Bringing Machine-Learning Enhanced Quantum Chemistry and Microwave Spectroscopy to Conformational Landscape Exploration: the Paradigmatic Case of 4-Fluoro-Threonine.

A combined experimental and theoretical study has been carried out on 4-fluoro-threonine, the only naturally occurring fluorinated amino acid. Fluorination of the methyl group significantly increases the conformational complexity with respect to the parent amino acid threonine. The conformational landscape has been characterized in great detail, with special attention given to the inter-conversion pathways between different conformers. This led to the identification of 13 stable low-energy minima. The equilibrium population of so many conformers produces a very complicated and congested rotational spectrum that could be assigned through a strategy that combines several levels of quantum chemical calculations with the principles of machine learning. Twelve conformers out of 13 could be experimentally characterized. The results obtained from the analysis of the intra-molecular interactions can be exploited to accurately model fluorine-substitution effects in biomolecules.

Unveiling the Shape of N-Acetylgalactosamine: A Cancer-Associated Sugar Derivative.

In the present work, we report the first rotational study of N-acetylgalactosamine, a cancer-associated sugar derivative, by means of high-resolution rotational spectroscopy. Two different conformers have been conclusively characterized using broadband Fourier transform microwave spectroscopy coupled with a laser ablation vaporization system. Additionally, we performed a comprehensive analysis of the intramolecular interactions that govern these structures, which allowed us to both characterize the existence of intramolecular hydrogen bond networks that drive the intrinsic conformation panorama of N-acetylgalactosamine and further rationalize the biological role of this aminosugar derivative as part of the Tn antigen.

Gas-Phase Conformational Map of the Amino Acid Isovaline.

Four conformers of the non-proteinogenic α-amino acid isovaline, vaporized by laser ablation, are characterized by Fourier-transform microwave techniques in a supersonic expansion. The comparison between the experimental rotational and 14 N nuclear quadrupole coupling constants and the ab initio calculated ones provides conclusive evidence for the identification of the conformers. The most stable species is stabilized by an N-H⋅⋅⋅O =C intramolecular hydrogen bond and a cis-COOH interaction, whereas the higher-energy conformers exhibit an N⋅⋅⋅H-O intramolecular hydrogen bond and trans-COOH, as in other aliphatic amino acids. The spectroscopic data herein reported can be used for the astrophysical purpose in a possible detection of isovaline in space.

A rotational study of the AlaAla dipeptide.

Herein, we present the first rotational study of the AlaAla dipeptide, brought into the gas phase by laser ablation. Two different structures have been unveiled in the isolated environment of a supersonic expansion by Fourier transform microwave spectroscopy. These structures have been identified through their rotational and 14N quadrupole coupling constants. The flexibility of the -NH2 and -COOH ends allows the formation of strong intramolecular interactions giving rise to five- and seven-membered ring configurations.

Elucidating the multiple structures of pipecolic acid by rotational spectroscopy.

The complex conformational space of the non-proteinogenic cyclic amino acid pipecolic acid has been explored in the gas phase for the first time. Solid pipecolic acid samples were vaporized by laser ablation and expanded in a supersonic jet where the rotational spectral signatures owing to nine different conformers were observed by Fourier transform microwave spectroscopy. All species were identified by comparison of the experimental rotational and nuclear quadrupole coupling constants with those predicted theoretically. Observation of type-III conformers, leading to a difference when compared against the conformational behavior of the analog amino acid proline, has been interpreted by an increment in steric hindrance when increasing the number of carbons present in the ring.

The effect of N-methylation on the conformational landscape of alanine: the case of N-methyl-l-alanine.

The non-proteinogenic amino acid N-methyl-l-alanine has been brought into the gas phase using laser ablation techniques and studied by high resolution chirped pulse and molecular-beam Fourier transform microwave spectroscopies coupled to supersonic expansion. Four conformers showing the three types of hydrogen bond interactions I (NHO[double bond, length as m-dash]C), II (OHN) and III (N-HO-H) have been unambiguously identified, based on the comparison of the experimental rotational and 14N nuclear quadrupole constants with the calculated ab initio values. The observation of a type III conformer evidences the role of methyl groups in both sides to impose the steric hindrance, precluding the relaxation from type III to type I conformers and explains the responsibility for the unique conformational landscape observed in the case of NMA.

The role of amino acid side chains in stabilizing dipeptides: the laser ablation Fourier transform microwave spectrum of Ac-Val-NH2.

The steric effects imposed by the isopropyl group of valine in the conformational stabilization of the capped dipeptide N-acetyl-l-valinamide (Ac-Val-NH2) have been studied by laser ablation molecular beam Fourier transform microwave (LA-MB-FTMW) spectroscopy. The rotational and quadrupole coupling constants of the two 14N nuclei determined in this work show that this dipeptide exists as a mixture of C7 and C5 conformers in the supersonic expansion. The conformers are stabilized by a C[double bond, length as m-dash]OH-N intramolecular hydrogen bond closing a seven- or a five-membered ring, respectively. The observation of both conformers is in good agreement with previous results on the related dipeptides containing different residues, confirming that the polarity/non-polarity of the side chains of the amino acid is responsible for the conformational locking/unlocking. The voluminous isopropyl group is not able to prevent the less stable C5 conformer from forming but it destabilizes the C[double bond, length as m-dash]OH-N interaction.

Pediatric and neonatal transport in Spain, Portugal and Latin America. / Transporte pediátrico y neonatal en España, Portugal y Latinoamérica.

OBJECTIVE: To study the organization of inter-hospital transport of pediatric and neonatal patients in Spain, Portugal and Latin America. DESIGN: An observational study was performed. An on-line survey was sent by email including questions about characteristics of national, regional and local health transport systems, vehicles, material, and composition of the transport team and their training. SETTING: Hospital pediatric healthcare professionals treating children in Spain, Portugal and Latin America RESULTS: A total of 117 surveys from 15 countries were analyzed. Of them, 55 (47%) come from 15 regions of Spain and the rest from Portugal and 13 Latin American countries. The inter-hospital transport of pediatric patients is unified only in the Spanish regions of Baleares and Cataluña and in Portugal. Chile has a mixed unified transport system for pediatric and adult patients. Only 51.4% of responders have an educational program for the transport personnel, and only in 36.4% of them the educational program is specific for pediatric patients. In Spain and Portugal the transport is executed mostly by public entities, while in Latin America public and private systems coexist. Specific pediatric equipment is more frequent in the transport teams in the Iberian Peninsula than in Latin American teams. The specific pediatric transport training is less frequent for teams in Latin America than on Spain and Portugal. CONCLUSIONS: There is a great variation in the organization of children transport in each country and region. Most of countries and cities do not have unified and specific teams of pediatric transport, with pediatric qualified personnel and specific material.

Composite modified Luneburg model of human eye lens.

A new lens model based on the gradient-index Luneburg lens and composed of two oblate half spheroids of different curvatures is presented. The spherically symmetric Luneburg lens is modified to create continuous isoindicial contours and to incorporate curvatures that are similar to those found in a human lens. The imaging capabilities of the model and the changes in the gradient index profile are tested for five object distances, for a fixed geometry and for a fixed image distance. The central refractive index decreases with decreasing object distance. This indicates that in order to focus at the same image distance as is required in the eye, a decrease in refractive power is needed for rays from closer objects that meet the lens surface at steeper angles compared to rays from more distant objects. This ensures a highly focused image with no spherical aberration.

IgM monoclonal gammopathy-associated neuropathies with different IgM specificity.

BACKGROUND AND PURPOSE: Antibodies directed against myelin-associated glycoprotein (MAG) are believed to be the most frequent biologic marker of the neuropathies associated with IgM monoclonal gammopathy of undetermined significance (MGUS). The objective of this study was to examine the prevalence of antiganglioside and/or sulfatide-positive patients and their clinical findings, including therapeutic response, compared to anti-MAG-positive or seronegative patients. METHODS: We prospectively followed 46 patients with MGUS who were diagnosed in our tertiary referral centers for polyneuropathy since 1997. All patients underwent nerve conduction studies and were tested for anti-MAG, gangliosides, and sulfatide antibodies. All the anagraphic and clinical data (including symptoms, disability scale, therapy, secondary malignancy development) were recorded in a database and compared between three patients' groups (anti-MAG-positive; antiganglioside/sulfatide-positive; no reactivity). RESULTS: Anti-MAG reactivity was present in 17 (37%) patients; other 17 patients (37%) had antiganglioside/sulfatide reactivity and 12 (26%) had no reactivity. Patients with antiganglioside/sulfatide positivity, although heterogeneous by a clinical and neurophysiological point of view, had the most severe neuropathic manifestations and a higher disability score at nadir (P < 0.001). These patients had a better response to both intravenous immunoglobulin therapy and rituximab. CONCLUSIONS: Our results suggest that antiganglioside/sulfatide-positive patients form a relevant portion of patients with MGUS-associated polyneuropathy seen in tertiary care centers and should be considered in future studies on treatment response.

Immunosuppressive treatment in refractory chronic inflammatory demyelinating polyradiculoneuropathy. A nationwide retrospective analysis.

BACKGROUND AND PURPOSE: There are other options open to patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who are non-responders to conventional treatment, including immunosuppressive and immunomodulatory agents (IA). The aim of this study was to assess whether the use of IA is able to increase the number of responders. METHODS: Clinical and electrophysiological data of patients with refractory CIDP, followed at 10 Italian centres, were collected, and the clinical outcome (Rankin Scale) and drug side effects (SE) for the different therapies were analysed. RESULTS: A total of 110 patients were included. These patients underwent 158 different therapeutic procedures with IA. Seventy-seven patients were treated with azathioprine, 18 rituximab, 13 cyclophosphamide, 12 mycophenolate mofetil, 12 cyclosporine, 12 methotrexate, 11 interferon-alpha and three interferon beta-1a. The percentage of patients who responded to azathioprine (27%) was comparable to the percentage of responders to other therapies, after the exclusion of interferon beta-1a that was not effective in any of the three patients treated. The percentage of SE ranges from 8% (methotrexate) to 50% (cyclosporine). CONCLUSIONS: One-fourth of patients, refractory to conventional treatment, showed an improvement in their disability with IA. Methotrexate had the lowest SE; cyclosporine was associated with severe SE and often led to drug discontinuation.

Rapid probe of the nicotine spectra by high-resolution rotational spectroscopy.

Nicotine has been investigated in the gas phase and two conformational forms were characterized through their rotational spectra. Two spectroscopic techniques have been used to obtain the spectra: a new design of broadband Fourier transform microwave (FTMW) spectroscopy with an in-phase/quadrature-phase-modulation passage-acquired-coherence technique (IMPACT) and narrowband FTMW spectroscopy with coaxially oriented beam-resonator arrangement (COBRA). The rotational, centrifugal distortion and hyperfine quadrupole coupling constants of two conformers of nicotine have been determined and found to be in N-methyl trans configurations with the pyridine and pyrrolidine rings perpendicular to one another. The quadrupole hyperfine structure originated by two (14)N nuclei has been completely resolved for both conformers and used for their unambiguous identification.

Rotational spectroscopic study and astronomical search for propiolamide in Sgr B2(N).

CONTEXT: For all the amides detected in the interstellar medium (ISM), the corresponding nitriles or isonitriles have also been detected in the ISM, some of which have relatively high abundances. Among the abundant nitriles for which the corresponding amide has not yet been detected is cyanoacetylene (HCCCN), whose amide counterpart is propiolamide (HCCC(O)NH2). AIMS: With the aim of supporting searches for this amide in the ISM, we provide a complete rotational study of propiolamide from 6 GHz to 440 GHz. METHODS: Time-domain Fourier transform microwave (FTMW) spectroscopy under supersonic expansion conditions between 6 GHz and 18 GHz was used to accurately measure and analyze ground-state rotational transitions with resolved hyperfine structure arising from nuclear quadrupole coupling interactions of the 14N nucleus. We combined this technique with the frequency-domain room-temperature millimeter wave and submillimeter wave spectroscopies from 75 GHz to 440 GHz in order to record and assign the rotational spectra in the ground state and in the low-lying excited vibrational states. We used the ReMoCA spectral line survey performed with the Atacama Large Millimeter/submillimeter Array toward the star-forming region Sgr B2(N) to search for propiolamide. RESULTS: We identified and measured more than 5500 distinct frequency lines of propiolamide in the laboratory. These lines were fitted using an effective semi-rigid rotor Hamiltonian with nuclear quadrupole coupling interactions taken into consideration. We obtained accurate sets of spectroscopic parameters for the ground state and the three low-lying excited vibrational states. We report the nondetection of propiolamide toward the hot cores Sgr B2(N1S) and Sgr B2(N2). We find that propiolamide is at least 50 and 13 times less abundant than acetamide in Sgr B2(N1S) and Sgr B2(N2), respectively, indicating that the abundance difference between both amides is more pronounced by at least a factor of 8 and 2, respectively, than for their corresponding nitriles. CONCLUSIONS: Although propiolamide has yet to be included in astrochemical modeling networks, the observed upper limit to the ratio of propiolamide to acetamide seems consistent with the ratios of related species as determined from past simulations. The comprehensive spectroscopic data presented in this paper will aid future astronomical searches.

A nationwide retrospective analysis on the effect of immune therapies in patients with chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND AND PURPOSE: The guidelines for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) therapy suggest to use immunoglobulins (IVIg) and steroid as first-line therapies. Patients who do not respond to one of the two drugs should be switched to the other drug. We collected therapeutic outcome data in patients followed at 11 centres in order to document the clinical practice in Italy. METHODS: Clinical and electrophysiological data of patients with CIDP were entered into a central database. The clinical outcome (Rankin Scale) and drug side effects (SE) for first- and second-line therapies were recorded. RESULTS: A total of 267 patients were included. The percentage of responders (R) to first-line therapy [steroid or IVIg or plasma exchange (PE)] was 69%; this number increased to 81% when patients who switched to different therapies were included. Overall, the percentage of R to IVIg was similar to R to steroids (P = 0.07) and higher than R to PE (P < 0.001). Of the main therapies, PE frequently caused SE (19%), followed by steroids (12.5%) and IVIg (4%). CONCLUSIONS: Switching between traditional therapies increases the number of responder patients. IVIg was confirmed to be a therapy with low SE.

[Surgical repair of a thigh muscle herniation with synthetic mesh].

We present the case of a 14-year-old female patient with a big muscle hernia in the thigh after extraction of a fascia lata strip to repair bilateral congenital ptosis. After three weeks, a progressive emergence of a large bulge between the two thigh incisions in a standing position was noticeable, with local discomfort, dull pain on exertion and unsightly ap-pearance that worried the patient. On surgery three months later, a large tear in the fascia lata and muscle herniation was revealed. The fascial tear was debrided and a synthetic mesh was applied. Ten years later, the patient confirmed her continued asymptomatic condition. Muscular hernia of significant size as a consequence of a fascia lata strip harvest is extremely infrequent in adoles-cents. Surgical repair of big muscular hernias in extremities with synthetic mesh, usually used in groin hernia repair, is an infrequent orthopaedic tool but is safe, easy to apply and inexpensive.

[Slipped capital femoral epiphysis in an ambulant patient with spastic cerebral palsy. A long-term evolution].

We report the case of a boy aged 13 years and 9 months, with predominantly right-sided spastic tetraparesis, who could walk with assistance, GMFCS III, phenotype consistent with adiposogenital syndrome. He presented a 4-week history of left-sided limp without pain, radiologically classified as a stable, chronic slipped capital femoral epiphysis (SCFE) with mild slippage (<30º) on the Southwick classification. In situ fixation of the hip was performed using a full-headed screw, followed by six weeks of rest. Twelve years since the intervention, the patient remains asymptomatic with no clinical or radiological changes. SCFE in patients with cerebral palsy, while highly unusual, is possible. A high level of suspicion is required for diagnosing it. We would suggest ruling out the appearance of SCFE during surveillance screening of patients with cerebral palsy, =?10 years-old, particularly in obese individuals with or without adiposogenital phenotype and limited ability to communicate verbally.

Interstellar glycolamide: A comprehensive rotational study and an astronomical search in Sgr B2(N).

CONTEXT: Glycolamide is a glycine isomer and also one of the simplest derivatives of acetamide (e.g., one hydrogen atom is replaced with a hydroxyl group), which is a known interstellar molecule. AIMS: In this context, the aim of our work is to provide direct experimental frequencies of the ground vibrational state of glycolamide in the centimeter-, millimeter- and submillimeter-wavelength regions in order to enable its identification in the interstellar medium. METHODS: We employed a battery of state-of-the-art rotational spectroscopic techniques in the frequency and time domain to measure the frequencies of glycolamide. We used the spectral line survey named Exploring Molecular Complexity with ALMA (EMoCA), which was performed toward the star forming region Sgr B2(N) with ALMA to search for glycolamide in space. We also searched for glycolamide toward Sgr B2(N) with the Effelsberg radio telescope. The astronomical spectra were analyzed under the local thermodynamic equilibrium approximation. We used the gas-grain chemical kinetics model MAGICKAL to interpret the results of the astronomical observations. RESULTS: About 1500 transitions have been newly assigned up to 460 GHz to the most stable conformer, and a precise set of spectroscopic constants was determined. Spectral features of glycolamide were then searched for in the prominent hot molecular core Sgr B2(N2). We report the nondetection of glycolamide toward this source with an abundance at least six and five times lower than that of acetamide and glycolaldehyde, respectively. Our astrochemical model suggests that glycolamide may be present in this source at a level just below the upper limit, which was derived from the EMoCA survey. We could also not detect the molecule in the region's extended molecular envelope, which was probed with the Effelsberg telescope. We find an upper limit to its column density that is similar to the column densities obtained earlier for acetamide and glycolaldehyde with the Green Bank Telescope.

Unilateral non-traumatic radiocarpal volar dislocation in a child. A long-term evolution.

We report an eight year-old female with trisomy 21 referred to our clinic for limitation of wrist mobility. The patient had been diagnosed and treated by polyarticular juvenile chronic arthritis for six months. Clinical and radiological study revealed volar radiocarpal dislocation of the left wrist. She was treated surgically by open reduction, temporary K-w fixation with six weeks of immobilization. The dislocation relapsed but the joint remained painless. One year later she had 5 masculine of dorsal flexion and 25 masculine of volar flexion and absence of pain. In spite of this situation the family said that the girl lived normal life without any limitation because of her condition, refusing further treatment. Eight years later the girl remains asymptomatic and does a normal life without limitation because of her condition. The patient and her family refused any treatment. Based in the failure of surgical treatment performed in our case we think that abstention could be the most reasonable option, mainly in the immature patients.

[Medial dislocation of the talus. Medium term evolution]. / Enucleación medial de astrágalo abierta. Evolución a medio plazo.

Fifty-seven year old patient with open medial dislocation of the left talus, with suprasyndesmotic fracture of the fibula, due to indirect traumatism. The following were carried out: washing, cleaning the talus and the soft parts, Friedrich, reduction, fixing with Kirschner needles, suture of the deltoid ligament, and osteosynthesis of the fibula. There were neither surface nor deep post-operational infections. The patient underwent six weeks of immobilisation and spent three months on discharge. Two years later there were no radiological signs of avascular necrosis. In the osseous gammagraphy carried out 18 months after the lesion, partial avascular necrosis of the talus was observed. Three years after the lesion, the patient was able to carry out a normal life, without pain in repose but with pain whilst moving, and mobility with limitation of dorsoinflection (-20 masculine). Five and a half years after the lesion, the patient presented sinking of the talar dome due to avascular necrosis, with painful symptomatology whilst moving, and tibiofibular distal diastasis, which required ankle arthrodesis.

Distal radial torus fracture in an adult. A new type of occult wrist fracture?

Torus or buckle fractures typically affect children who have suffered indirect minor wrist injuries. They are axial compression-type metaphyseal fractures of cortical and cancellous bone, which are stable and their treatment therefore consists in immobilisation of the joint for three to four weeks. We present an atypical case of distal radius torus fracture in a 19-year-old adult male, which has not been previously reported in adults and can be considered a new type of occult fracture. Knowledge of this possibility is mandatory to be able to make a differential diagnosis of wrist sprain in adults, and avoid performing superfluous complementary tests due to the persistence of pain and functional incapacity.