Recent advances in understanding inheritance of holoprosencephaly

Holoprosencephaly (HPE) is a complex genetic disorder of the developing forebrain characterized by high phenotypic and genetic heterogeneity. HPE was initially defined as an autosomal dominant disease, but recent research has shown that its mode of transmission is more complex. The past decade has witnessed rapid development of novel genetic technologies and significant progresses in clinical studies of HPE. In this review, we recapitulate genetic epidemiological studies of the largest European HPE cohort and summarize the novel genetic discoveries of HPE based on recently developed diagnostic methods. Our main purpose is to present different inheritance patterns that exist for HPE with a particular emphasis on oligogenic inheritance and its implications in genetic counseling.     

Quantification of dopamine transporter by 123I-PE2I SPECT and the noninvasive Logan graphical method in Parkinson's disease.

(E)-N-(3-iodoprop-2-enyl)-2beta-carbomethoxy-3beta-(4'-methyl-phenyl) nortropane (PE2I), a cocaine analog, is a new, highly specific tracer for imaging dopamine transporter labeled with (123)I for in vivo SPECT. Its reversible binding on dopamine transporter and its rapid kinetics allow quantification of its binding potential according to a 3-compartment model. For quantification of distribution volume of reversible tracer, Logan developed a noninvasive and graphical method that allows accurate estimation of binding potential. In this study, we performed (123)I-PE2I SPECT on healthy volunteers and patients with Parkinson's disease (PD) to validate the Logan graphical method for quantification of (123)I-PE2I binding and to analyze the relationship between (123)I-PE2I SPECT and clinical features of this frequent degenerative disease. METHODS: Eight PD patients (3 women, 5 men; mean age, 64 +/- 7.9 y; disease duration range, 1-8 y, Hoehn and Yahr stage range, 1-2.5) and 8 age-matched healthy volunteers (4 women, 4 men; mean age, 61.5 +/- 9.5 y) were included in 2 centers and studied with SPECT. Four sequential SPECT imaging sessions of 15-min duration were performed from 5 to 65 min after bolus injection of 140 +/- 30 MBq of (123)I-PE2I. RESULTS: The kinetics of PE2I in healthy volunteers and PD patients were rapid, and the Logan graphical method allowed quantification of distribution volume ratio (DVR) in the caudate nucleus and putamen. (123)I-PE2I striatal specific binding was significantly reduced in PD patients, compared with healthy volunteers, in the caudate and putamen. The decrease of DVR in the putamen was significantly and inversely correlated to disease duration and Hoehn and Yahr stage. In asymmetric PD patients, (123)I-PE2I uptake was significantly more reduced in the putamen contralateral to the side with predominant clinical symptoms. However, (123)I-PE2I uptake was also significantly reduced in the ipsilateral putamen, compared with that in healthy volunteers, suggesting that (123)I-PE2I SPECT can detect nigrostriatal degeneration before the appearance of clinical symptoms. CONCLUSION: Our data indicate that the Logan graphical method is accurate for noninvasive quantification of PE2I and that (123)I-PE2I SPECT is a useful quantitative method for accurate estimation of nigrostriatal dopaminergic nerve terminal degeneration. The close relationships between SPECT findings and clinical data suggest that this method is useful for objectively following the progression of PD and for assessing the effect of potential neuroprotective treatments. Finally, our findings suggest that (123)I-PE2I SPECT can be used for preclinical and early diagnosis of PD.     

Characterization of Responder Profiles for Cardiac Resynchronization Therapy through Unsupervised Clustering of Clinical and Strain Data

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Left ventricular non-compaction and idiopathic dilated cardiomyopathy: the significant diagnostic value of longitudinal strain

Left ventricular non-compaction (LV NC) is characterized by abnormal trabeculations that are mainly at the LV apex. Distinction between LV NC and non-specific dilated cardiomyopathies (DCMs) remains often challenging. We sought to find additive tools comparing the longitudinal strain characteristics of LVNC versus idiopathic DCM in a cohort of patients. 48 cases of LVNC (derivation cohort) were compared with 45 cases of DCM. Global and regional multi-layer (sub-endocardial, mid-wall, and sub-epicardial) LV longitudinal strain analysis was performed. Results were compared to define the best tool for distinguishing LVNC from DCM. A validation cohort (41 LVNC patients) was then used to assess the performance of the proposed diagnostic tools. In the derivation cohort, longitudinal deformation (strain) was greater in LVNC than in DCM patients. Longitudinal shortening was greater in the non-compacted segments than in the compacted ones. A mid-wall strain base-apex gradient had 88.4?% sensitivity and 66.7?% specificity in distinguishing LVNC from DCM (AUC?=?0.83; cut-off of ?23 or |0.23|%). In a multivariable model, the base-apex mid-wall gradient in an apical 4-chamber view was the only independent echocardiographic criteria (OR?=?0.76, CI 95?% [0.66; 0.90], p?=?0.0010) allowing the distinction between LVNC and DCM. In the validation cohort, the base-apex mid-wall gradient of strain had 88.4?% sensitivity, 85.7?% negative predictive values for the diagnosis of LVNC. Longitudinal strain, especially the base-apex longitudinal gradient of strain, appears as an additive valuable tool for distinguishing LVNC from DCM.     

Angiotensinogen gene M235T polymorphism and reduction in wall thickness in response to antihypertensive treatment

The angiotensinogen M235T polymorphism has been linked to hypertension and cardiovascular disease. Carotid intima-media thickness (IMT) is an early marker of atherosclerosis. The objectives of the present study were to determine in previously untreated essential hypertensive patients whether carotid IMT was associated with the M235T polymorphism, and to determine whether the M235T polymorphism could influence the reduction of carotid IMT by antihypertensive treatment. Common carotid artery IMT was determined with a high-definition echotracking system in 98 previously untreated hypertensive patients in a cross-sectional study. A subgroup of 56 patients was included in a randomized double-blind parallel group study comparing the effect of the angiotensin-converting-enzyme-inhibitor enalapril with that of the beta-blocker celiprolol during a 5 month period. In the cross-sectional study, a multivariate analysis showed that the M235T genotype was a significant independent determinant of carotid IMT, explaining 7% of the variance. Carotid IMT was higher in patients homozygous for the T allele than in MM patients. In the longitudinal study, the reduction in carotid IMT after antihypertensive treatment was significantly ( P <0.01) higher in patients carrying the TT genotype than in patients carrying the MM genotype, despite similar reductions in blood pressure and independently of drug type. In conclusion, these data suggest that the angiotensinogen TT genotype at position 235 is a genetic marker for early carotid atherosclerosis in a hypertensive population and its regression under antihypertensive treatment.     

Endoscopic ultrasound-guided endoscopic transmural drainage of pancreatic pseudocysts

BACKGROUND: Surgery is the traditional treatment for symptomatic pancreatic pseudocysts, but the morbidity is still too high. Minimally invasive endoscopic approaches have been encouraged. AIMS: To evaluate the efficacy of endoscopic ultrasound-guided endoscopic transmural drainage of pancreatic pseudocysts. METHODS: From January, 2003 to August, 2006, 31 consecutive symptomatic patients submitted to 37 procedures at the same endoscopic unit were retrospectively analysed. Chronic and acute pancreatitis were found in, respectively, 17 (54.8%) and 10 (32.3%) cases. Bulging was present in 14 (37.8%) cases. Cystogastrostomy or cystoduodenostomy were created with an interventional linear echoendoscope under endosonographic and fluoroscopic control. By protocol, only a single plastic stent, without nasocystic drain, was used. Straight or double pigtail stents were used in, respectively, 22 (59.5%) and 15 (40.5%) procedures. RESULTS: Endoscopic ultrasound-guided transmural drainage was successful in 29 (93.5%) patients. Two cases needed surgery, both due to procedure-related complications. There was no mortality related to the procedure. Twenty-four patients were followed-up longer than 4 weeks. During a mean follow-up of 12.6 months, there were six (25%) symptomatic recurrences due to stent clogging or migration, with two secondary infections. Median time for developing complications and recurrence of the collections was 3 weeks. These cases were successfully managed with new stents. Complications were more frequent in patients treated with straight stents and in those with a recent episode of acute pancreatitis. CONCLUSIONS: Endoscopic transmural drainage provides an effective approach to the management of pancreatic pseudocysts.     

Bench-test comparison of 26 emergency and transport ventilators

Introduction

Numerous emergency and transport ventilators are commercialized and new generations arise constantly. The aim of this study was to evaluate a large panel of ventilators to allow clinicians to choose a device, taking into account their specificities of use.

Methods

This experimental bench-test took into account general characteristics and technical performances. Performances were assessed under different levels of FIO₂ (100%, 50% or Air-Mix), respiratory mechanics (compliance 30,70,120 mL/cmH₂O; resistance 5,10,20 cmH₂O/mL/s), and levels of leaks (3.5 to 12.5 L/min), using a test lung.

Results

In total 26 emergency and transport ventilators were analyzed and classified into four categories (ICU-like, n = 5; Sophisticated, n = 10; Simple, n = 9; Mass-casualty and military, n = 2). Oxygen consumption (7.1 to 15.8 L/min at F_IO₂ 100%) and the Air-Mix mode (F_IO₂ 45 to 86%) differed from one device to the other. Triggering performance was heterogeneous, but several sophisticated ventilators depicted triggering capabilities as efficient as ICU-like ventilators. Pressurization was not adequate for all devices. At baseline, all the ventilators were able to synchronize, but with variations among respiratory conditions. Leak compensation in most ICU-like and 4/10 sophisticated devices was able to correct at least partially for system leaks, but with variations among ventilators.

Conclusion

Major differences were observed between devices and categories, either in terms of general characteristics or technical reliability, across the spectrum of operation. Huge variability of tidal volume delivery with some devices in response to modifications in respiratory mechanics and F_IO₂ should make clinicians question their use in the clinical setting.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-014-0506-0) contains supplementary material, which is available to authorized users.     

Expression of alpha- and beta-subunits and activity of Na+K+ ATPase in pig thyroid cells in primary culture: modulation by thyrotropin and thyroid hormones

Na+ K+ ATPase located at the basolateral pole of thyroid epithelial cells, contributes to thyroid hormone synthesis by generating the driving force for the uptake of the substrate, iodide. We have investigated whether the expression of the alpha- and beta-subunits and activity of Na+ K+ ATPase were subjected to variations in response, (a) to TSH, that controls the expression of differentiation in thyroid cells and (b) to thyroid hormones as potential autocrine factors. Studies were carried out on pig thyroid cells cultured (a) without TSH to obtain thyroid cell monolayers (TCM) in basal state or (b) with TSH in the form of cell monolayers (TCM-T) or as reconstituted thyroid follicles (RTF). Iodide uptake activity, thyroperoxidase protein and thyroglobulin mRNA taken as parameters of thyroid cell differentiation were 6 to 25-fold higher in RTF and TCM-T than in TCM. Western blot analyses of Na+ K+ ATPase subunits revealed that the alpha-subunit (105 kDa) content of TCM-T and RTF was similar but 8-fold higher than that of TCM. In contrast, the beta-subunit (50 kDa) content of TCM-T and RTF was only about twice that of TCM. Similar relative variations were observed at the mRNA level for both alpha- and beta-subunits. Na+ K+ ATPase activity was only 40% higher in RTF and TCM-T than in TCM. A 48 h treatment of RTF by either T4 or T3 (1-100 nM) induced a 3-fold increase of the alpha-subunit but did neither alter the beta-subunit nor the Na+ K+ ATPase activity. In conclusion, Na+ K+ ATPase activity and the level of expression of its beta-subunit, known to control the assembly and targetting of alpha-beta oligomers and thus the amount of functional sodium pump at the plasma membrane, are only moderately altered when thyroid cells undergo major changes in their differentiation status. Our data show that the expression of the alpha-subunit of Na+ K+ ATPase by thyroid cells is up-regulated by TSH and thyroid hormones.     

Determination of the learning curve for ultrasound-guided jugular central venous catheter placement

Purpose

Use of ultrasound (US) when introducing central venous catheters (CVC) may improve success rates, reduce the number of needle punctures, and decrease complication rates, but has been hampered by supposed difficulty in learning how to perform the technique. This study describes the learning curve for US-guided jugular CVC placement after a training program.

Methods

After an initial slide presentation and a video, intensivists who had not previously used US for CVC placement were evaluated qualitatively for US set up (score S1) and technical skills (score S2). Quantitative measures included durations of different components of the procedure (T ₁, time from entry of the US into the patient’s room to sterile dressing of the intensivist; T ₂, time needed for sterile drapes, venous line preparation, and sterile sheath placement; T ₃, time from skin puncture to venous flashback; T ₄, time from guide insertion to dressing; T _tot, total duration of the procedure); number of skin punctures; and a difficulty score allocated by the intensivist.

Results

We performed 150 evaluations of 30 intensivists: 50 % had no prior experience of CVC placement and 50 % no prior US experience. Maximal S1 and S2 scores were obtained with the fourth and eighth placement procedures, respectively. T ₁ and T ₂ did not change with ongoing training (5 and 8 min, respectively), but T ₃ and T ₄ decreased, from 5 min (first procedure) to less than 1 min (seventh procedure), and from 10 min (first procedure) to 7 min (sixth procedure), respectively. T _tot decreased from 34 to 21 min at the eighth procedure. The number of skin punctures and the difficulty score decreased rapidly with the number of evaluations.

Conclusions

Our study demonstrates that skills in US-guided CVC placement can easily be acquired with training.