Context:
Cushing's syndrome (CS) is challenging to diagnose. Increased prevalence of CS in specific patient populations has been reported, but routine screening for CS remains questionable. To ...decrease the diagnostic delay and improve disease outcomes, simple new screening methods for CS in at-risk populations are needed.
Objective:
To develop and validate a simple scoring system to predict CS based on clinical signs and an easy-to-use biochemical test.
Design:
Observational, prospective, multicenter.
Setting:
Referral hospital.
Patients:
A cohort of 353 patients attending endocrinology units for outpatient visits.
Interventions:
All patients were evaluated with late-night salivary cortisol (LNSC) and a low-dose dexamethasone suppression test for CS.
Main Outcome Measures:
Diagnosis or exclusion of CS.
Results:
Twenty-six cases of CS were diagnosed in the cohort. A risk scoring system was developed by logistic regression analysis, and cutoff values were derived from a receiver operating characteristic curve. This risk score included clinical signs and symptoms (muscular atrophy, osteoporosis, and dorsocervical fat pad) and LNSC levels. The estimated area under the receiver operating characteristic curve was 0.93, with a sensitivity of 96.2% and specificity of 82.9%.
Conclusions:
We developed a risk score to predict CS in an at-risk population. This score may help to identify at-risk patients in non-endocrinological settings such as primary care, but external validation is warranted.
A prediction model for Cushing's syndrome diagnosis in at-risk populations was developed based on clinical variables and late night salivary cortisol levels.
Background
SPG4 is a subtype of hereditary spastic paraplegia (HSP), an upper motor neuron disorder characterized by axonal degeneration of the corticospinal tracts and the fasciculus gracilis. The ...few neuroimaging studies that have focused on the spinal cord in HSP are based mainly on the analysis of structural characteristics.
Methods
We assessed diffusion-related characteristics of the spinal cord using diffusion tensor imaging (DTI), as well as structural and shape-related properties in 12 SPG4 patients and 14 controls. We used linear mixed effects models up to T3 in order to analyze the global effects of 'group' and 'clinical data' on structural and diffusion data. For DTI, we carried out a region of interest (ROI) analysis in native space for the whole spinal cord, the anterior and lateral funiculi, and the dorsal columns. We also performed a voxelwise analysis of the spinal cord to study local diffusion-related changes.
Results
A reduced cross-sectional area was observed in the cervical region of SPG4 patients, with significant anteroposterior flattening. DTI analyses revealed significantly decreased fractional anisotropy (FA) and increased radial diffusivity at all the cervical and thoracic levels, particularly in the lateral funiculi and dorsal columns. The FA changes in SPG4 patients were significantly related to disease severity, measured as the Spastic Paraplegia Rating Scale score.
Conclusions
Our results in SPG4 indicate tract-specific axonal damage at the level of the cervical and thoracic spinal cord. This finding is correlated with the degree of motor disability.
SPG4 is an autosomal dominant pure form of hereditary spastic paraplegia (HSP) caused by mutations in the
SPAST
gene. HSP is considered an upper motor neuron disorder characterized by progressive ...spasticity and weakness of the lower limbs caused by degeneration of the corticospinal tract. In other neurodegenerative motor disorders, the thalamus and basal ganglia are affected, with a considerable impact on disease progression. However, only a few works have studied these brain structures in HSP, mainly in complex forms of this disease. Our research aims to detect potential alterations in the volume and shape of the thalamus and various basal ganglia structures by comparing 12 patients with pure HSP and 18 healthy controls. We used two neuroimaging procedures: automated segmentation of the subcortical structures (thalamus, hippocampus, caudate nucleus, globus pallidus, and putamen) in native space and shape analysis of the structures. We found a significant reduction in thalamic volume bilaterally, as well as an inward deformation, mainly in the sensory-motor thalamic regions in patients with pure HSP and a mutation in
SPG4
. We also observed a significant negative correlation between the shape of the thalamus and clinical scores (the Spastic Paraplegia Rating Scale score and disease duration). Moreover, we found a ‘Group × Age’ interaction that was closely related to the severity of the disease. No differences in volume or in shape were found in the remaining subcortical structures studied. Our results suggest that changes in structure of the thalamus could be an imaging biomarker of disease progression in pHSP.
Objective: SPG4 is an autosomal dominant pure form of hereditary spastic paraplegia (HSP) caused by mutations in the SPAST gene. HSP is considered an upper motor neuron disorder characterized by ...progressive retrograde degeneration, or "dying-back" phenomenon, of the corticospinal tract's longest axons. Neuroimaging studies mainly focus on white matter changes and, although previous studies reported cortical thinning in complicated HSP forms, cortical changes remain unclear in SPG4 patients. This work aimed to compare changes in white matter microstructure and cortical thickness between 12 SPG4 patients and 22 healthy age-matched controls. We also explore whether white matter alterations are related to cortical thickness and their correlation with clinical symptoms. Methods: we used fixel-based analysis, an advanced diffusion-weighted imaging technique, and probabilistic tractography of the corticospinal tracts. We also analyzed cortical morphometry using whole-brain surface-based and atlas-based methods in sensorimotor areas. Results: SPG4 patients showed bilateral involvement in the corticospinal tracts; this was more intense in the distal portion than in the upper segments and was associated with the degree of clinical impairment. We found a significant correlation between disease severity and fiber density and cross-section of the corticospinal tracts. Furthermore, corticospinal tract changes were significantly correlated with bilateral cortical thinning in the precentral gyrus in SPG4 patients. Conclusions: Our data point to axonal damage of the corticospinal motor neurons in SPG4 patients might be related to cortical thinning in motor regions.
The main objective was to evaluate if consensus “bundle” measures to optimize the treatment of sepsis have been integrated in our routine practice. We also tried to identify variables significantly ...associated to mortality.
An observational, unblinded study of those patients who, according to their physicians, met criteria for sepsis under its different stages of severity was conducted. Six items as proposed by surviving sepsis campaign were evaluated: (1) measurement of blood lactate; (2) obtaining blood samples for culture before use of antibiotics; (3) early use of antibiotics (>3h); (4) fluid replacement with at least 20 mL/kg of crystalloids in the first hour, unless contraindicated, if hypotension or blood lactate >4 mmol/L; (5) use of vasoactive drugs, other than dopaminergic doses of dopamine, if hypotension or shock; (6) measurement of central venous pressure and central venous O
2 saturation in shock. Data concerning several aspects of diagnosis, treatment, and consultation to ICU were collected.
Compliance with published guidelines is poor after evaluating the 6 items proposed: 12.5% of shocked patients had determinations of blood lactate; 15% of septic patients had no blood cultures drawn; 32% had received their first dose of antibiotics in the first 3 hours after admission; 46.6% of the cases of severe sepsis or shock received a fluid aggressive therapy; 43.3% of the patients with an indication for vasoactive drugs received them; no patient had central venous pressure monitoring at the ED. In addition, intensive care specialists were seldom consulted (17%). Having used dopaminergic doses of dopamine and having a respiratory focus as a source of infection were independently associated to mortality, respective OR: 21 (1.7-254.9; 95% CI) and 9.6 (1.7-52; 95% CI).
The “bundle” measures proposed in the surviving sepsis campaign seem not to have had enough impact in our ED. This is the start point of a “plan-do-study-act” process directed to improve the outcome of patients with sepsis at our institution.
Abstract Purposes We had previously demonstrated surviving sepsis campaign guidelines had not had enough impact at our Emergency Department. Basic Procedures Actions directed to increase the ...qualification of our staff and residents, to facilitate guidelines divulgation and to improve spatial conditions by creating a High Dependency Unit were implemented as a bundle. The impact of these actions on the achievement of early objectives of the campaign and on mortality was analyzed. Main Findings Following campaign guidelines was more frequent after the implementation of these actions, as shown by less restrictive fluids administration for more severe cases ( P = .001), earlier administration of antibiotics ( P = .001) and lactate determination rate (46% vs. 12%). In-hospital mortality difference did not reach statistical difference. Physicians were able to identify high-risk patients on clinical grounds. Principal Conclusions The bundle of actions has had a moderate beneficial effect on our Emergency Department. High Dependency Units are useful for managing patients not fulfilling criteria for Intensive Care Unit admission.
eEF1A2 is one of the isoforms of the alpha subunit of the eukaryotic Elongation Factor 1. It is overexpressed in human tumors and is endowed with oncogenic properties, favoring tumor cell ...proliferation while inhibiting apoptosis. We demonstrate that plitidepsin, an antitumor agent of marine origin that has successfully completed a phase-III clinical trial for multiple myeloma, exerts its antitumor activity by targeting eEF1A2. The drug interacts with eEF1A2 with a K
of 80 nM and a target residence time of circa 9 min. This protein was also identified as capable of binding
C-plitidepsin in a cell lysate from K-562 tumor cells. A molecular modelling approach was used to identify a favorable binding site for plitidepsin at the interface between domains 1 and 2 of eEF1A2 in the GTP conformation. Three tumor cell lines selected for at least 100-fold more resistance to plitidepsin than their respective parental cells showed reduced levels of eEF1A2 protein. Ectopic expression of eEF1A2 in resistant cells restored the sensitivity to plitidepsin. FLIM-phasor FRET experiments demonstrated that plitidepsin localizes in tumor cells sufficiently close to eEF1A2 as to suggest the formation of drug-protein complexes in living cells. Altogether, our results strongly suggest that eEF1A2 is the primary target of plitidepsin.
To describe the outcome of patients after noninvasive ventilation in a high dependency unit (HDU) of an emergency department (ED). Secondary aims were to define the role of intensive care ...consultation and to identify variables associated with mortality.
Observational, prospective 6-month study.
Two hundred and nine cases were analysed. Thirty-four patients were initially rejected by the intensive care unit (ICU). Physicians in the ED did not request ICU consultation in the remaining 175 (83%) because of 'belief of improvable medical condition in the ED in patients without therapeutic limits' in 93 (group 1) and to 'preset therapeutic limits' or 'comfort measures only' in 82 (groups 2 and 3). Ten out of these 175 were subsequently admitted to the ICU. The global in-hospital mortality rate was 22% (3.3% in the high dependency unit), but only 10% in group 1. Place of referral for ventilation (P<0.001), absence of subsequent ventilation on the general ward (P<0.001), group of assignation (P=0.004), intensive care initial rejection (P=0.022), no previous home ventilation (P=0.028), older age (P=0.03) and longer duration on ventilation (P=0.047) were significantly associated with mortality. In the multivariate regression model, ventilating patients from general wards (odds ratio=7.1; 2.3-25, 95% confidence interval) and ventilation under preset limits (odds ratio=3.57; 1.42-8.98, 95% confidence interval) remained significantly associated with mortality.
Noninvasive ventilation is a relatively safe and effective treatment in the ED when performed in carefully controlled settings. ICU consultation may be securely deferred in this setting.
A complex of formula {CuCl{H2C(3,5‐Me2pz)}}2(µ‐Cl)2 (1) is obtained and its structure is determined by single‐crystal X‐ray diffraction crystallography, revealing dinuclear character supporting a ...(CuN2Cl2)2 core. Compound 1 undergoes water dissociation that generates a change in the coordination sphere of the metals, yielding a mononuclear CuII complex of the formula CuCl{H2C(3,5‐Me2pz)2}2Cl·3H2O (2), as supported by LeBail analysis and visible absorption spectroscopy. Interestingly, the optical features of 1 unravel characteristic patterns in the absorption spectrum, attributed solely to the formation of the (CuN2Cl2)2 core. The study of the magnetic properties of 1 reveals weak antiferromagnetic exchange coupling between the two CuII ions that is transmitted through the double‐chloro bridge, which is supported by broken‐symmetry DFT calculations.
A dinuclear CuII complex, with a (CuN2Cl2)2 core, is identified by X‐ray diffraction. The complex dissociates in water, with changes in the metal coordination spheres, revealing characteristic patterns in the absorption spectrum of the Cu2Cl2 core. Experimentally, we found weak antiferromagnetic exchange coupling between the two CuII ions; this is supported by broken‐symmetry DFT calculations.
Objective
To analyze the reference range of thyroid‐stimulating hormone (TSH) in different BMI categories and its impact on the classification of hypothyroidism.
Methods
The study included 3,928 ...individuals free of thyroid disease (without previous thyroid disease, no interfering medications, TSH <10 µUI/mL and thyroid peroxidase antibodies TPO Abs <50 IU/mL) who participated in a national, cross‐sectional, population‐based study and were representative of the adult population of Spain. Data gathered included clinical and demographic characteristics, physical examination, and blood and urine sampling. TSH, free thyroxine, free triiodothyronine, and TPO Ab were analyzed by electrochemiluminescence (E170, Roche Diagnostics, Basel, Switzerland).
Results
The reference range (p2.5‐97.5) for TSH was estimated as 0.6 to 4.8 µUI/mL in the underweight category (BMI<20 kg/m2), 0.6 to 5.5 µUI/mL in the normal‐weight category (BMI 20‐24.9 kg/m2), 0.6 to 5.5 µUI/mL in the overweight category (BMI 25‐29.9 kg/m2), 0.5 to 5.9 µUI/mL in the obesity category (BMI 30‐39.9 kg/m2), and 0.7 to 7.5 µUI/mL in the morbid obesity category (BMI ≥40). By using the reference criteria for the normal‐weight population, the prevalence of high TSH levels increased threefold in the morbid obesity category (P < 0.01).
Conclusions
Persons with morbid obesity might be inappropriately classified if the standard ranges of normality of TSH for the normal‐weight population are applied to them.
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