Most chilblains observed during the COVID-19 outbreak occur in patients who are negative for COVID-19 on polymerase chain reaction and serology testing.

BACKGROUND: Acral lesions, mainly chilblains, are the most frequently reported cutaneous lesions associated with COVID-19. In more than 80% of patients tested, nasopharyngeal swabs were negative on reverse transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2 when performed, and serology was generally not performed. METHODS: A national survey was launched on 30 March 2020 by the French Society of Dermatology asking physicians to report cases of skin manifestations in patients with suspected or confirmed COVID-19 by using a standardized questionnaire. We report the results for acral manifestations. RESULTS: We collected 311 cases of acral manifestations [58.5% women, median age 25.7 years (range 18-39)]. The most frequent clinical presentation (65%) was typical chilblains. In total, 93 cases (30%) showed clinical suspicion of COVID-19, 67 (22%) had only less specific infectious symptoms and 151 (49%) had no clinical signs preceding or during the course of acral lesions. Histology of skin biopsies was consistent with chilblains. Overall, 12 patients showed significant immunological abnormalities. Of the 150 (48%) patients who were tested, 10 patients were positive. Seven of 121 (6%) RT-PCR-tested patients were positive for SARS-CoV-2, and five of 75 (7%) serology-tested patients had IgG anti-SARS-CoV-2. Tested/untested patients or those with/without confirmed COVID-19 did not differ in age, sex, history or acral lesion clinical characteristics. CONCLUSIONS: The results of this survey do not rule out that SARS-CoV-2 could be directly responsible for some cases of chilblains, but we found no evidence of SARS-CoV-2 infection in the large majority of patients with acral lesions during the COVID-19 lockdown period in France. What is already known about this topic? About 1000 cases of acral lesions, mainly chilblains, were reported during the COVID-19 outbreak. Chilblains were reported to occur in young people within 2 weeks of infectious signs, which were mild when present. Most cases did not have COVID-19 confirmed by reverse transcription polymerase chain reaction (RT-PCR), and few serology results were available. What does this study add? Among 311 patients with acral lesions, mainly chilblains, during the COVID-19 lockdown period in France, the majority of patients tested had no evidence of SARS-CoV-2 infection. Overall, 70 of 75 patients were seronegative for SARS-Cov-2 serology and 114 of 121 patients were negative for SARS-CoV-2 RT-PCR.

Medical history of discordant twins and environmental etiologies of autism.

The environmental contributions to autism spectrum disorder (ASD) and their informative content for diagnosing the condition are still largely unknown. The objective of this study was to investigate associations between early medical events and ASD, as well as autistic traits, in twins, to test the hypothesis of a cumulative environmental effect on ASD risk. A total of 80 monozygotic (MZ) twin pairs (including a rare sample of 13 twin pairs discordant for clinical ASD) and 46 dizygotic (DZ) twin pairs with varying autistic traits, were examined for intra-pair differences in early medical events (for example, obstetric and neonatal factors, first year infections). First, differences in early medical events were investigated using multisource medical records in pairs qualitatively discordant for ASD. The significant intra-pair differences identified were then tested in relation to autistic traits in the remaining sample of 100 pairs, applying generalized estimating equations analyses. Significant association of the intra-pair differences in the MZ pairs were found for the cumulative load of early medical events and clinical ASD (Z=-2.85, P=0.004) and autistic traits (ß=78.18, P=0.002), as well as infant dysregulation (feeding, sleeping abnormalities, excessive crying and worriedness), when controlling for intelligence quotient and attention deficit hyperactivity disorder comorbidity. The cumulative load of early medical events in general, and infant dysregulation in particular, may index children at risk of ASD owing to non-shared environmental contributions. In clinical practice, these findings may facilitate screening and early detection of ASD.

How can clinicians detect and treat autism early? Methodological trends of technology use in research.

UNLABELLED: We reviewed original research papers that used quantifiable technology to detect early autism spectrum disorder (ASD) and identified 376 studies from 34 countries from 1965 to 2013. Publications have increased significantly since 2000, with most coming from the USA. Electroencephalogram, magnetic resonance imaging and eye tracking were the most frequently used technologies. CONCLUSION: The use of quantifiable technology to detect early ASD has increased in recent decades, but has had limited impact on early detection and treatment. Further scientific developments are anticipated, and we hope that they will increasingly be used in clinical practice for early ASD screening, diagnosis and intervention.

A candidate syntenic genetic locus is associated with voluntary exercise levels in mice and humans.

Individual levels of physical activity, and especially of voluntary physical exercise, highly contribute to the susceptibility for developing metabolic, cardiovascular diseases, and potentially to psychiatric disorders. Here, we applied a cross-species approach to explore a candidate genetic region for voluntary exercise levels. First, a panel of mouse chromosome substitution strains was used to map a genomic region on mouse chromosome 2 that contributes to voluntary wheel running levels - a behavioral readout considered a model of voluntary exercise in humans. Subsequently, we tested the syntenic region (HSA20: 51,212,545-55,212,986) in a human sample (Saint Thomas Twin Register; n=3038) and found a significant association between voluntary exercise levels (categorized into excessive and non-excessive exercise) and an intergenic SNP rs459465 (adjusted P-value of 0.001). Taking under consideration the methodological challenges embedded in this translational approach in the research of complex phenotypes, we wanted to further test the validity of this finding. Therefore, we repeated the analysis in an independent human population (ALSPAC data set; n=2557). We found a significant association of excessive exercise with two SNPs in the same genomic region (rs6022999, adjusted P-value of P=0.011 and rs6092090, adjusted P-value of 0.012). We explored the locus for possible candidate genes by means of literature search and bioinformatics analysis of gene function and of trans-regulatory elements. We propose three potential human candidate genes for voluntary physical exercise levels (MC3R, CYP24A1, and GRM8). To conclude, the identified genetic variance in the human locus 20q13.2 may affect voluntary exercise levels.

Pharmacological manipulations in animal models of anorexia and binge eating in relation to humans.

Eating disorders, such as anorexia nervosa (AN), bulimia nervosa (BN) and binge eating disorders (BED), are described as abnormal eating habits that usually involve insufficient or excessive food intake. Animal models have been developed that provide insight into certain aspects of eating disorders. Several drugs have been found efficacious in these animal models and some of them have eventually proven useful in the treatment of eating disorders. This review will cover the role of monoaminergic neurotransmitters in eating disorders and their pharmacological manipulations in animal models and humans. Dopamine, 5-HT (serotonin) and noradrenaline in hypothalamic and striatal regions regulate food intake by affecting hunger and satiety and by affecting rewarding and motivational aspects of feeding. Reduced neurotransmission by dopamine, 5-HT and noradrenaline and compensatory changes, at least in dopamine D2 and 5-HT(2C/2A) receptors, have been related to the pathophysiology of AN in humans and animal models. Also, in disorders and animal models of BN and BED, monoaminergic neurotransmission is down-regulated but receptor level changes are different from those seen in AN. A hypofunctional dopamine system or overactive α2-adrenoceptors may contribute to an attenuated response to (palatable) food and result in hedonic binge eating. Evidence for the efficacy of monoaminergic treatments for AN is limited, while more support exists for the treatment of BN or BED with monoaminergic drugs.

The use of mouse models to unravel genetic architecture of physical activity: a review.

The discovery of genetic variants that underlie a complex phenotype is challenging. One possible approach to facilitate this endeavor is to identify quantitative trait loci (QTL) that contribute to the phenotype and consequently unravel the candidate genes within these loci. Each proposed candidate locus contains multiple genes and, therefore, further analysis is required to choose plausible candidate genes. One of such methods is to use comparative genomics in order to narrow down the QTL to a region containing only a few genes. We illustrate this strategy by applying it to genetic findings regarding physical activity (PA) in mice and human. Here, we show that PA is a complex phenotype with a strong biological basis and complex genetic architecture. Furthermore, we provide considerations for the translatability of this phenotype between species. Finally, we review studies which point to candidate genetic regions for PA in humans (genetic association and linkage studies) or use mouse models of PA (QTL studies) and we identify candidate genetic regions that overlap between species. On the basis of a large variety of studies in mice and human, statistical analysis reveals that the number of overlapping regions is not higher than expected on a chance level. We conclude that the discovery of new candidate genes for complex phenotypes, such as PA levels, is hampered by various factors, including genetic background differences, phenotype definition and a wide variety of methodological differences between studies.

Imatinib mesylate in scleroderma-associated diffuse skin fibrosis: a phase II multicentre randomized double-blinded controlled trial.

BACKGROUND: Imatinib mesylate is a potent inhibitor of platelet-derived growth factor and transforming growth factor-ß signalling pathways which may play a role in systemic sclerosis (SSc)-associated skin changes. OBJECTIVES: We aimed primarily at assessing the efficacy of imatinib mesylate in scleroderma skin fibrosis. METHODS: We performed a phase II double-blinded trial on patients with scleroderma with either morphoea involving > 20% of body surface area or SSc with extensive skin involvement: modified Rodnan Skin Score (mRSS) ≥ 20/51. Each patient was randomized to receive either imatinib mesylate 400 mg or placebo daily for a total of 6 months, and then was followed up 6 months after therapy discontinuation. Skin fibrosis was assessed by mRSS and measurement of the dermal thickness using skin biopsies performed at inclusion and at 6 months of treatment. In addition, quality of life (Dermatology Life Quality Index and modified Health Assessment Questionnaire for Scleroderma) was recorded at each visit, and pulmonary function before and after intervention. RESULTS: Twenty-eight patients were included in the study with a mean age of 48·9 years (range 30-71): 25 had a diagnosis of a SSc and three of diffuse cutaneous scleroderma. Demographic data, frequency of organ involvement of SSc and mRSS were comparable between groups. At 6 months, the proportion of variation of mRSS from inclusion was not statistically significantly different between the two groups (median +0·10 in imatinib group vs. -0·16 in placebo group, P = 0·098). Similarly, changes in dermal thickness, quality of life and diffusion capacity for carbon monoxide were not significantly different between groups. CONCLUSIONS: This study failed to demonstrate the efficacy of imatinib 400 mg daily to improve skin fibrosis of diffuse scleroderma after 6 months of treatment based on validated outcome measurements.

Use of autologous platelet-rich clots for the prevention of local injury bleeding in patients with severe inherited mucocutaneous bleeding disorders.

Stopping or preventing local bleeding in patients with inherited bleeding disorders linked to abnormal platelet function is traditionally treated by transfusion of blood cell products or recombinant factor VIIa. We now report the use in such patients of autologous platelet-rich clots as an aid to preventing bleeding and to facilitating tissue regeneration at superficial sites. Two patients with von Willebrand's disease (VWD) type 2B and one patient with type I Glanzmann thrombasthenia were treated after tooth extraction and dental surgery. A fourth patient with platelet-type VWD underwent a skin biopsy. Whereas all four patients had a lifelong history of bleeding complications, the application of an autologous platelet-rich clot immediately after surgery combined with tranexamic acid intake to slow fibrinolysis prevented blood loss and resulted in rapid and normal healing. This new procedure is simple, safe and inexpensive; it provides extra security for patients with a bleeding risk undergoing dentistry or superficial surgery.

[Cutaneous infection due to Mycobacterium chelonae during anti-TNF therapy]. / Infection cutanée a Mycobacterium chelonae au cours d'un traitement par anti-TNF.

BACKGROUND: Mycobacterium chelonae is a ubiquitous, rapidly growing, opportunistic, non-tuberculous mycobacterium that can cause skin and bone tissue infections. We report a case of cutaneous infection due to M. chelonae following anti-TNF therapy. CASE REPORT: A 70-year-old woman with a medical history of rheumatoid arthritis was admitted for several purple nodular cutaneous lesions on her right leg evolving for 2 months. At admission, she was on prednisone, methotrexate and adalimumab for her rheumatoid arthritis. Skin lesions appeared 5 days before etanercept, which was taken for 5 months before being discontinued for adalimumab. Both the histopathological examination and bacterial culture of involved skin showed the presence of M. chelonae. Adalimumab was immediately discontinued and a combination of amoxicillin-clavulanic acid and tigecyclin was started. DISCUSSION: TNF-alpha plays a pivotal role in immune reaction to intracellular pathogens. Very few cases of cutaneous infection involving M. chelonae in association with an anti-TNF-alpha therapy have been reported in the literature. To our knowledge, this is the first case occurring during treatment with etanercept and symptoms worsened with the introduction of adalimumab. In addition, this case underlines the difficulties of effectively treating this mycobacterium.

[Childhood-onset multifocal atrophic dermatofibrosarcoma]. / Dermatofibrosarcome atrophique multifocal à début pédiatrique.

BACKGROUND: Atrophic dermatofibrosarcoma is a rare clinical variant of dermatofibrosarcoma protuberans (or Darier-Ferrand tumor) preferentially observed in childhood and early adulthood. OBSERVATION: We report a case of multifocal atrophic dermatofibrosarcoma protuberans of childhood onset only diagnosed when the patient was 29 years old. The clinical presentation was an asymptomatic macular brown plaque on the right thigh measuring 10 cm. Initially, because of the large size of the lesion, treatment consisted of limited surgical excision. DISCUSSION: Diagnosis of the atrophic variant of dermatofibrosarcoma in childhood is difficult, and is usually made several years later in early adulthood because of its slow development, lack of symptoms and generally benign appearance. Histological tests and immunohistochemical staining may confirm clinically suspected diagnosis, and in complex cases, cytogenetic studies can help confirm a diagnosis of dermatofibrosarcoma through detection of reciprocal translocation t (17,22), which fuses collagen type Ialpha1 (COLIA1) and platelet-derived growth factor (PDGDFbeta), and which is highly characteristic of dermatofibrosarcoma protuberans. Conventional treatment of dermatofibrosarcoma protuberans consists of extensive surgical excision, but Mohs micrographic surgery is also advocated for removal of certain dermatofibrosarcoma protuberans, while use of tyrosine kinase PDGF receptor inhibitors such as imatinib mesylate (Glivec) is limited to distant metastases.

Drug-resistant tuberculosis in Poland in 2000: second national survey and comparison with the 1997 survey.

SETTING: Three years after the last survey of drug-resistant tuberculosis in Poland, a nationwide survey was conducted by the National Tuberculosis Reference Laboratory in cooperation with all TB laboratories. OBJECTIVE: To determine the prevalence and patterns of primary and acquired drug resistance among Mycobacterium tuberculosis isolates recovered from tuberculosis patients in Poland in 2000 and to compare the results with an earlier survey carried out in 1997. DESIGN: In a prospective survey based on the questionnaires and strains of M. tuberculosis from all 16 regional centres participating in the study, 3705 questionnaires and cultures were obtained from 3037 new and 668 previously treated patients excreting TB bacilli during the 12-month period of 2000. Tests of resistance to isoniazid, rifampicin, streptomycin and ethambutol were performed using Löwenstein-Jensen and the Bactec system. RESULTS AND CONCLUSION: Compared with the previous survey in 1997, the current survey showed a twofold increase in tuberculosis resistance in new cases: any resistance was 3.6% in 1997 vs. 6.1% in 2000 (P < 0.001), multidrug resistance was 0.6% vs. 1.2% (P < 0.01), and no cases of four-drug resistance in 1997 vs. 15 cases in 2000. No statistical differences were observed in the rate of acquired resistance in both surveys.

A new technology for the production of valuable vitamin extracts from wheat and rye germs.

A method for nearly complete extraction of the lipid fraction from wheat and rye germs was developed, and the technological parameters of the production process were specified. The resulting preparations are extracts rich in vitamin E and other biologically active components. Dermatological studies and application in the cosmetic industry have testified to the suitability of these preparations for use in cosmetic and pharmaceutical products. Owing to their high content of unsaturated fatty acids and to a natural combination of biologically active compounds, the preparations from wheat and rye germs obtained by our method on an industrial scale find increasingly wider application. The post-extraction residue free from the lipid fraction is high-value feed.

Production and application of flavour isolates of plant origin.

A method for preparation of natural flavour isolates from fruits, vegetables and herb spices, developed at the Institute of Fermentation Industry in Warsaw, was presented. It involves extraction of raw materials with CCl2F2 at 5 X 10(5) Pa. For the different groups of raw materials, three types of extracting apparatuses were developed. The quality of the preparations, technological parameters of their production, storage conditions and applications are the subject of several publications and non-published materials; therefore, the present paper is of an only general nature.