Dihydropyridine Reductase Deficiency: Acute Encephalopathy Related to Folinic Acid Treatment Interruption in a Girl.

We reported the case of acute encephalopathy related to colonic acid treatment interruption in a 12-year-old female child presenting to our unit with episodes of vomiting, headache, irritability, acute confusional state, seizures, and left lower limb hypotonia. Brain magnetic resonance imaging (MRI) showed signs of vasogenic and cytotoxic edema at the cerebellar level bilaterally, and lesions at the temporo-occipito-parietal right level, temporomandibular left, and right thalamic with swelling of the convolutions and reduced differentiation between white and gray matter. The patient had suspended the folinic acid treatment at least 6 months before the present admission. The relation between the clinical signs presented by the girl and folic acid deficiency was confirmed by the result of laboratory assessment and by the answer to the notable clinical improvement with the renewal of folinic acid treatment. Dihydropteridine reductase (DHPR) deficiency is a rare autosomal recessive genetic disorder caused by the quinoid dihydropteridine reductase (QDPR) gene mutations. DHPR deficiency impairs the synthesis of the tetrahydrobiopterin (BH4), an essential cofactor for the hydroxylation of the aromatic amino acids phenylalanine, tyrosine, and tryptophan. When not precociously treated, the disorder may present whit severe neurologic impairment including developmental delay/intellective disability (DD/ID), microcephaly, seizures, movement disorders, cerebral palsy, and other neurological impairments. The clinical and neuroradiologic anomalies observed in our case were unusual, with signs previously unreported in patients with folic acid deficiency. The present case shows that the clinical presentation and MRI anomalies of the cerebral folic acid deficiency may be various and unusual compared with those reported in the literature, and it confirms the usefulness of the continuation of folinic acid treatment during the course of the disorder in patients with DHPR deficiency.

On clinical findings of Bickerstaff's brainstem encephalitis in childhood.

A short review on the clinical presentation of pediatrics cases of Bickerstaff brain encephalitis emphasizing the broad clinical spectrum of the disease. Cases of pediatric Bickerstaff's brainstem encephalitis collected on three electronic medical databases (PubMed, Cochrane Library and Scopus Web of Science) are reviewed. The inclusion criteria of the cases were based on the clinical characteristics of the disorder in the pediatric age. We reviewed 20 articles on Bickerstaff's brainstem encephalitis, identifying 40 pediatric cases focused on the clinical symptoms. We saw that the prevalence was higher in male subjects, and the median age at diagnosis was 8 years. The phenotype of pediatrics patients was similar to previously published literature. We identify three cases of overlapping forms between Bickerstaff brain encephalitis and Guillain-Barré Syndrome in patients with lower limbs weakness and typical signs of Bickerstaff brain encephalitis, suggesting a combined involvement of the central and peripheral nervous system. Although there is no defined data on incidence and prevalence in the literature, Bickerstaff's brainstem encephalitis appears to be a rare disorder, especially in children. The incidence of Bickerstaff brain encephalitis and Guillain-Barré Syndrome, and Miller Fisher Syndrome has been underrated in the past, primarily due to an underestimation of the forms with a Peripheral Nervous System involvement. Bickerstaff brain encephalitis usually has a rapid and acute onset within 2-4 weeks, characterized by a typical picture of ophthalmoplegia, hyperreflexia, cerebellar symptoms as ataxia. The subsequent manifestations of hyperreflexia or consciousness disturbances as drowsiness, sleepiness, or coma, indicative of central involvement, suggest a Bickerstaff brain encephalitis clinical diagnosis.

Neonatal hyperinsulinemic hypoglycemia: case report of kabuki syndrome due to a novel KMT2D splicing-site mutation.

BACKGROUND: Persistent neonatal hypoglycemia, owing to the possibility of severe neurodevelopmental consequences, is a leading cause of neonatal care admission. Hyperinsulinemic hypoglycemia is often resistant to dextrose infusion and needs rapid diagnosis and treatment. Several congenital conditions, from single gene defects to genetic syndromes should be considered in the diagnostic approach. Kabuki syndrome type 1 (MIM# 147920) and Kabuki syndrome type 2 (MIM# 300867), can be associated with neonatal hyperinsulinemic hypoglycemia. PATIENT PRESENTATION: We report a female Italian (Sicilian) child, born preterm at 35 weeks gestation, with persistent hypoglycemia. Peculiar facial dysmorphisms, neonatal hypotonia, and cerebellar vermis hypoplasia raised suspicion of Kabuki syndrome. Hyperinsulinemic hypoglycemia was confirmed with glucagon test and whole-exome sequencing (WES) found a novel heterozygous splicing-site mutation (c.674-1G > A) in KMT2D gene. Hyperinsulinemic hypoglycemia was successfully treated with diazoxide. At 3 months corrected age for prematurity, a mild global neurodevelopmental delay, postnatal weight and occipitofrontal circumference growth failure were reported. CONCLUSIONS: Kabuki syndrome should be considered when facing neonatal persistent hypoglycemia. Diazoxide may help to improve hyperinsulinemic hypoglycemia. A multidisciplinary and individualized follow-up should be carried out for early diagnosis and treatment of severe pathological associated conditions.

Measurement of nitric oxide and assessment of airway diseases in children: an update.

INTRODUCTION: Nitric oxide (NO) is a gas synthesized by the inducible NO synthase enzyme in airway cells and it is thought to make important functions in the airway inflammation of several respiratory diseases. EVIDENCE ACQUISITION: This current study is a review of the literature from 1990 to present about NO and its use in clinical practice. The databases used were PubMed, Scopus, and Cochrane Library. EVIDENCE SYNTHESIS: At the respiratory level there are three different measurements sites of NO: nNO (nasal nitric oxide), FeNO (exhaled fraction of nitric oxide), CaNO (alveolar nitric oxide). Each of them is produced at different levels of the respiratory tract and is involved in various diseases. nNO finds its use, principally, in the allergic rhinitis in fact it can be used as a measure of therapeutic efficacy, but not for the evaluation of the severity; also in primary ciliary dyskinesia (PCD), where high levels exclude the disease, and in chronic rhinosinusitis, but it is not currently used as a diagnostic or prognostic marker. FeNO has a greatest use in bronchial asthma, particularly, it is considered a non-invasive biomarker to identify and to monitor airway inflammation but currently, there is not a consensus on the use of the FeNO in the management of asthma treatment. Finally, CaNO is the least used in clinical practice, because lack of standardization of measurement techniques. CONCLUSIONS: Nitric oxide is a sensitive indicator of the presence of airway inflammation and ciliary dysfunction, although some studies have shown varying or conflicting results.

Congenital emphysematous lung disease associated with a novel Filamin A mutation. Case report and literature review.

BACKGROUND: Progressive lung involvement in Filamin A (FLNA)-related cerebral periventricular nodular heterotopia (PVNH) has been reported in a limited number of cases. CASE PRESENTATION: We report a new pathogenic FLNA gene variant (c.7391_7403del; p.Val2464Alafs*5) in a male infant who developed progressive lung disease with emphysematous lesions and interstitial involvement. Following lobar resection, chronic respiratory failure ensued necessitating continuous mechanical ventilation and tracheostomy. Cerebral periventricular nodular heterotopia was also present. CONCLUSIONS: We report a novel variant of the FLNA gene, associated with a severe lung disorder and PNVH. The lung disorder led to respiratory failure during infancy and these pulmonary complications may be the first sign of this disorder. Early recognition with thoracic imaging is important to guide genetic testing, neuroimaging and to define optimal timing of potential therapies, such as lung transplant in progressive lung disease.

Influence of peroxisome proliferator-activated receptor-γ exon 2 and exon 6 and insulin receptor substrate (IRS)-1 Gly972Arg polymorphisms on insulin resistance and beta-cell function in southern mediterranean women with polycystic ovary syndrome.

BACKGROUND AND OBJECTIVE: The Pro12Ala (exon 2) and His447His (exon 6) polymorphisms of PPAR-γ, and Gly972Arg polymorphism of IRS-1 have been implicated in insulin resistance (IR) and adiposity. Our aim was to investigate the influence of these polymorphisms on metabolic features of polycystic ovary syndrome (PCOS). METHODS: Fifty-three PCOS women and 26 control women underwent a clinical and biochemical evaluation, including a 75-g oral glucose tolerance test. Insulin secretion and insulin sensitivity indices were calculated. RESULTS: Frequencies of PPAR-γ polymorphisms did not differ from those predicted by the Hardy-Weinberg equilibrium. Instead, the IRS-1 Gly972Arg allele was significantly more frequent in the PCOS group compared to controls. The most frequent allelic combinations were IRS1+/exon2-/exon6- (which prevailed in PCOS) and IRS-1-/exon2-/exon6- (which prevailed in controls). Among PCOS women, compared with the wild type patients, carriers of the Gly972Arg IRS-1 allele had lower E2 levels, while carriers of the Pro12Ala PPAR-γ (exon 2) allele had lower free testosterone levels. No other significant relationships were noted. When compared with the wild type, in PCOS group IR and beta-cell function were: (i) trendwise greater in carriers of the variant IRS-1 allele; (ii) trendwise lower in carriers of the variant PPAR-γ exon 6 allele; (iii) significantly lower in carriers of the variant PPAR-γ exon 2 allele. CONCLUSIONS: Our data support the protective influence of PPAR-γ-exon 2 and exon 6 variants on IR and beta cell function, whereas IRS-1 polymorphism is associated with an unfavorable metabolic profile. However, these associations do not fully explain the high metabolic risk associated with PCOS.

Preliminary Experience with a Novel System of Facet Fixation to Treat Patients with Lumbar Degenerative Disease. A New Perspective in Minimally Invasive Spine Surgery?

PURPOSE: We report our experience with a novel surgical device for the treatment of lumbar degenerative microinstability. Facet Wedge (DePuy Synthes, Raynham, Massachusetts, United States) is a novel technique of intra-articular lumbar facet fixation that provides a minimally invasive alternative to standard posterior fixation. MATERIALS AND METHODS: From November 2014 to July 2015, 38 patients underwent single-level Facet Wedge implantation. The main surgical indications included herniated disk (18 patients), spinal canal and foraminal stenosis (14 patients), and Meyerding grade I degenerative spondylolisthesis (6 patients). All the patients showed radiologic signs of microinstability: hyperintensity in both facet joints (facet fluid signal) in T2-weighted magnetic resonance imaging and a black disk as a sign of degenerative disease. No slippage was evident at dynamic radiograph. After a period of conservative treatment (minimum of 6 months), surgery was performed. All patients' follow-up lasted over at least 12 months. RESULTS: The low back visual analog scale score decreased significantly after surgery (from an average of 8.2 to 3.1 at final follow-up). Postoperatively, the Oswestry Disability Index showed a significant reduction (14.7 on average). No slippage or signs of adjacent segment degeneration was detected in neuroimaging follow-up. CONCLUSION: Facet Wedge allows facet fixation in lumbar degenerative microinstability. To the best of our knowledge, this is the first clinical series reported in the literature on this novel device.

An LP1 analogue, selective MOR agonist with a peculiar pharmacological profile, used to scrutiny the ligand binding domain.

The hypothesis that central analgesia with reduced side effects is obtainable by occupying an 'allosteric' site in the MOR ligand binding domain requires the development of new ligands with peculiar pharmacological profile to be used as tools. New benzomorphan derivatives, analogues of LP1, a multitarget MOR agonist/DOR antagonist, were designed to examine in depth MOR ligand binding domain. Compound 5, bearing a diphenylic N-substituent on the benzomorphan nucleus, showed an affinity (Kiµ=0.5±0.2nM) comparable to that of LP1 and a better selectivity versus DOR and KOR. It elicits antinociceptive effects in ex vivo (GPI) and in vivo. This new compound engages receptor amino acidic residues not reached by LP1 and by other established MOR ligands. Molecular modeling studies, conducted on 5 and on several reference compounds, allowed us to propose possible residues in the MOR ligand binding domain essential for their interactions with 'orthosteric' and 'allosteric' binding sites.

Hypothyroid myopathy: A peculiar clinical presentation of thyroid failure. Review of the literature.

Abnormalities in thyroid function are common endocrine disorders that affect 5-10 % of the general population, with hypothyroidism occurring more frequently than hyperthyroidism. Clinical symptoms and signs are often nonspecific, particularly in hypothyroidism. Muscular symptoms (stiffness, myalgias, cramps, easy fatigability) are mentioned by the majority of patients with frank hypothyroidism. Often underestimated is the fact that muscle symptoms may represent the predominant or the only clinical manifestation of hypothyroidism, raising the issue of a differential diagnosis with other causes of myopathy, which sometimes can be difficult. Elevated serum creatine kinase, which not necessarily correlates with the severity of the myopathic symptoms, is certainly suggestive of muscle impairment, though it does not explain the cause. Rare muscular manifestations, associated with hypothyroidism, are rhabdomyolysis, acute compartment syndrome, Hoffman's syndrome and Kocher-Debré-Sémélaigne syndrome. Though the pathogenesis of hypothyroid myopathy is not entirely known, proposed mechanisms include altered glycogenolytic and oxidative metabolism, altered expression of contractile proteins, and neuro-mediated damage. Correlation studies of haplotype, muscle gene expression and protein characterization, could help understanding the pathophysiological mechanisms of this myopathic presentation of hypothyroidism.

Sequential boost in neoadjuvant irradiation for T3N0-1 rectal cancer: long-term results from a single-center experience.

PURPOSE: To evaluate the influence of radiation dose on tumor regression grade (TRG) and sphincter preservation rate in a series of cT3N0-1 rectal cancer patients treated with neoadjuvant chemoradiotherapy (CT-RT) with or without a sequential radiation boost. MATERIALS AND METHODS: Between May 2002 and September 2013, 116 cases were eligible for retrospective evaluation. Radiotherapy was delivered for a total dose of 45 Gy (no boost arm) or 50.4 Gy (boost arm). TRG was evaluated with the Dworak scale. RESULTS: Median follow-up was 62 months (range, 12-138 months). The 5-year overall survival and local control rates were 72% and 93%, respectively. Fifty-five patients (47%) were treated with a sequential radiation boost and 61 (53%) without a boost. Eighty patients (72%) presented T3N0 disease and 32 (28%) T3N1 disease. Concomitant capecitabine was administered in 92 cases (79%) and intravenous 5-fluorouracil in 24 cases (21%). Sphincter preservation was performed in 82% of patients in the boost arm and 66% in the no-boost arm. A higher TRG was related to a longer interval between neoadjuvant treatment and surgery (p<0.001). The probability of a TRG ≥2 was 2.5 times higher in the boost arm. A gain in local control, estimated at 4% during the first 3 years after CT-RT, favored the boost arm. CONCLUSIONS: The long-term results from our single-center experience confirm literature data on the role of a sequential boost in tumor response after neoadjuvant CT-RT in a series of cT3N0-1 rectal cancer patients.

Moderate hypofractionation and simultaneous integrated boost by helical tomotherapy in prostate cancer: monoinstitutional report of acute tolerability assessment with different toxicity scales.

INTRODUCTION: Based on radiobiology evidence, hypofractionated radiotherapy has the potential of improving treatment outcome in prostate cancer patients. In this study, we evaluated the safety, in terms of acutetoxicity, of using moderate hypofractionated radiotherapy delivered with Helical Tomotherapy (HT) to treat prostate cancer patients. MATERIALS AND METHODS: Between December 2012 and April 2014, 42 consecutive patients were treated with hypofractionated radiotherapy using HT. All patients received 70 Gy in 28 fractions to PTV1, which included the prostate. In the intermediate risk group, 61.6 Gy were delivered to PTV2, which included the seminal vesicles. In high risk patients, the pelvic nodes were added (PTV3) and received 50.4 Gy. Acute toxicity was recorded prospectively with RTOG and Common Terminology Criteria for Adverse Events 3.0, retrospectively with CTCAE 4.0. Expanded Prostate Cancer Index Composite (EPIC) was measured at baseline and 3 months after end of treatment, to investigate health related quality of life with regards to bladder and gastrointestinal function. RESULTS: Acute toxicity was acceptable, independently from the system used to score side effects. Moderate genitourinary toxicity was more frequent than gastrointestinal toxicity. No correlation between acute side effects and patients' characteristics or physical dose parameters was registered. EPIC evaluation showed a negligible difference in urinary and bowel function post-treatment, that did not reach statistical significance. CONCLUSIONS: Our experience confirms the safety of moderate hypofractionation delivered with HT in prostate cancer patients with low, intermediate and high risk.

First self-adjuvant multicomponent potential vaccine candidates by tethering of four or eight MUC1 antigenic immunodominant PDTRP units on a calixarene platform: synthesis and biological evaluation.

MUC1 protein overexpressed in human epithelial carcinoma is a target in development of novel anticancer vaccines. Multiple units of immunodominant B-cell epitope PDTRP MUC1 core sequence were conjugated to calix[4,8]arene platforms containing TLR2 ligand, to produce two novel anticancer self-adjuvant vaccine candidates. The immunogenicity of the synthetic constructs was investigated by immunization of mice in vivo. ELISA assay evidenced that the vaccine candidates stimulate anti MUC1 IgG antibody production (major for the octavalent construct) and no additive effect but a multivalency effect was observed when compared to an analogous monovalent. Octa- and tetravalent constructs lacking in PDTRP peptide moieties did not show anti MUC1 IgG antibody production in mice. The antibodies induced by the synthesized constructs are able to recognize the MUC1 structures present on MCF7 tumor cells. The results display that calixarenes are convenient platforms for building multicomponent self-adjuvant vaccine constructs promising as immunotherapeutic anticancer agents.

Gender differences in locomotor and stereotypic behavior associated with l-carnitine treatment in mice.

BACKGROUND: The carnitines exert neuroprotective and neuromodulatory actions, and carnitine supplementation increases locomotor activity (LMA) in experimental animals. METHODS: We measured 13 indexes of LMA and 3 indexes of stereotypic activity (STA) in adult male and female caged mice. In a randomized 4-week trial, 10 males and 10 females received 50 mg/kg body weight PO l-carnitine, and another 10 males and 10 females received placebo. RESULTS: Compared with placebo-treated females, placebo-treated males had a greater number of stereotypies (NSTs), stereotypy counts (STCs), stereotypy time (STT), and right front time (RFT), but smaller total distance traveled (TDT), margin distance (MD), number of vertical movements (NVMs), and left rear time (LRT). Compared with placebo-treated males, carnitine-treated males had greater horizontal activity (HA), movement time (MT), NVM, STT, TDT, STC, MD, LRT, and clockwise revolutions (CRs), but smaller left front time (LFT) and RFT. Compared with placebo-treated females, carnitine-treated females had greater NST, STC, STT, LFT, and RFT, but smaller NM, HA, NVM, VA, MT, anticlockwise revolutions (ACRs), CR, TDT, and MD; right rear time (RRT) remained statistically insignificant across all comparisons. CONCLUSIONS: In summary, l-carnitine caused gender differences to persist for STC, diminish for NST and STT, disappear for LRT and NVM, change in the opposite direction for TDT and MD, appear de novo for HA, VA, NM, MT, and LFT, and remain absent for RRT and ACR. Some indexes of LMA and STA are sexually dimorphic in adult mice, and l-carnitine differentially maintains, diminishes/cancels, inverts, or creates the sexual dimorphism of particular indexes.

Altered intestinal absorption of L-thyroxine caused by coffee.

OBJECTIVE: To report eight case histories, and in vivo and in vitro studies showing coffee's potential to impair thyroxine (T4) intestinal absorption. DESIGN: Of eight women with inappropriately high or nonsuppressed thyroid-stimulating hormone (TSH) when T4 was swallowed with coffee/espresso, six consented to the evaluation of their T4 intestinal absorption. This in vivo test was also administered to nine volunteers. In three separate tests, two 100 microg T4 tablets were swallowed with coffee, water, or water followed, 60 minutes later, by coffee. Serum T4 was assayed over the 4-hour period of the test. Two patients and two volunteers also agreed on having tested the intestinal absorption of T4 swallowed with solubilized dietary fibers. In the in vitro studies, classical recovery tests on known concentrations of T4 were performed in the presence of saline, coffee, or known T4 sequestrants (dietary fibers, aluminium hydroxide, and sucralfate). MAIN OUTCOME: For the in vivo test, average and peak incremental rise of serum T4 (AIRST4 and PIRST4), time of maximal incremental rise of serum T4 (TMIRST4), and area under the curve (AUC) were determined. In patients and volunteers, the four outcome measures were similar in the water and water + coffee tests. In patients and volunteers, compared to water, coffee lowered AIRST4 (by 36% and 29%), PIRST4 (by 30% and 19%), and AUC (by 36% and 27%) and delayed TMIRST4 (by 38 and 43 minutes); bran was a superior interferer. In the in vitro studies, coffee was weaker than known T4 sequestrants. CONCLUSION: Coffee should be added to the list of interferers of T4 intestinal absorption, and T4 to the list of compounds whose absorption is affected by coffee.

Calix[4]arene decorated with four Tn antigen glycomimetic units and P3CS immunoadjuvant: synthesis, characterization, and anticancer immunological evaluation.

A novel anticancer vaccine candidate built on a nonpeptidic scaffold has been synthesized. Four S-Tn tumor-associated glycomimetic antigens have been clustered onto a calix[4]arene scaffold bearing an immunoadjuvant moiety (P3CS). The immunogenicity of the synthetic construct has been investigated by immunization of mice in vivo. ELISA assay has evidenced that the tetravalent construct stimulates a higher production of anti-Tn antigen IgG antibodies when compared to an analogous monovalent compound. This result is ascribable to an antigen cluster effect and makes the reported vaccine candidate a good mimic of the natural motifs present on the mucine surface.

Synthesis of new P3CS derivatives and their mitogenic activity on in vitro mice splenocytes.

Vaccination against tumors represents a relevant issue in current human cancer therapy. The N-terminal part of the lipoprotein from the outer membrane of Escherichia coli, tripalmitoyl-S-glyceryl-Cys-Ser (P(3)CS) and analogs with longer aminoacidic sequence are polyclonal activators for B-lymphocytes. Previous study reported that their N-2,2,2-trichloroethoxycarbonyl (Troc) derivatives increase immunocyte mitogenic activity. Therefore, in order to obtain compounds of greater activity and to investigate relationships between molecular structure of S-glyceryl skeleton and biological activity, we synthesized new Troc derivatives of P(3)CS. The mitogenicity of compounds was determined in vitro, by measuring in vitro [3H]-thymidine incorporation into splenocytes from Balb/c mice. Concentrations of compounds ranged from 0 to 64 micro g/ml. In particular, S-[2,3-bis(trichloroethoxycarbonyloxy)]-N-trichloroethoxycarbonyl dipeptide derivative exhibited significant mitogenic activity endowed with high pharmacological potency. These new series of compounds could be used as potent immunoadjuvants for the development of novel synthetic vaccines for tumor immunotherapy.

Synthesis of (+)- and (-)-cis-2-[(1-adamantylamino)-methyl]-1-phenylcyclopropane derivatives as high affinity probes for sigma1 and sigma2 binding sites.

Selective ligands for either sigma1 (sigma1) or sigma2 binding sites are potentially useful for gaining a better understanding of the physiological functions of these proteins. Moreover, potent and selective homochiral sigma1 and sigma2 binding site ligands represent leads to potential radioligands for tumour imaging with positron emission tomography (PET). On the basis of their structural similarity to previous leads, new (+)- and (-)-cis-2-[(1-adamantylamino)-methyl]-1-phenylcyclopropane derivatives were synthesised and their binding affinities for sigma1 and sigma2 binding sites were determined. Each enantiomer showed high affinity for both sigma1 and sigma2 binding sites, but only (-)-cis-methyl-2-[[1-adamantyl(methyl)amino]methyl]-1-phenylcyclopropane-carboxylate, (-)-4, showed appreciable selectivity for binding to sigma1 versus sigma2 sites. The enantiomers of cis-(2-[[1-adamantyl(methyl)amino]methyl]-1-phenylcyclopropyl)methanol, 6, expressed the highest affinity for sigma1 and sigma2 binding sites. Ligands (-)-4, (+)-6 and (-)-6 might be rapidly labelled in their N-methyl groups by methylation of the N-desmethyl analogues with [11C]iodomethane to provide prospective radioligands for PET. The N-desmethyl analogues, which are also high affinity ligands, were prepared and shown to undergo satisfactory methylation with iodomethane.