Genetic and phenotypic findings in 34 novel Spanish patients with DDX3X neurodevelopmental disorder.

DDX3X is a multifunctional ATP-dependent RNA helicase involved in several processes of RNA metabolism and in other biological pathways such as cell cycle control, innate immunity, apoptosis and tumorigenesis. Variants in DDX3X have been associated with a developmental disorder named intellectual developmental disorder, X-linked syndromic, Snijders Blok type (MRXSSB, MIM #300958) or DDX3X neurodevelopmental disorder (DDX3X-NDD). DDX3X-NDD is mainly characterized by intellectual disability, brain abnormalities, hypotonia and behavioral problems. Other common findings include gastrointestinal abnormalities, abnormal gait, speech delay and microcephaly. DDX3X-NDD is predominantly found in females who carry de novo variants in DDX3X. However, hemizygous pathogenic DDX3X variants have been also found in males who inherited their variants from unaffected mothers. To date, more than 200 patients have been reported in the literature. Here, we describe 34 new patients with a variant in DDX3X and reviewed 200 additional patients previously reported in the literature. This article describes 34 additional patients to those already reported, contributing with 25 novel variants and a deep phenotypic characterization. A clinical review of our cohort of DDX3X-NDD patients is performed comparing them to those previously published.

Human radiation for medicine, spiritism and hypnosis in Argentina: scientific controversies around vital radiations (1880-1930).

In the mid-nineteenth century, magnetic theories penetrated other recognized medical practices in Argentina in order to rationalize their procedures, in a culture that accepted and validated magnetism as a positive science. At the start of the twentieth century, mesmerists created a society, published books and journals, and carried out a large welfare programme; there were public lectures, and magnetic treatment for spiritualists and the general public, emphasizing the therapeutic properties of mesmerism. Magnetologists/mesmerists measured vital radiation and built devices using sensitive objects as 'physical' evidence of it. There was an interest in acquiring and using artefacts to measure human radiation useful in medicine. Magnetic practices survived until the end of the 1920s, when they lost importance.

Adult experiences in Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth and epigenetic disorder caused by changes on chromosome 11p15. The primary features requiring management in childhood include macroglossia, omphalocele, lateralized overgrowth, hyperinsulinism, and embryonal tumors. Management guidelines have not been developed for adults with BWS and there have been few studies to assess the clinical needs of these patients. Furthermore, there have been few studies on the psychosocial implications of BWS in children or adults. Here, we present a descriptive summary of data gathered from two separate adult BWS cohorts. The first, a patient-based survey cohort, includes self-reported health information and recollections about BWS experiences, while the second provides results of a medical record-based assessment from patients in an overgrowth registry. Results highlight the clinical features and medical issues affecting two large independent cohorts of adults with BWS while noting similarities. Open-ended questions asked of the survey cohort yielded themes to guide future qualitative studies. Finally, the study demonstrated the reliability of patient-reported data and the utility of international partnerships in this context.

Lamb-Shaffer syndrome: 20 Spanish patients and literature review expands the view of neurodevelopmental disorders caused by SOX5 haploinsufficiency.

Lamb-Shaffer Syndrome (LSS; OMIM #616803; ORPHA #313892; ORPHA #313884) is an infrequent genetic disorder that affects multiple aspects of human development especially those related to the development of the nervous system. LSS is caused by variants in the SOX5 gene. At the molecular level, SOX5 gene encodes for a transcription factor containing a High Mobility Group (HMG) DNA-Binding domain with relevant functions in brain development in different vertebrate species. Clinical features of Lamb-Shaffer syndrome may include intellectual disability, delayed speech and language development, attention deficits, hyperactivity, autism spectrum disorder, visual problems and seizures. Additionally, patients with the syndrome may present distinct facial dimorphism such as a wide mouth with full lips, small chin, broad nasal bridge, and deep-set eyes. Other physical features that have been reported in some patients include short stature, scoliosis, and joint hypermobility. Here, we report the clinical and molecular characterization of a Spanish LSS cohort of new 20 patients and review all the patients published so far which amount for 111 patients. The most frequent features included developmental delay, intellectual disability, visual problems, poor speech development and facial dysmorphic features. Strikingly, pain insensitivity and hypermetropia seems to be more frequent than previously reported, based on the frequency seen in the Spanish cohort. Eighty-three variants have been reported so far, single nucleotide variants (SNV) and copy number variants represent 47% and 53%, respectively, from the total of variants reported. Similarly to previous reports, the majority of the SNVs variants of the novel patients reported herein fall in the HMG domain of the protein. However, new variants, affecting other functional domains, were also detected. In conclusion, LLS is a rare genetic disorder mostly characterized by a wide range of developmental and neurological symptoms. Early diagnosis would allow to start of care programs, clinical follow up, prospective studies and appropriate genetic counseling, to promote clinical and social improvement to have profound lifelong benefits for patients and their families. Further research is needed to better understand the underlying mechanisms of the syndrome related to SOX5 haploinsufficiency.

Chiral Hypervalent Iodines: Active Players in Asymmetric Synthesis.

Asymmetric organocatalytic oxidations have been witnessed to an impressive development in the last years thanks to the establishment of important chiral hypervalent iodines(III/V). Many different approaches involving both stoichiometric and catalytic versions have provided a fundamental advance in this area within asymmetric synthesis. The easily handing, nontoxic, mild, environmentally friendly (green oxidants), and high stability that are features of these reagents have been applied to many reactions and also have allowed exploring further unprecedented enantioselective transformations. The intention of the present review is thus to highlight as a whole the many approaches utilized up to date to prepare chiral iodines(III/V), as well as their reactivity in a comprehensive manner.

Stereoselective Diboration of Spirocyclobutenes: A Platform for the Synthesis of Spirocycles with Orthogonal Exit Vectors.

The diastereo- and enantioselective diboration of spirocyclobutenes provides a platform for the rapid preparation of a wide variety of chiral spirocyclic building blocks. The chemoselective functionalization of the carbon-boron bond in the products, including a stereospecific sp3 -sp2 Suzuki-Miyaura cross-coupling reaction, provides a powerful tool to control the directionality and the nature of the exit vectors in the spirocyclic framework.

Copper, Boron and Vinyl Epoxides: from 1,4-Diols to Cyclopropylboronates.

Herein we describe the reactivity found between vinyl epoxides and catalytically generated copper-boryl complexes. By tuning the substituents of the alkene and/or the reaction conditions, 1,4-diols, allylic alcohols or cyclopropylboronates can be prepared. The stereochemical information of the vinyl epoxide is transferred to the products with high levels of stereocontrol.

Negative Experiences in Childhood, Parental Style, and Resilience Among People Reporting Paranormal Experiences.

There are relatively few studies examining the parental style, childhood trauma, and paranormal experiences/beliefs; therefore, the aim of this study is to measure the dominant parental style of those who have experienced paranormal events and their correlation with negative events in childhood and resilience. Four questionnaires were administered to 644 participants. The results showed high frequency of experiences such as sense of presence, premonitory dreams, telepathy, mystical experiences, apparitions, and out-of-body experiences, among others. The results confirmed three hypotheses that predict a positive and significant correlation between the paranormal experiences in adult life and negative experiences in childhood, such as abuse and neglect. One possible interpretation is that "flexible" parental style is the more permissive ones (greater openness and sensitivity to capture alternative realities), in contrast to "rigid" parental style (whose perspectives generate restrictions to capitalize on the unconventional experiences of their children).

Stereospecific Synthesis of α-Hydroxy-Cyclopropylboronates from Allylic Epoxides.

Herein, we report a catalytic and stereospecific method for the preparation of enantioenriched α-hydroxy cyclopropylboronates with control in four contiguous stereocenters. The reaction involves the borylation of readily available allylic epoxides using an inexpensive Cu(I) salt and a commercially available phosphine ligand. High diastereocontrol is achieved and different diastereomers can be selectively prepared. Functionalization of the carbon-boron bond provides access to different enantiomerically enriched trisubstituted cyclopropanes from a common intermediate.

Stereoselective Traceless Borylation-Allenation of Propargylic Epoxides: Dual Role of the Copper Catalyst.

Chiral α-allenols are prepared with high diastereocontrol through an unprecedented and spontaneous ß-oxygen elimination of an α-epoxy vinyl boronate. Stochiometric experiments and DFT calculations support a dual role of the copper catalyst, which orchestrates the hydroboration and the syn-elimination step.

Mild Aliphatic and Benzylic Hydrocarbon C-H Bond Chlorination Using Trichloroisocyanuric Acid.

We present the controlled monochlorination of aliphatic and benzylic hydrocarbons with only 1 equiv of substrate at 25-30 °C using N-hydroxyphthalimide (NHPI) as radical initiator and commercially available trichloroisocyanuric acid (TCCA) as the chlorine source. Catalytic amounts of CBr4 reduced the reaction times considerably due to the formation of chain-carrying ·CBr3 radicals. Benzylic C-H chlorination affords moderate to good yields for arenes carrying electron-withdrawing (50-85%) or weakly electron-donating groups (31-73%); cyclic aliphatic substrates provide low yields (24-38%). The products could be synthesized on a gram scale followed by simple purification via distillation. We report the first direct side-chain chlorination of 3-methylbenzoate affording methyl 3-(chloromethyl)benzoate, which is an important building block for the synthesis of vasodilator taprostene.

Enantioselective Synthesis of Cyclobutylboronates via a Copper-Catalyzed Desymmetrization Approach.

The first catalytic enantioselective synthesis of cyclobutylboronates, by using a chiral copper(I) complex, is reported. A broad variety of cyclobutanes have been prepared with consistently high levels of diastereo- and enantiocontrol. Moreover, this method constitutes the first report of an enantioselective desymmetrization of meso-cyclobutenes to prepare chiral cyclobutanes.

Copper-catalyzed diastereo- and enantioselective desymmetrization of cyclopropenes: synthesis of cyclopropylboronates.

A novel Cu-catalyzed diastereo- and enantioselective desymmetrization of cyclopropenes to afford nonracemic cyclopropylboronates is described. Trapping the cyclopropylcopper intermediate with electrophilic amines allows for the synthesis of cyclopropylaminoboronic esters and demonstrates the potential of the approach for the synthesis of functionalized cyclopropanes.

Control of the dual reactivity (iminium-dienamine) of ß-arylmethyl α,ß-unsaturated aldehydes in organocatalytic 1,3-dipolar cycloadditions with N-benzoyl C,N-cyclic azomethine imines.

1,3-Dipolar cycloadditions of C,N-cyclic azomethine imines with α,ß-unsaturated aldehydes can be performed with complete control of the regio-, exo-, and enantioselectivity under aminocatalytic conditions. The so far never studied competence of the iminium-dienamine reactivity inherent to ß-alkyl α,ß-unsaturated aldehydes was studied, which was possible by allowing achievement of complete control of the chemoselectivity in reactions of the ß-arylmethyl derivatives with azomethine imines by using different additives and organocatalysts, whose role has been rationalized by DFT calculations and chemical proofs. Thus, it has been possible to selectively obtain the pyrazolidines resulting from both the attack to the C2-C3 (via iminium) and the C3-C4 (via dienamine) bonds at the starting enals, which can be used as precursors of interesting tetrahydroisoquinolinic compounds.

Asymmetric nucleophilic monofluorobenzylation of allyl and propargyl halides mediated by a remote sulfinyl group: synthesis of homoallylic and homopropargylic fluorides.

Fluorinated 2-(p-tolylsulfinyl)benzyl carbanions react with allyl and propargyl halides in a highly stereoselective way, providing homoallylic and homopropargylic fluorides, respectively, with high optical purity. Theoretical calculations found transition states for these transformations whose relative stabilities are consistent with the experimentally observed stereoselectivity.

Highly enantioselective construction of tricyclic derivatives by the desymmetrization of cyclohexadienones.

The asymmetric synthesis of tricyclic compounds by the desymmetrization of cyclohexadienones is presented. The reaction tolerated a large variety of substituents at different positions of the cyclohexadienone, and heterocyclic rings of different sizes were accessible. Density functional theory calculations showed that the reaction proceeds through an asynchronous [4+2] cycloaddition.

[Multiple endocrine neoplasia and very early onset inflammatory bowel disease. An unexpected association]. / Neoplasia endócrina múltiple y enfermedad inflamatoria intestinal de inicio muy temprano. Una asociación inesperada.

Very early onset inflammatory bowel disease (VEOIBD) is a rare entity in pediatrics. Its association with primary immunodeficiencies of monogenic origin is known. We present the case of a patient diagnosed with VEOIBD who underwent massive paralleled exome sequencing. The result of the study showed a pathogenic variant in the RET proto-oncogene, associated with multiple endocrine neoplasia type 2A disease. There are no previous reports of association of RET proto-oncogene variants with VEOIBD. The presence of these two clinical entities cannot be attributed to a single genetic cause.

La enfermedad inflamatoria intestinal de inicio muy temprano (VEOIBD) es una entidad rara en pediatría. Es conocida su asociación con inmunodeficiencias primarias de origen monogénico. Presentamos el caso de una paciente con diagnóstico de VEOIBD a quien se le realizó una secuenciación masiva del exoma. El resultado del estudio permitió identificar una variante patogénica en el proto oncogen RET, asociada con enfermedad neoplasia endocrina múltiple tipo 2A. No hay reportes de asociación de variantes en el proto oncogen RET con VEOIBD. No se puede adjudicar la presencia de estas dos entidades clínicas a una única causa genética.

Chiral hypervalent iodine reagents: synthesis and reactivity.

Chiral hypervalent iodine chemistry has been steadily increasing in importance in recent years. This review catalogues enantioselective transformations triggered by chiral hypervalent iodine(III/V) reagents, in stoichiometric or catalytic quantities, highlighting the different reactivities in terms of yield and enantioselectivity. Moreover, the synthesis of the most remarkable and successful catalysts has been illustrated in detail.

Mucin-secreting clear cell renal cell carcinoma. A rare variant of conventional renal cell carcinoma.

We report herein one case of conventional renal cell carcinoma (RCC) producing extensive extracellular mucinous secretion in a 71-year-old man. To the best of our knowledge, the presence of mucinous secretion in this tumor has not been documented. Mucin production, despite its low frequency, can be considered an additional feature of conventional RCC. Therefore, clear cell RCC should be added to the list of parenchymal renal tumors that can show significant mucin secretion; and it should be included in the inventory of morphologic variations of this tumor, which may cause diagnostic difficulties. It is of primary importance to distinguish mucin-secreting clear cell RCC from the metastasis of a mucin-secreting tumor to conventional RCC. Presence of mucin in a clear cell carcinoma does not exclude a renal origin.

Lobular Endocervical Glandular Hyperplasia, a mimicker and potential pitfall for HPV-independent well differentiated Gastric-type Endocervical Adenocarcinoma: Case report and literature review focusing on histology, immunophenotype, and molecular findings.

Lobular glandular endocervical hyperplasia is an uncommon benign entity within the spectrum of gastric-type endocervical lesions. We report a case of a 48-year-old woman who presented with a palpable mass and watery vaginal discharge. Ultrasound revealed an 8 cm × 4 cm × 3 cm multicystic mass affecting the cervix, and hysterectomy was performed. The well-delimited multicystic, mucinous mass distorted the entire cervix. Microscopically, endocervical glandular proliferation with a lobular architecture was observed. The glands were lined with a single layer of tall, mucin-rich, columnar cells with basal and bland nuclei. The lesion was positive for MUC6 marker and hormonal receptors were negative, while P53 expression was normal. Three years later, the patient remained disease free. Here, we discuss the differential diagnosis between lobular glandular endocervical hyperplasia and similar conditions, particularly gastric-type endocervical adenocarcinoma, and review the literature focusing on the molecular pathways underlying gastric-type endocervical lesions. This case highlights the importance of accurate diagnosis to ensure favorable outcomes.