We report a reduction in cholesterol ef ﬂux capacity from human THP-1 macrophages in dyslipidemic patients with clinicalfeatures of MetS. Numerous studies have demon- strated that HDL isolated from patients displaying metabolic disorders associated with a low HDL-C phenotype display a panel of functional anomalies including reduced capacity to mediate SR-BI/Cla1 receptor –dependent efﬂux. 20–23 Such impaired functions have been proposed to account for residual cardiovascular risk in these patients. In agreement with our present observation, Lucero et al 24 recently reported that ABCA1-mediated cholesterol ef ﬂux, evaluated using a stably transfected BHK cell line overexpressing ABCA1, is enhanced in patients with MetS as a result of an increase in
SCAs of different types show similar clinicalfeatures and are therefore not or hardly distinguishable. Generally, the SCAs typically manifest in adulthood. However, the age of the disease onset in SCA2 varies, occurring between early childhood and late adult- hood with features of anticipation. On average, the disease starts around the age of 35 years. All SCA2 patients suffer from a progressive cerebellar syn- drome with ataxia of gait, ataxia of limb movements and dysarthria. Saccade slowing is a highly char- acteristic feature that is observed in the majority of SCA2 patients. Cerebellar oculomotor abnormalities are rarely found in SCA2. Typically, tendon reflexes are absent or decreased. Pyramidal tract signs are present in <20% of the patients. Vibration sense is decreased in most patients [10–12].
T his prospective observational cohort study aimed to explore the clinicalfeatures of incident immune thrombocytopenia in adults and predictors of outcome, while determining if a family history of autoimmune disorder is a risk factor for immune thrombocytopenia. All adults, 18 years of age or older, recently diagnosed with immune thrombocytopenia were consecutively recruited across 21 hospital cen- ters in France. Data were collected at diagnosis and after 12 months. Predictors of chronicity at 12 months were explored using logistic regression models. The association between family history of autoim- mune disorder and the risk of developing immune thrombocytopenia was explored using a conditional logistic regression model after match- ing each case to 10 controls. One hundred and forty-three patients were included: 63% female, mean age 48 years old (Standard Deviation=19), and 84% presented with bleeding symptoms. Median platelet count was 10x10 9 /L. Initial treatment was required in 82% of patients. After 12 months, only 37% of patients not subject to disease-modifying inter- ventions achieved cure. The sole possible predictor of chronicity at 12 months was a higher platelet count at baseline [Odds Ratio 1.03; 95%CI: 1.00, 1.06]. No association was found between outcome and any of the following features: age, sex, presence of either bleeding symptoms or antinuclear antibodies at diagnosis. Likewise, family his- tory of autoimmune disorder was not associated with incident immune thrombocytopenia. Immune thrombocytopenia in adults has been shown to progress to a chronic form in the majority of patients. A lower platelet count could be indicative of a more favorable outcome.
Abstract: The novel severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) pandemic has spread rapidly across the globe. In contrast to initial reports, recent studies suggest that children are just as likely as adults to become infected with the virus but have fewer symptoms and less severe disease. In this review, we summarize the epidemiologic and clinicalfeatures of children infected with SARS-CoV-2 reported in pediat- ric case series to date. We also summarize the perinatal outcomes of neo- nates born to women infected with SARS-CoV-2 in pregnancy. We found 11 case series including a total of 333 infants and children. Overall, 83% of the children had a positive contact history, mostly with family mem- bers. The incubation period varied between 2 and 25 days with a mean of 7 days. The virus could be isolated from nasopharyngeal secretions for up to 22 days and from stool for more than 30 days. Co-infections were reported in up to 79% of children (mainly mycoplasma and inﬂuenza). Up to 35% of children were asymptomatic. The most common symptoms were cough (48%; range 19%–100%), fever (42%; 11%–100%) and phar- yngitis (30%; 11%–100%). Further symptoms were nasal congestion, rhi- norrhea, tachypnoea, wheezing, diarrhea, vomiting, headache and fatigue. Laboratory test parameters were only minimally altered. Radiologic ﬁnd- ings were unspeciﬁc and included unilateral or bilateral inﬁltrates with, in some cases, ground-glass opacities or consolidation with a surrounding halo sign. Children rarely needed admission to intensive care units (3%), and to date, only a small number of deaths have been reported in chil- dren globally. Nine case series and 2 case reports described outcomes of maternal SARS-CoV-2 infection during pregnancy in 65 women and 67 neonates. Two mothers (3%) were admitted to intensive care unit. Fetal dis- tress was reported in 30% of pregnancies. Thirty-seven percent of women delivered preterm. Neonatal complications included respiratory distress or pneumonia (18%), disseminated intravascular coagulation (3%), asphyxia (2%) and 2 perinatal deaths. Four neonates (3 with pneumonia) have been reported to be SARS-CoV-2 positive despite strict infection control and prevention procedures during delivery and separation of mother and neo- nates, meaning vertical transmission could not be excluded.
diagnosis of LPAC syndrome within all diagnostic strata ( Table S1 ).
The relationships between ABCB4 variations and the clinicalfeatures and comorbidities of LPAC syndrome were assessed from the entire cohort. ABCB4 gene variations were detected in 122 (45%) out of 269 LPAC patients with a genotyping test available (87% of all patients), including 63% missense variants and 37% nonsense or frame-shift truncating variants (for more details, see Table S2 ). The vast majority (95%) of ABCB4 variants were in the heterozygous state. In a univariate analysis, the features associated with the presence of ABCB4 gene variations included history of CBD lithiasis (34.5% vs. 20.0%; p = 0.008), history of endoscopic sphincterotomy (39.3% vs. 25.5%; p = 0.017), chronic elevation of GGT (33.3% vs. 14.2%; p <0.001), and personal or family history of hepato-biliary cancer (10.1% vs. 2.2%; p = 0.011). Patients with ABCB4 pathogenic variants showed more frequently chronic elevation of transaminases than those without (16.1% vs. 8.5%), but the difference did not reach the level of signi ﬁcance (p = 0.065). In the female population with a pregnancy history, no signi ﬁcant association was found between a history of ICP and the presence of ABCB4 gene variations (48.4% vs. 40.4%; p = 0.40). In a multivariate analysis adjusted for age and sex, the features independently associated with the presence of ABCB4 gene variation were a history of CBD lithiasis, a chronic elevation of GGT, and a personal or family history of hepato- biliary cancer ( Table 4 ). Among all patients exhibiting ABCB4 gene variations, those with truncating variants were not different from those with missense variants, except for a more frequent family history of symptomatic cholelithiasis in ﬁrst- degree relatives (71.1% vs. 45.5%; p = 0.012).
Streptococcal bone and joint infections are less common than staphylococcal cases. Few studies have reported the cases with well-identi ﬁed Streptococcus species. Their clinicalfeatures and prognosis are not clearly known to date. Moreover, no treatment regimen has yet been clari ﬁed. We reviewed the streptococcal bone and joint infection cases managed in our centres from January 2009 to December 2013. We described the epidemiology, clinical and microbiologic characteristics, treatment approach and outcome. Among the 93 cases, 83% of patients were men with a median age of 60 years, and 90% of patients had comorbidities or risk factors. Bacteraemia occurred in 14% of cases. Serious complications occurred in six patients, including severe sepsis (two cases) and infective endocarditis (two cases). Orthopaedic device infections were observed in 35% of cases, including 17 patients with internal osteosynthesis device infection, 14 with prosthetic joint infection and three with vertebral osteosynthesis device infection. The median time between orthopaedic device implantation and onset of infection was 447 days. Fourteen species of Streptococcus were identiﬁed, including 97 isolates using matrix- assisted laser desorption/ionization time-of- ﬂight mass spectrometry and three isolates using molecular identiﬁcation. The ﬁve most represented species included S. agalactiae (37%), S. dysgalactiae (12%), S. anginosus (11%), S. constellatus (10%) and S. pneumoniae (9%). Streptococci isolates were susceptible to amoxicillin, with the exception of one S. mitis isolate. Remission 1 year after the end of treatment was recorded in 83%. One patient died of infection; eight patients had infections that failed to respond to treatment; and seven patients experienced relapse. Twenty patients (22%) had an unfavourable functional outcome, including 19 amputations and one arthrodesis. Five signi ﬁcant prognostic factors associated with an unfavourable clinical outcome were identiﬁed, including peripheral neuropathy (p 0.009), peripheral arterial disease (p 0.019), diabetes mellitus (p 0.031), location in the femur (p 0.0036), location in the foot (p 0.0475), osteitis without an orthopaedic device (p 0.041) and infection caused by S. dysgalactiae (p 0.020). The rate of poor outcomes remains high despite the low number of Streptococcus isolates resistant to antibiotics. Some prognostic factors, such as the presence of S. dysgalactiae, are associated with an unfavourable clinical outcome. Antibiotic regimens of streptococcal bone and joint infections are not standardized and need to be further investigated.
The questionnaire included items relating to demographic data, IL12RB1 mutations, and infectious diseases. For candidiasis, we recorded the date and patient age at the time of the episode, the Candida species identi ﬁed, sites involved, whether the episode was community-acquired or hospital-acquired candidiasis, clini- cal signs and duration before treatment, use of antibiotics during or before candidiasis, use of immunosuppresants, polymorpho- nuclear granulocyte counts, the presence of comorbid conditions and age at onset of these conditions, clinicalfeatures for each episode, antifungal treatment and duration, and time to clinical remission. Informed consent was obtained from each patient or the patient ’s family. The protocol was approved by the local ethics committees of the various institutions involved.
Our results identified the deregulation of two miRNAs, miR-96 and miR-126*, as significantly associated with different risk factors of HCC, HBV infection and alcohol consumption, respectively. To our knowledge, miR-96 and miR-126* have not been directly implicated in pathways related to carcinogenesis. Because no significant variation in the expression of these two microRNAs was observed in non-tumor tissues according to HBV infection or alcohol intake, it suggests that microRNAs deregulations are directly linked to carcinogenetic processes specifically induced by these two risk factors. In fact, using transcriptomic and genetic global analyses we have previously shown that carcinogenesis mechanisms in HBV related HCC were particular, closely related to chromosome instability, AKT activation and fetal features in gene expression (7, 8). In contrast, microRNA profiling is the first global genomic approach that enabled to discriminate HCC related to alcohol abuse from the other tumors. Consequences of the miR-126* deregulation remained to be explored in alcohol related tumors and HCC associated to other risk factors.
Owing to its reduced solubility in acidic urine, urinary cystine in high concentrations in affected individuals precipitates to form crystals and uroliths leading to urinary obstruction [1,2]. Neutered males were overrepresented in the present case series, accounting for the majority of cases. The same trends have been reported in a previous study in which male ferrets accounted for 77% of the affected individuals and appeared to be 2.5 times more likely to develop cystine uroliths as females [4,8,9]. As no difference in urine pH was found between males and females, this sex difference may likely be related to the anatomy of the urethra of male ferrets that could predispose to partial or total urethral obstruction [4,9,10]. Male ferrets have a longer lower urinary tract combined with a tightly angled pelvic urethral flexure, rigid os penis, and narrow urethral diameter that may predispose them to urinary blockage . The more straightforward urethra of female ferrets may allow the passage of small stones. Hence, some females may remain asymptomatic while having cystine uroliths in their urinary tract. The mean age at diagnosis in the present study was 1.8 year with most cases between one and three years of age. This is younger than the mean age of 4.1 years reported in the case series of Nwaokorie and others (2013), however, in the same study, 51% of the cases occurred between two and four years old. Our data were also in agreement with a recent study that demonstrated a strong association between cystine urolithiasis and younger age of the ferret . In this large-scale retrospective study from 2010 to 2018, two other features were strongly associated with cystine urolithiasis: North American origin, and later year of submission. The marked difference in prevalence between populations of different origins and the increase in prevalence in the
cause congenital miosis. The disease likely involves the loss of elements regulating the expression of genes neighboring the deletions. The deleted sequences are contained in a topologically associated domain (TAD) spanning 600 kb on chromosome 13q32.1. The dele- tions may change the enhancer dosage, resulting in the loss of function of one or more of the 8 genes in the TAD or result in upregulation or tissue-specific misexpression [ 12 ]. DCT encoding daupachrome tautomerase is among the genes of interest. It is involved in the biosynthesis of eumelanin [ 73 ]. Recently, biallelic loss-of-function mutations in DCT have been described in oculocutaneous albinism (OCA8) [ 74 ]. Misexpression of this gene may contribute to the disease or at least the excessively light pigmentation of the iris reported in subjects with congenital miosis. SOX21 encodes a transcription factor of the SRY-related HMG-box (SOX) family which is transiently expressed during the early phases of optic vesi- cle morphogenesis in chicks and during specification in the lens and retina but is switched of afterwards, i.e., before the iris starts developing [ 75 ]. Its loss of function in chicks, as in zebrafish, interferes with normal lens development [ 76 ]. Ectopic expression during iris development could be induced by 13q32.1 deletions and therefore compromise the development of the iris and chamber angle. Finally, ABCC4 (MRP4) immunoreactivity has been demonstrated throughout the aqueous outflow pathway, including the trabeculum meshwork, Schlemm’s canal, and juxtacanalicular tissue [ 77 ]. This gene has been suggested to regulate intracellular cAMP and cGMP levels in the TM and IOP, possibly through the regulation of ECM homeostasis. Whether misexpression of this gene contributes to con- genital miosis-associated glaucoma merits consideration. However, in the five-generation Breton family, 29 of the 31 MCOR patients shared a 4 Mb haplotype encompassing the 600 kb TAD (markers D13S1300 and D13S154) at the 13q32 locus [ 10 ]. As myopia and glaucoma were not consistent features among the 29 haploidentical individuals, and as crossovers are highly unlikely in a 4 Mb interval, it is unlikely that structural variants are directly involved.
Different case deﬁnitions for COVID-19 cases in adults and children from authoritive sources as of March 2020 are detailed in Table 2. Children are less commonly affected by SARS-CoV-2, the Chinese Centers for Disease Control and Prevention reports that of the 72,314 cases reported as of February 11, 2020, only 2% were in individuals of less than 19 years of age. 114 There are 3 case series of children who have been infected with SARS-CoV-2. 61,72,77 The ﬁrst included 20 children up to January 31, 2020, in the Province of Zhe- jiang, 72 the second 34 children between January 19, 2020, and Feb- ruary 7, 2020, in the Province of Shenzhen, 61 and the third 9 infants from different provinces in China. 77 The case series with 34 chil- dren provides the most clinical details: none of the children had an underlying disease, 65% had common respiratory symptoms, 26% had mild disease and 9% were asymptomatic. 61 The most common symptoms were fever (50%) and cough (38%). 61 In the case series of 20 children, presentation was with low to moderate or no fever, rhinitis, cough, fatigue, headache, diarrhea and, in more severe cases, with dyspnea, cyanosis and poor feeding, but the numbers were not speciﬁed. 72 In the series of 9 infants, only 4 were reported to have fever. One infant was asymptomatic. 77 Additional asympto- matic children infected with SARS-CoV-2 outside these case series have also been described (eg, a 10-year-old asymptomatic child with radiologic ground-glass lung opacities on chest CT). 28 Most infected children recover 1–2 weeks after the onset of symptoms and no deaths from SARS-CoV-2 had been reported by February 2020. 72
After its approval by the Ethics Committee of the Cochin-Paris V Faculty of medicine, the study was prospectively performed between November 2001 and May 2004 and included all children between 0 months and 15 years of age hospitalized with acute diarrhoea. Acute diarrhoea was defined as at least 3 looser-than normal stools within a 24-h period. All admissions to the hospital were based on clinical examinations at the request of the hospital emergency team. Patients with chronic diarrhoea (> 10 days) were excluded. For each child, clinical data including, age, sex and admission date were prospectively collected at inclusion. Each episode was graded using the 20-point severity score scale [13, 14]. Furthermore, the occurrence of bloody diarrhoea, the use of intravenous rehydration and the length of hospitalization were documented. Stool samples were systematically collected to screen for etiologic agents of diarrhoea. Bacteria (Salmonella, Shigella and Campylobacter spp.) were detected by routine cultivation in the Bacteriology Laboratory of the Saint Vincent de Paul Hospital. After collection, the samples were stored frozen (- 20°C) at the Virology Laboratory. The stools were sent together to the enteric viruses NRC (Dijon), for viral investigation.
In conclusion, this is the first study to examine in depth the clinical, hormonal, and radiological features
of a large FIPA kindred with three patients with pituitary adenomas (acromegaly and prolactinoma) associated with mutations in AIP. Among seven asymptomatic mutation carriers, elevations in IGF-I were seen in two adult individuals, while an infant girl presented a progressing pattern of sexual precocity. These results suggest that the same AIP mutation can be associated with a variable phenotype of pituitary tumors among related family members (as suggested previously (11) ) and raises the possibility of the involvement of non-tumoral pituitary pathology in mutation carriers. The field of AIP research in the setting of pituitary endocrinology is at an early stage and fundamental data on mutated AIP protein expression and function from in vitro and animal studies is lacking at this time. Before firm conclusions can be drawn regarding clinical disease characteristics related to AIP mutations, the analysis of data from larger cohorts of affected patients will be required.
METHODS AND RESULTS
Study Design, Data Collection, and De ﬁnitions
A retrospective study was conducted at the Centre de Diagnostic et de Traitement de la Lèpre et de l ′Ulcère de Buruli (CDTLUB) in Pobè, Benin, which has one of the largest databases for cases of Buruli ulcer con ﬁrmed by polymerase chain reaction (PCR) [ 14 ]. We ﬁrst conducted a preliminary analysis of 545 Buruli ulcer patients treated at the CDTLUB in Pobè from 2010 to 2013. For the selection of medical records, we used several key words de- ﬁned on the basis of publications in this ﬁeld: spontaneous heal- ing, spontaneous clearance, scar, old ulcer, scarring lesion. During this review step, medical records containing at least 1 of the chosen key words were selected. If the clinical records were incomplete (eg, lack of photographic monitoring, patients lost to follow-up), the patient was excluded.
We describe the clinical, electrodiagnostic, and genetic findings of three homozygous FIG4-c.122T>C patients suffering from Charcot-Marie-Tooth dis- ease type 4J (AR-CMT-FIG4). This syndrome usually involves compound heterozygosity associating FIG4-c.122T>C, a hypomorphic allele coding an unstable FIG4-p.Ile41Thr protein, and a null allele. While the compound heterozygous patients presenting with early onset usually show rapid progres- sion, the homozygous patients described here show the signs of relative clinical stability. As FIG4 activity is known to be dose dependent, these patients’ obser- vations could suggest that the therapeutic perspective of increasing levels of the protein to improve the phenotype of AR-CMT-FIG4-patients might be efficient.
PATIENTS, MATERIALS, AND METHODS
The present series included 11 unrelated boys ranging in age from one to 20 years. All patients were followed at the Department of Genetics of the Necker-Enfants Malades Hospital, Paris. They were diagnosed with CdLS on the basis of four major criteria: (i) pre- and/or postnatal growth retardation, (ii) pre- and/or postnatal microcephaly, (iii) moderate to profound mental retardation with abnormal speech development, ranging from minimal speech to complete absence of speech, and (iv) facial dysmorphic features including arched eyebrows with synophrys, short nose with anteverted nares, long philtrum, and thin upper lip. In addition, at least two of the following four clinical signs or symptoms were required for diagnosis, namely: (i) behavioral problems including self-injurious behavior, hyperactivity, repetitive and autistic behavior, (ii) feeding problems in infancy and/or gastroesophageal reflux, (iii) major or minor anomalies of the upper limbs, and (iv) skin anomalies, particularly hirsutism and cutis marmorata.
The hallmark clinicalfeatures of nfvPPA are effortful speech and agrammatism. Effortful speech is characterized by slow, labored speech production, mainly due to a speech motor planning deficit, i.e., apraxia of speech (AOS) ( 20 ). Speech sound errors, consisting of distortions, deletions, substitutions, insertions, or transpositions of speech sounds are present. Distortions are considered as phonetic errors and are caused by AOS, while deletions, substitutions, insertions and transpositions are phonemic errors and can be caused by a motor speech impairment or a phoneme selection deficit ( 21 , 22 ). However, there are some significant challenges in differentiating these two types of errors clinically, and both studies showing higher rates of phonetic errors ( 23 , 24 ) or higher rates of phonemic errors ( 21 , 22 ) in nfvPPA patients have been reported. Prosody is also typically affected in nfvPPA. Dysarthric features often co- occur with AOS, usually with mixed hypophonic and spastic features ( 20 ). Agrammatism is characterized by short, simple phrases, and omission of grammatical morphemes. Difficulties are present in language production (e.g., omission of articles, use of incorrect morphological endings), as well as in comprehension (e.g., difficulties in understanding complex syntactic structures, such as passives and relative clauses) ( 25 ). Patients with nfvPPA often use fewer verbs compared with healthy controls, in part because verbs play a critical part in syntactically structuring a sentence. They also have difficulty with verb naming and comprehension tasks ( 26 ).
EPIDEMIOLOGY: RAPID SPREAD AND THE ROLE OF SYMPTOMATIC CASES
Despite seven years since first discovery, MERS-CoV trans- mission dynamics remain largely undefined and the roles of transmission, direct or indirect contact, airborne, drop- let, or ingestion, have yet to be defined. MERS-CoV does not easily transmit from person to person unless contact with a MERS-CoV-infected subject is close. Several reports from Saudi Arabia describe transmission of silent or sub- clinical secondary infections after exposure to patients with MERS-CoV infections, some being apparently healthy individuals who were household contacts carrying MERS- CoV in their upper respiratory tract at low levels low amounts indicating that MERS-CoV can be transmitted from asymptomatic household or hospital contacts [21-23]. The ongoing SARS-CoV-2 outbreak has rapidly evolved and spread globally. As of Feb 29, 2020, there have been 83,652 laboratory confirmed cases of COVID-19, with 2791 deaths (3.4% mortality). Outside China, there have been 4691 cases reported from 51 countries with 67 deaths . Whilst there have been several epidemiological links to bats, and other animals have been proposed, the source of primary SARS-CoV-2 transmission to humans remains un- known. The main clinicalfeatures of COVID-19 disease ap- pear similar to other CoVs infections of humans. SARS-CoV- 2 is generally associated with upper respiratory tract and high viral loads in upper respiratory tract secretions. This
The viewing condition also affected the attractiveness ratings, as observers’ ratings increased when the peripheral vision was increasingly restricted. Moreover, the back view was preferred over the front view during natural viewing, but this effect reversed when vision was restricted to foveal vision (spotlight with 2° of visual angle) and both hips could not be perceived with a single fixation. This observation favors the view that the hips region might play a critical role in attractive ratings. However, this result could also be due to the nature of the stimuli we used. Given that in the front view condition the observers were processing multiple body features simultaneously, the artificial nature of the stimuli might have decreased the attractiveness ratings compared to the back view condition (displaying mainly a single body region of interest). Regardless of both explanations, further experiments using real women or body parts shown separately are necessary to further clarify this issue.