27 of these individuals and in all healthy controls. X-inactivation did not correlate with age of first manifestation, proteinuria or eGFR neither in blood, nor in urine. The degree of X-inactivation showed a moderate association with age, especially in urine-derived cells of the patient cohort (
rho
= 0.403,
p
= 0.037). Determination of X-inactivation allelity revealed a shift of X-inactivation toward the
COL4A5
variant bearing allele. This is the first study examining X-inactivation of urine-derived cells from female individuals with AS. A correlation between phenotype and X-inactivation could not be observed suspecting other genetic modifiers shaping the phenotype in female individuals with AS. The association of X-inactivation with age in urine-derived cells suggests an escape-mechanism inactivating the
COL4A5
variant carrying allele in female individuals with AS.
Lower urinary tract obstruction (LUTO) is, in most cases, caused by anatomical blockage of the bladder outlet. The most common form are posterior urethral valves (PUVs), a male-limited phenotype. ...Here, we surveyed the genome of 155 LUTO patients to identify disease-causing CNVs. Raw intensity data were collected for CNVs detected in LUTO patients and 4.392 healthy controls using CNVPartition, QuantiSNP and PennCNV. Overlapping CNVs between patients and controls were discarded. Additional filtering implicated CNV frequency in the database of genomic variants, gene content and final visual inspection detecting 37 ultra-rare CNVs. After, prioritization qPCR analysis confirmed 3 microduplications, all detected in PUV patients. One microduplication (5q23.2) occurred de novo in the two remaining microduplications found on chromosome 1p36.21 and 10q23.31. Parental DNA was not available for segregation analysis. All three duplications comprised 11 coding genes: four human specific lncRNA and one microRNA. Three coding genes (
,
,
) and the microRNA MIR107 have previously been shown to be expressed in the developing urinary tract of mouse embryos. We propose that duplications, rare or de novo, contribute to PUV formation, a male-limited phenotype.
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