Mutations in the transforming growth factor beta receptor type I and II genes (TGFBR1 and TGFBR2) cause Loeys-Dietz syndrome (LDS), characterised by thoracic aortic aneurysms and dissections (TAAD), ...aneurysms and dissections of other arteries, craniosynostosis, cleft palate/bifid uvula, hypertelorism, congenital heart defects, arterial tortuosity, and mental retardation. TGFBR2 mutations can also cause TAAD in the absence of features of LDS in large multigenerational families, yet only sporadic LDS cases or parent-child pairs with TGFBR1 mutations have been reported to date.
The authors identified TGFBR1 missense mutations in multigenerational families with TAAD by DNA sequencing. Clinical features of affected individuals were assessed and compared with clinical features of previously described TGFBR2 families.
Statistical analyses of the clinical features of the TGFBR1 cohort (n = 30) were compared with clinical features of TGFBR2 cohort (n = 77). Significant differences were identified in clinical presentation and survival based on gender in TGFBR1 families but not in TGFBR2 families. In families with TGFBR1 mutations, men died younger than women based on Kaplan-Meier survival curves. In addition, men presented with TAAD and women often presented with dissections and aneurysms of arteries other than the ascending thoracic aorta. The data also suggest that individuals with TGFBR2 mutations are more likely to dissect at aortic diameters <5.0 cm than individuals with TGFBR1 mutations.
This study is the first to demonstrate clinical differences between patients with TGFBR1 and TGFBR2 mutations. These differences are important for the clinical management and outcome of vascular diseases in these patients.
Summary
Administration of cross‐sex hormones to male‐to‐female transsexual subjects, usually oestrogens + often anti‐androgens, such as cyproterone acetate, carries a risk of venous thromboembolism ...(VTE). VTE usually occurs in the first year of oestrogen administration. Ethinyl oestradiol, due to its chemical structure, was in 2003 identified as a major factor in the occurrence of VTE. Most clinics do not prescribe ethinyl oestradiol any longer, but people who take hormones without medical supervision use often oral contraceptives containing ethinyl oestradiol, many times in overdose. Cessation of use of ethinyl oestradiol and peri‐operative thrombosis prophylaxis for surgery have reduced prevalence rate of VTE. Other oral oestrogens should not be overdosed, and transdermal oestrogen is to be preferred. Thrombosis prophylaxis for surgery is mandatory. It seems advisable to stop hormone use at least 2 weeks before major surgery, to be resumed only after 3 weeks following full mobilisation.
In May 2013, Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection was diagnosed in an adult male in France with severe respiratory illness, who had travelled to the United Arab Emirates ...before symptom onset. Contact tracing identified a secondary case in a patient hospitalised in the same hospital room. No other cases of MERS-CoV infection were identified among the index case’s 123 contacts, nor among 39 contacts of the secondary case, during the 10-day follow-up period.
Rare ovarian tumors represent >20% of all ovarian cancers. Given the rarity of these tumors, natural history, prognostic factors are not clearly identified. The extreme variability of patients (age, ...histological subtypes, stage) induces multiple and complex therapeutic strategies.
Since 2011, a national network with a dedicated system for referral, up to 22 regional and three national reference centers (RC) has been supported by the French National Cancer Institute (INCa). The network aims to prospectively monitor the management of rare ovarian tumors and provide an equal access to medical expertise and innovative treatments to all French patients through a dedicated website,www.ovaire-rare.org.
Over a 5-year activity, 4612 patients have been included. Patients’ inclusions increased from 553 in 2011 to 1202 in 2015. Expert pathology review and patients’ files discussion in dedicated multidisciplinary tumor boards increased from 166 cases in 2011 (25%) to 538 (45%) in 2015. Pathology review consistently modified the medical strategy in 5–9% every year. The rate of patients’ files discussed in RC similarly increased from 294 (53%) to 789 (66%). An increasing number (357 in 5 years) of gynecologic (non-ovarian) rare tumors were also registered by physicians seeking for pathological or medical advice from expert tumor boards.
Such a nation-wide organization for rare gynecological tumors has invaluable benefits, not only for patients, but also for epidemiological, clinical and biological research.
Background More attention should be paid to rare serious adverse events such as anaphylaxis to increase the safety of anesthesia. Objective To report the results of an 8-year survey of anaphylaxis ...during anesthesia in France. Methods Data from patients who experienced anaphylaxis between January 1, 1997, and December 31, 2004, were analyzed. Estimated incidences were obtained by combining this database with data from the French pharmacovigilance system by using a capture-recapture method. The number of patients exposed to the offending agents was obtained from data collected during the national survey of anesthesia practice. Results A total of 2516 patients was included. A diagnosis of IgE-mediated reaction was established in 1816 cases (72.18%). The most common causes were neuromuscular blocking agents (NMBAs; n = 1067; 58.08%), latex (n = 361; 19.65%), and antibiotics (n = 236; 12.85%). The median annual incidence per million procedures was higher for females 154.9 (5th-95th percentile, 117.2-193.1) than for males 55.4 (5th-95th percentile, 42.0-68.0). It reached 250.9 (5th-95th percentile, 189.8-312.9) for women in cases of allergic reactions to NMBAs. In children, a diagnosis of IgE-mediated reactions was obtained in 122 cases (45.9%). The most common causes were latex (n = 51; 41.8%), NMBAs (n = 39; 31.97%), and antibiotics (n = 11; 9.02%). In contrast with adults, no female predominance was observed. Conclusion The incidence of allergic reactions during anesthesia, estimated on a national basis, is higher than previously estimated. These results should be taken into account in the evaluation of the benefit-to-risk ratio of the various anesthetic techniques in individuals. The similar incidence of reactions according to sex before adolescence suggests a role for sex hormones in the increase of anaphylaxis observed in women.
Abstract Type 1 diabetes (T1D) is due to the loss of both beta-cell insulin secretion and glucose sensing, leading to glucose variability and a lack of predictability, a daily issue for patients. ...Guidelines for the treatment of T1D have become stricter as results from the Diabetes Control and Complications Trial (DCCT) demonstrated the close relationship between microangiopathy and HbA1c levels. In this regard, glucometers, ambulatory continuous glucose monitoring, and subcutaneous and intraperitoneal pumps have been major developments in the management of glucose imbalance. Besides this technological approach, islet transplantation (IT) has emerged as an acceptable safe procedure with results that continue to improve. Research in the last decade of the 20th century focused on the feasibility of islet isolation and transplantation and, since 2000, the success and reproducibility of the Edmonton protocol have been proven, and the mid-term (5-year) benefit–risk ratio evaluated. Currently, a 5-year 50% rate of insulin independence can be expected, with stabilization of microangiopathy and macroangiopathy, but the possible side-effects of immunosuppressants, limited availability of islets and still limited duration of insulin independence restrict the procedure to cases of brittle diabetes in patients who are not overweight or have no associated insulin resistance. However, various prognostic factors have been identified that may extend islet graft survival and reduce the number of islet injections required; these include graft quality, autoimmunity, immunosuppressant regimen and non-specific inflammatory reactions. Finally, alternative injection sites and unlimited sources of islets are likely to make IT a routine procedure in the future.
The effects of steroids on the outcome of sepsis are dose dependent. Low doses appear to be beneficial, but high doses do not improve outcome for reasons that are insufficiently understood. The ...effects of steroids on systemic inflammation as a function of dose have not previously been studied in humans. To determine the effects of increasing doses of prednisolone on inflammation and coagulation in humans exposed to LPS, 32 healthy males received prednisolone orally at doses of 0, 3, 10, or 30 mg (n = 8 per group) at 2 h before i.v. injection of Escherichia coli LPS (4 ng/kg). Prednisolone dose-dependently inhibited the LPS-induced release of cytokines (TNF-alpha and IL-6) and chemokines (IL-8 and MCP-1), while enhancing the release of the anti-inflammatory cytokine IL-10. Prednisolone attenuated neutrophil activation (plasma elastase levels) and endothelial cell activation (von Willebrand factor). Most remarkably, prednisolone did not inhibit LPS-induced coagulation activation, measured by plasma concentrations of thrombin-antithrombin complexes, prothrombin fragment F1+2, and soluble tissue factor. In addition, activation of the fibrinolytic pathway (tissue-type plasminogen activator and plasmin-alpha(2)-antiplasmin complexes) was dose-dependently enhanced by prednisolone. These data indicate that prednisolone dose-dependently and differentially influences the systemic activation of different host response pathways during human endotoxemia.
The full LEP-1 data set collected with the ALEPH detector at the
Z pole during 1991–1995 is analysed in order to measure the
τ
decay branching fractions. The analysis follows the global method used ...in the published study based on 1991–1993 data, but several improvements are introduced, especially concerning the treatment of photons and
π
0
's. Extensive systematic studies are performed, in order to match the large statistics of the data sample corresponding to over 300
000 measured and identified
τ
decays. Branching fractions are obtained for the two leptonic channels and 11 hadronic channels defined by their respective numbers of charged particles and
π
0
's. Using previously published ALEPH results on final states with charged and neutral kaons, corrections are applied to the hadronic channels to derive branching ratios for exclusive final states without kaons. Thus the analyses of the full LEP-1 ALEPH data are combined to yield a complete description of
τ
decays, encompassing 22 non-strange and 11 strange hadronic modes. Some physics implications of the results are given, in particular related to universality in the leptonic charged weak current, isospin invariance in
a
1
decays, and the separation of vector and axial-vector components of the total hadronic rate. Finally, spectral functions are determined for the dominant hadronic modes and updates are given for several analyses. These include: tests of isospin invariance between the weak charged and electromagnetic hadronic currents, fits of the
ρ
resonance lineshape, and a QCD analysis of the non-strange hadronic decays using spectral moments, yielding the value
α
s
(
m
τ
2
)
=
0.340
±
0
.
005
exp
±
0
.
014
th
. The evolution to the
Z mass scale yields
α
s
(
M
Z
2
)
=
0.1209
±
0.0018
. This value agrees well with the direct determination from the
Z width and provides the most accurate test to date of asymptotic freedom in the QCD gauge theory.
Although aldosterone has been implicated in the pathogenesis of cardiac hypertrophy and heart failure, its cellular mechanism of action on cardiomyocyte function is not yet completely elucidated. ...This study was designed to investigate the effect of aldosterone on calcium channel expression and cardiomyocyte contraction frequency.
Cultured neonatal rat ventricular cardiomyocytes were stimulated in vitro with 1 micromol/L aldosterone for 24 h. Calcium currents were then measured with the patch clamp technique, while calcium channel expression was assessed by real-time RT-PCR.
In the present study, we show that aldosterone increases Ca2+ currents by inducing channel expression. Indeed, aldosterone led to a substantial increase of L- and T-type Ca2+ current amplitudes, and we found a concomitant 55% increase of the mRNA coding for alpha1C and beta2 subunits of cardiac L channels. Although T-type currents were relatively small under control conditions, they increased 4-fold and T channel alpha1H isoform expression rose in the same proportion after aldosterone treatment. Because T channels have been implicated in the modulation of membrane electrical activity, we investigated whether aldosterone affects the beating frequency of isolated cardiomyocytes. In fact, aldosterone dose-dependently increased the spontaneous beating frequency more than 4-fold. This effect of aldosterone was prevented by actinomycin D and spironolactone and reduced by RU486, suggesting a mixed mineralocorticoid/glucocorticoid receptor-dependent transcriptional mechanism. Moreover, inhibition of T currents with Ni2+ or mibefradil significantly reduced beating frequency towards control values, while conditions affecting L-type currents completely blocked contractions.
Aldosterone modulates the expression of cardiac voltage-operated Ca2+ channels and accelerates beating in cultured neonatal rat ventricular myocytes. This chronotropic action of aldosterone appears to be linked to increased T channel activity and could contribute to the deleterious effect of an excess of this steroid in vivo on cardiac function.
Aim
This aim of this study was to detail maternal and fetal anomalies observed on a national scale in a large French cohort of patients presenting high hCG values (≥10 multiple of the median MoM) at ...Down syndrome screening in order to define clear and optimal guidelines.
Methods
This is a retrospective multicenter study based on a French annual database of all trisomy 21 screenings. Our study targeted and studied cases with hCG or hCGβ values ≥10 MoM. Complementary exams and outcomes were analyzed.
Results
The calculated frequency was 0.05% for hCGβ ≥10 MoM in unselected patients. For this series of 289 cases, a complication of the pregnancy or a poor outcome was observed in 145 cases (51%) as follows: 96 (66%) cases of fetal disease, 23 (16%) of maternal disease, 5 (3.5%) of placental anomalies and 21 (14.5%) of systemic disease concerning mother, fetus and placenta.
Conclusion
This study establishes the frequency of hCG or hCGβ values ≥10 MoM, presents a flow chart that optimizes follow‐up, and gives clear information for patients presenting with such abnormal values at trisomy 21 screening.
Key points
What's already known about this topic?
High hCG or hCGβ values have been previously reported to be associated with poor prognosis, when over 2.5 multiple of the median (MoM).
What does this study add?
This study specifies maternal and fetal anomalies observed in patients presenting high hCG values (≥10 MoM) at Down syndrome screening in order to define clear and optimal guidelines. We calculate the frequency of this abnormal value of hCGβ, detail the outcomes, present a flow chart that optimizes follow‐up and provide clear information for patients.
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