Transvaginal ultrasound for diagnosis of deeply infiltrating endometriosis

Deeply infiltrating endometriosis is the clinical form of the disease that is generally associated with conditions of more intense pain and may require more complex surgical management, consequently resulting in greater risks to the patient. In recent years, various investigators have confirmed the usefulness of methods such as magnetic resonance imaging (MRI), transrectal ultrasound and transvaginal ultrasound (TVUS) for the diagnosis of deep endometriotic lesions. The objectives of the present study are to describe the method used to perform TVUS for the detection of deeply infiltrating endometriosis, and to discuss the clinical benefits that the data obtained may offer clinicians providing care for patients suspected of having this type of endometriosis.     

Comorbidities Drive the Majority of Overall Mortality in Low-Risk Mucinous Pancreatic Cysts Under Surveillance

Background & AimsThe Charlson Comorbidity Index (CACI) has been suggested as a tool to determine comorbidity burden and guide management for patients with mucinous pancreatic cysts (Intrapapillary Mucinous Neoplasms and Mucinous Cystic Neoplasms), but has not been studied well among “low-risk” mucinous pancreatic cysts i.e. without worrisome features (WF) and high-risk stigmata (HRS). This study sought to determine the comorbidity burden among surveillance population of low-risk pancreatic cysts and provide their follow-up mortality outcomes.MethodsA single center study retrospectively reviewed a prospective pancreatic cyst database and included individuals with low-risk cysts undergoing serial imaging during 2016. Electronic medical records were reviewed to determine their baseline age-adjusted CACI (age-CACI). After 4 years, their progression to WF, disease specific (pancreatic malignancy-related, DSM), extra-pancreatic (EPM), and overall mortalities (OM) were determined using Kaplan-Meir Survival Analysis.Results502 individuals underwent prospective surveillance. The study included 440 individuals with low-risk suspected or presumed mucinous cysts and excluded 50 and 12 individuals with WF and HRS respectively. Over a median follow-up of 56 months, 12 WF progressions, 2 DSMs, 42 EPMs, and 44 OMs were observed. Baseline age-CACI had good predictive capacity for 4-year EPM (Area-Under Curve: 0.87; p< .0001). The median age-CACI of 4 enabled cohort stratification into Low (age-CACI <4) and High CACI (age-CACI ≥4) groups. A significantly higher OM (p< .001) was observed among the High CACI group as compared to the Low CACI group.ConclusionThrough real-time application of CACI to patient outcomes, our analysis supports incorporation of this comorbidity assessment tool in making shared surveillance decisions among low-risk pancreatic cyst population.     

Validation of quantitative analysis of intravascular ultrasound images

This study investigated the accuracy and reproducibility of a computer-aided method for quantification of intravascular ultrasound. The computer analysis system was developed on an IBM compatible PC/AT equipped with a framegrabber. The quantitative assessment of lumen area, lesion area and percent area obstruction was performed by tracing the boundaries of the free lumen and original lumen.Accuracy of the analysis system was tested in a phantom study. Echographic measurements of lumen and lesion area derived from 16 arterial specimens were compared with data obtained by histology. The differences in lesion area measurements between histology and ultrasound were minimal (mean ± SD: –0.27±1.79 mm², p>0.05). Lumen area measurements from histology were significantly smaller than those with ultrasound due to mechanical deformation of histologic specimens (–5.38±5.09 mm², p<0.05). For comparison with angiography, 18 ultrasound cross-sections were obtainedin vivo from 8 healthy peripheral arteries. Luminal areas obtained by angiography were similar to those by ultrasound (–0.52±5.15 mm², p>0.05). Finally, intra- and interobserver variability of our quantitative method was evaluated in measurements of 100in vivo ultrasound images. The results showed that variations in lumen area measurements were low (5%) whereas variations in lesion area and percent area obstruction were relatively high (13%, 10%, respectively).Results of this study indicate that our quantitative method provides accurate and reproducible measurements of lumen and lesion area. Thus, intravascular ultrasound can be used for clinical investigation, including assessment of vascular stenosis and evaluation of therapeutic intervention.Dr. C.D. Mario, Div. of Cardiology, Vicenza, Italy, is the recipient of the E.S.C. Research Fellowship 1991.     

Compensatory enlargement of human coronary arteries during progression of atherosclerosis is unrelated to atheroma burden: serial intravascular ultrasound observations from the REVERSAL trial.

AIMS: On the basis of the evidence from autopsy studies, it is accepted that compensatory enlargement (remodelling) of coronary arteries during progression of atherosclerosis diminishes once atheroma burden (cross-sectional area stenosis) reaches approximately 40%. Our aim was to evaluate whether atheroma burden is a limiting factor for coronary arterial remodelling using in vivo serial intravascular ultrasound (IVUS). METHODS AND RESULTS: From the cohort of the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial, we identified 210 focal coronary lesions at baseline IVUS. Of these, 128 lesions that had an increase in atheroma area at the 18-month follow-up IVUS were included in the analysis. Lesions were matched at baseline and follow-up. The increase in external elastic membrane (EEM) area for each mm(2) increase in atheroma area was not significantly different in lesions with <40 and >or=40% atheroma burden at baseline (1.62 vs. 1.28 mm(2), P=0.30). There were no correlations between atheroma burden at baseline and change in EEM (r=0.02, P=0.86) or change in lumen (r=0.04, P=0.64) areas. CONCLUSION: Assessment of coronary arterial remodelling by serial IVUS revealed that compensatory remodelling is not limited by atheroma burden. Atheroma burden is not a determinant of arterial enlargement during the progression of atherosclerosis.     

How good is endoscopic ultrasound for TNM staging of gastric cancers？ A meta-analysis and systematic review

AIM： To evaluate the accuracy of endoscopic ultrasound （EUS） for staging of gastric cancers.
METHODS： Only EUS studies confirmed by surgery were selected. Only studies from which a 2×2 table could be constructed for true positive, false negative, false positive and true negative values were included. Articles were searched in Medline, Pubmed, Ovid journals, Cumulative index for nursing ＆ allied health literature, International pharmaceutical abstracts, old Medline, Medline nonindexed citations, and Cochrane control trial registry. Two reviewers independently searched and extracted data. The differences were resolved by mutual agreement. 2×2 tables were constructed with the data extracted from each study. Meta-analysis for the accuracy of EUS was analyzed by calculating pooled estimates of sensitivity, specificity, likelihood ratios, and diagnostic odds ratio. Pooling was conducted by both the Mantel-Haenszel method （fixed effects model） and DerSimonian Laird method （random effects model）. The heterogeneity of studies was tested using Cochran＇s Q test based upon inverse variance weights.
RESULTS： Initial search identified 1620 reference articles and of these, 376 relevant articles were selected and reviewed. Twenty-two studies （n = 1896） which met the inclusion criteria were included in this analysis. Pooled sensitivity of T1 was 88.1% （95% CI： 84.5-91.1） and T2 was 82.3% （95% CI： 78.2-86.0）. For T3, pooled sensitivity was 89.7% （95% CI： 87.1-92.0）. T4 had a pooled sensitivity of 99.2% （95% CI： 97.1-99.9）. For nodal staging, the pooled sensitivity for N1 was 58.2% （95% CI： 53.5-62.8） and N2 was 64.9% （95% CI： 60.8-68.8）. Pooled sensitivity to diagnose distant metastasis was 73.2% （95% CI： 63.2-81.7）. The P for chi-squared heterogeneity for all the pooled accuracy estimates was 〉0. 10.
CONCLUSION： EUS results are more accurate with advanced disease than early disease. If EUS diagnoses advanced disease, such as T4 disease, the patient is     

Adverse events and mortality: comparative analysis between diagnostic and interventional endoscopic ultrasound

Abstract

Background and aims

Escalating an indication of EUS for diagnosis and treatment justifies the evaluation of the conditions associated with the adverse events (AE) and related deaths. The aim is to evaluate and compare the incidence of AE and deaths after diagnostic-EUS (D-EUS) and interventional-EUS (I-EUS).     

Asymptomatic hyperglycaemia is associated with increased intimal plus medial thickness of the carotid artery

Summary Atherosclerotic changes have not been demonstrated directly in asymptomatic hyperglycaemic non-diabetic subjects, although high mortality due to coronary heart disease has been reported. We measured arterial wall thickness non-invasively, in order to directly demonstrate atherosclerosis of the carotid arteries of hyperglycaemic non-diabetic subjects and to evaluate its risk factors.The thicknesses of the intimal plus medial complex (IMT) of the carotid arteries of 112 asymptomatic hyperglycaemic non-diabetic subjects (aged 22–81, 95 males and 17 females) were compared with those of 55 healthy male subjects and 211 non-insulin-dependent NIDDM male diabetic patients. The subjects were subgrouped into impaired glucose-tolerant (IGT) subjects who had a 2-h glycaemic level of more than 7.8 mmol/l, and non-IGT subjects whose 2-h glycaemic levels were within 6.7–7.7 mmol/l.Non-IGT and IGT subjects showed significantly greater IMTs than age-matched healthy males and showed no significant differences compared to age-matched NIDDM patients. Multivariate analysis demonstrated that the risk factors for IMT of non-IGT and IGT subjects were age and systolic blood pressure. According to data on the accumulation of atherogenic risks (hypertension, dyslipidaemia, and smoking), IMT increased linearly in non-IGT and IGT subjects. However, non-IGT and IGT subjects without hyperlipidaemia, hypertension, or smoking risk still had significantly greater IMT than age-matched normal males (1.019±0.063 vs 0.770±0.111 mm, p<0.05). Prevalence of ECG-indicated coronary heart disease was significantly higher in hyperglycaemic non-diabetic subjects and NIDDM with increased carotid arterial wall thickness (IMT 1.1 mm) than in those without increased thickness (IMT<1.1 mm). Asymptomatic hyperglycaemic non-diabetic subjects have increased thickness of their carotid arteries compared to age-matched male NIDDM patients. As one of several independent risk factors, mild hyperglycaemia advances atherosclerosis, which leads to coronary heart disease.Abbreviations IMT Intimal plus medial complex - NIDDM non-insulin-dependent diabetes mellitus - IGT impaired glucose tolerance - CHD coronary heart disease - T-Chol serum total cholesterol - HDL-C high-density lipoprotein cholesterol - TG serum triglycerides     

Effects of mexiletine on delayed after-depolarization and triggered activity

Summary The effects of mexiletine on delayed afterdepolarization (DAD) and triggered activity (TA) were studied in the rabbit ventricular muscle using standard microelectrode techniques. First, three kinds of perfusate (modified Tyrode's solution, K⁺-free solution, and 1 mM K⁺ + 5.4 mM Ca²⁺ solution) were used to see whether DAD and TA could be induced by rapid stimulations (cycle lengths of 1000, 600, and 300 ms with trains of 10 and 20 stimuli). The inducibility of DAD and TA in modified Tyrode's solution, in K⁺-free solution, and in low K⁺ + high Ca²⁺ solution was 0%, 8%, and 83%, respectively. The last value was significantly higher than the former values. DAD and TA were induced only by stimulation at the shortest cycle length of 300 ms, and the inducibility was significantly higher with trains of 20 than with those of 10 stimuli. When DAD and/or TA were induced, the effects of mexiletine (5 mg/l) were tested. Mexiletine totally suppressed DAD and TA in 94% of the preparations within 20 min after its addition. Abolition of DAD and TA was associated with a failure of the 1 : 1 response to the stimuli in 53% of the preparations. The drug tended to prolong the coupling interval of DAD and TA, and significantly reduced the DAD amplitude. Possible mechanisms of action are: (1) lowered intracellular Ca²⁺ concentration either via the blocking of the fast Na⁺ current or the reduction of the number of action potentials; and (2) a decrease in the transient inward current due to blockage of the Ca²⁺ current.     

Follow-up study of thyroid function in polytransfused thalassemic patients

The aim of our investigation was to evaluate thyroid function by a follow-up study in 45 polytransfused thalassemic patients, since endocrine abnormalities are frequent consequences of iron overload in thalassemia major. Significant changes of thyroid function have been revealed in the time elapsing the observation, despite unchanged haematological parameters; at the end of the present study five patients were affected by overt hypothyroidism and 15 patients by subclinical hypothyroidism. Ultrasound thyroid volume in 13 randomly selected patients was greatly reduced, while thyroid Magnetic Resonance Imaging (MRI) was not able to detect tissue alterations. Inversely, liver MRI was markedly reduced in 14 patients and negatively related to ferritine levels (P< 0.01). We conclude that polytransfused thalassemics are frequently affected by thyroid disfunction; haepatic haemosiderosis due to iron overload seems influence hormonal peripheral metabolism, although the patients display a moderate compliance with iron chelation therapy. Therefore, periodic thyroid investigation should be carried out in thalassemic subjects in order to detect patients who need hormone replacement therapy.     

Ultrasound activates mechanosensitive TRAAK K+ channels through the lipid membrane

Ultrasound modulates the electrical activity of excitable cells and offers advantages over other neuromodulatory techniques; for example, it can be noninvasively transmitted through the skull and focused to deep brain regions. However, the fundamental cellular, molecular, and mechanistic bases of ultrasonic neuromodulation are largely unknown. Here, we demonstrate ultrasound activation of the mechanosensitive K⁺ channel TRAAK with submillisecond kinetics to an extent comparable to canonical mechanical activation. Single-channel recordings reveal a common basis for ultrasonic and mechanical activation with stimulus-graded destabilization of long-duration closures and promotion of full conductance openings. Ultrasonic energy is transduced to TRAAK through the membrane in the absence of other cellular components, likely increasing membrane tension to promote channel opening. We further demonstrate ultrasonic modulation of neuronally expressed TRAAK. These results suggest mechanosensitive channels underlie physiological responses to ultrasound and could serve as sonogenetic actuators for acoustic neuromodulation of genetically targeted cells.

Manipulating cellular electrical activity is central to basic research and is clinically important for the treatment of neurological disorders including Parkinson’s disease, depression, epilepsy, and schizophrenia (1–4). Optogenetics, chemogenetics, deep brain stimulation (DBS), transcranial electrical stimulation, and transcranial magnetic stimulation are widely utilized neuromodulatory techniques, but each is associated with physical or biological limitations (5). Transcranial stimulation affords poor spatial resolution; deep brain stimulation and optogenetic manipulation typically require surgical implantation of stimulus delivery systems, and optogenetic and chemogenetic approaches necessitate genetic targeting of light- or small-molecule–responsive proteins.Ultrasound was first recognized to modulate cellular electrical activity almost a century ago, and ultrasonic neuromodulation has since been widely reported in the brain, peripheral nervous system, and heart of humans and model organisms (5–12). Ultrasonic neuromodulation has garnered increased attention for its advantageous physical properties. Ultrasound penetrates deeply through biological tissues and can be focused to sub-mm (3) volumes without transferring substantial energy to overlaying tissue, so it can be delivered noninvasively, for example, to deep structures in the brain through the skull. Notably, ultrasound generates excitatory and/or inhibitory effects depending on the system under study and stimulus paradigm (5, 13, 14).The mechanisms underlying the effects of ultrasound on excitable cells remain largely unknown (5, 13). Ultrasound can generate a combination of thermal and mechanical effects on targeted tissue (15, 16) in addition to potential off-target effects through the auditory system (17, 18). Thermal and cavitation effects, while productively harnessed to ablate tissue or transiently open the blood–brain barrier (19), require stimulation of higher power, frequency, and/or duration than typically utilized for neuromodulation (5). Intramembrane cavitation or compressive and expansive effects on lipid bilayers could generate nonselective currents that alter cellular electrical activity (5, 13). Alternatively, ultrasound could activate mechanosensitive ion channels through the deposition of acoustic radiation force that increases membrane tension or geometrically deforms the lipid bilayer (5, 15). Consistent with this notion, behavioral responses to ultrasound in Caenorhabditis elegans require mechanosensitive, but not thermosensitive, ion channels (20), and a number of mechanosensitive (and force-sensitive, but noncanonically mechanosensitive) ion channels have been implicated in cellular responses to ultrasound including two-pore domain K⁺ channels (K2Ps), Piezo1, MEC-4, TRPA1, MscL, and voltage-gated Na⁺ and Ca²⁺ channels (20–24, 25). Precisely how ultrasound impacts the activity of these channels is not known.To better understand mechanisms underlying ultrasonic neuromodulation, we investigated the effects of ultrasound on the mechanosensitive ion channel TRAAK (26, 27). K2P channels including TRAAK are responsible for so called “leak-type” currents because they approximate voltage- and time-independent K⁺-selective holes in the membrane, although more complex gating and regulation of K2P channels is increasingly appreciated (28, 29). TRAAK has a very low open probability in the absence of membrane tension and is robustly activated by force through the lipid bilayer (30–32). Mechanical activation of TRAAK involves conformational changes that prevent lipids from entering the channel to block K⁺ conduction (31). Gating conformational changes are associated with shape changes that expand the channel and make it more cylindrical in the membrane plane upon opening. These shape changes are energetically favored in the presence of membrane tension, resulting in a tension-dependent energy difference between states that favors channel opening (31). TRAAK is expressed in neurons and has been localized exclusively to nodes of Ranvier, the excitable action potential propagating regions of myelinated axons (33, 34). TRAAK is found in most (∼80%) myelinated nerve fibers in both the central and peripheral nervous systems, where it accounts for ∼25% of basal nodal K⁺ currents. As in heterologous systems, mechanical stimulation robustly activates nodal TRAAK. TRAAK is functionally important for setting the resting potential and maintaining voltage-gated Na⁺ channel availability for spiking in nodes; loss of TRAAK function impairs high-speed and high-frequency nerve conduction (33, 34). Changes in TRAAK activity therefore appear well poised to widely impact neuronal excitability.We find that low-intensity and short-duration ultrasound rapidly and robustly activates TRAAK channels. Activation is observed in patches from TRAAK-expressing Xenopus oocytes, in patches containing purified channels reconstituted into lipid membranes, and in TRAAK-expressing mouse cortical neurons. Single-channel recordings reveal that canonical mechanical and ultrasonic activation are accomplished through a shared mechanism. We conclude that ultrasound activates TRAAK through the lipid membrane, likely by increasing membrane tension to promote channel opening. This work demonstrates direct mechanical activation of an ion channel by ultrasound using purified and reconstituted components, is consistent with endogenous mechanosensitive channel activity underlying physiological effects of ultrasound, and provides a framework for the development of exogenously expressed sonogenetic tools for ultrasonic control of neural activity.