Hyperlysinemia, an ultrarare inborn error of metabolism: Review and update.

Familial hyperlysinemia is a rare autosomal recessive disorder due to defects of the AASS (α-aminoadipate δ-semialdehyde synthase) gene, which encodes for a bifunctional enzyme. Two types of hyperlysinemia have been identified namely type 1, due to the deficit of the alfa-ketoglutarate activity, and type 2, due to the deficit of the saccharopine dehydrogenase activity. METHODS: To better characterize the phenotypic spectrum of familial hyperlysinemia type 1, we conducted a systematic review of cases in the literature following PRISMA guidelines. We selected 16 articles describing 23 patients with hyperlysinemia type 1, twelve of whom with homozygous or compound heterozygous mutations in AASS gene. We also included a novel patient with a homozygous c.799C>T; p.(Arg267Cys) mutation in AASS gene. We collected genetic, clinical, brain imaging and electroencephalogram (EEG) features when available. RESULTS: The phenotype of this disease is heterogeneous, ranging from more severe forms with spastic tetraparesis, intellectual disability and epilepsy and mild-moderate forms with only intellectual disability or behavioural problem and/or epilepsy to normal clinical conditions. Only our patient has neuropathy unrelated to infectious event. CONCLUSIONS: We described the heterogeneous phenotypic spectrum of familial hyperlysinemia type 1 and we identified a new symptom, axonal neuropathy, never before described in this condition.

Silent thyroiditis following vaccination against COVID-19: report of two cases.

PURPOSE: It is well established that thyroiditis and other thyroid disorders can be induced by COVID-19 infection, but there is limited information about the autoimmune/inflammatory syndrome induced by adjuvants (ASIA) after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. We report two cases of thyrotoxicosis following SARS-CoV-2 vaccine. METHODS AND RESULTS: Two young health care peoples (wife and husband) received a first dose of SARS-CoV-2 vaccine, and few weeks later developed clinical manifestations of thyroid hyperactivity, with increased thyroid hormone levels on thyroid function tests, suppressed thyroid-stimulating hormone and negative antithyroid antibodies, despite being healthy before vaccination. They were diagnosed at the 4th week after first dose of SARS-Cov-2 vaccine as silent thyroiditis and followed without treatment, since their symptoms were not severe. At the 6th week, the patients became wholly asymptomatic and their thyroid function returned to normal. CONCLUSIONS: Thyrotoxicosis can occur after SARS-CoV-2 vaccination probably related to silent thyroiditis.

Recent advances in models for screening potential osteoporosis drugs.

INTRODUCTION: Osteoporosis is a growing health and health-economic problem due to the increased proportion of elderly people in the population. Basic and clinical advances in research over the past two decades have led to the development of different compounds with antiresorptive or anabolic activity on bone that improved substantially the management of patients with osteoporosis over calcitonin or estrogen replacement. New compounds are in preclinical and clinical development. Areas covered: In this review, the authors review the approaches for the preclinical and clinical development of antiresorptive and anabolic agents for osteoporosis, particularly focusing on the recent advances in technology and in the understanding of skeletal biology, together with their implications on novel osteoporosis drug discovery. Expert opinion: Based on the available evidence from the approved drugs for the treatment osteoporosis as well as from the different compounds under clinical development, it has become clear that long term nonclinical pharmacological studies with either bone quality and off-target effects as the main outcomes should be required for new drugs intended to treat osteoporosis. At the same time, basic and clinical advances in research have underlined the necessity to develop new technologies and new models for a thorough screening of the effects of new drugs on the different components of skeletal aging and bone fragility that cannot be assessed by bone mass measurement.

Clinical and neuroimaging features of autosomal recessive spastic paraplegia 35 (SPG35): case reports, new mutations, and brief literature review.

Spastic paraplegia 35 (SPG35) is a recessive condition characterized by childhood onset, progressive course, complicated by dystonia, dysarthria, cognitive impairment, and epilepsy. Mutations in the FA2H gene have been described in several families, leading to the proposal of a single entity, named fatty acid hydrolase-associated neurodegeneration (FAHN). Several reports have described a polymorphic radiological picture with white matter lesions of various degrees and a distinct form of neurodegeneration with brain iron accumulation. While we reviewed the pertinent literature, we also report three new patients with SPG35, highlighting the possible absence of white matter lesions even after a long neuroimaging follow-up. Three-dimensional modeling of the mutated proteins was helpful to elucidate the role of the site of mutations and the correlation with the residual enzyme activity as determined in cultured skin fibroblasts.

Fifteen-year follow-up of Italian families affected by arginine glycine amidinotransferase deficiency.

BACKGROUND: Arginine:glycine amidinotransferase deficiency (AGAT-d) is a very rare inborn error of creatine synthesis mainly characterized by absence of brain Creatine (Cr) peak, intellectual disability, severe language impairment and behavioural disorder and susceptible to supplementary Cr treatment per os. Serial examinations by magnetic resonance spectroscopy are required to evaluate Cr recovery in brain during treatment of high doses of Cr per os, which have been proved beneficial and effective in treating main clinical symptoms. A long term study with detailed reports on clinical, neurochemical and neuropsychological outcomes of the first Italian patients affected by AGAT-d here reported can represent a landmark in management of this disorder thus enhancing medical knowledge and clinical practice. RESULTS: We have evaluated the long term effects of Cr supplementation management in four Italian patients affected by AGAT-d, correlating specific treatments with serial clinical, biochemical and magnetic resonance spectroscopy examinations as well as the neuropsychological outcome by standardized developmental scales. Consecutive MRS examinations have confirmed that Cr depletion in AGAT-d patients is reversible under Cr supplementation. Cr treatment is considered safe and well tolerated but side effects, including weight gain and kidney stones, have been reported. CONCLUSIONS: Early treatment prevents adverse developmental outcome, while patients diagnosed and treated at an older age showed partial but significant cognitive recovery with clear improvements in adaptive functioning.

Influence of thyrotropin and thyroid volume on basal serum calcitonin.

Thyroid volume was found to be a determinant of serum calcitonin levels in animal models and in thyroid-healthy subjects, as recently reported. This study aims to evaluate if this finding is confirmed in patients undergoing ultrasonography-guided fine-needle aspiration cytology of suspicious thyroid nodules. A dataset of 561 patients including basal serum FT4, FT3, TSH, calcitonin, thyroid volume, anti-thyroperoxidase antibodies (TPOAb), and cytology report, was retrospectively analysed. The median thyroid volume was 20.5 ml (14.5-26.8) in males and 12.0 ml (9.3-17.0) in females (p<0.001). The overall median serum calcitonin value was 2.00 pg/ml (2.00-3.10). A Spearman's correlation was performed between serum calcitonin levels and thyroid volume, showing a weak direct relationship (rs=0.173, p<0.001). This relationship is confirmed both in the smokers group (rs=0.337, p=0.003) and in non-smokers group (rs=0.115, p=0.012), and both in the TPOAb-positive patients (rs=0.419, p<0.001) and negative ones (rs=0.107, p=0.025). There is no correlation between serum TSH and calcitonin levels. In patients grouped according to morphologic diagnosis, calcitonin levels are slightly higher in the high-volume groups: the interquartile range was 2.00-2.00 pg/ml in the atrophy, 2.00-2.82 pg/ml in the normal volume, and 2.00-3.85 pg/ml in the goiter group (p=0.02). When males and females are computed separately, the statistical significance is lost. In conclusion, thyroid volume can mildly influence calcitonin levels. Gender acts as a "surrogate marker" of thyroid volume and the application of a gender-specific cut-off can probably overcome this issue in clinical practice.

Pain management in internal medicine and effects of a standardised educational intervention: the FADOI-DOMINO study.

PURPOSE: Few real-world data are available on the frequency and management of pain in Internal Medicine (IM). Aims of our study were to assess the prevalence of pain in IM, and to evaluate the effects on pain management of a standardised educational programme. MATERIALS AND METHODS: The study was performed in 26 IM Units in Italy, with two cross-sectional surveys (PRE phase and POST phase) interspersed with an educational programme. In PRE phase each Centre reviewed the hospital charts of the last 100 consecutive patients hospitalised for any cause. An educational programme was conducted in each Centre by means of the 'outreach visit', a face-to-face meeting between health personnel and a trained external expert. Six months after, each Centre repeated the data collection (POST phase), specular to the PRE. RESULTS: A total of 5200 medical charts were analysed. Pain was documented in 37.5% of the patients. After the educational intervention, the intensity of pain was appropriately assessed in a higher percentage of patients (77.4% vs. 47.8%, p = 0.0001), and it was more frequently monitored during hospitalisation. Qualitative definition of pain (pathogenesis, duration, etc.) increased in POST phase (75.4% vs. 62.7%, p = 0.0001). A 73.3% increase in the use of strong opioids was detected following educational programme. CONCLUSIONS: Pain affects 4 out of 10 patients hospitalised in IM. According to our large real-world study, to implement a standardised one-shot educational programme may persistently improve the attitude of health personnel towards the characterisation and management of pain.

Influence of biological matrix and artificial electrospun scaffolds on proliferation, differentiation and trophic factor synthesis of rat embryonic stem cells.

Two-dimensional vs three-dimensional culture conditions, such as the presence of extracellular matrix components, could deeply influence the cell fate and properties. In this paper we investigated proliferation, differentiation, survival, apoptosis, growth and neurotrophic factor synthesis of rat embryonic stem cells (RESCs) cultured in 2D and 3D conditions generated using Cultrex® Basement Membrane Extract (BME) and in poly-(L-lactic acid) (PLLA) electrospun sub-micrometric fibres. It is demonstrated that, in the absence of other instructive stimuli, growth, differentiation and paracrine activity of RESCs are directly affected by the different microenvironment provided by the scaffold. In particular, RESCs grown on an electrospun PLLA scaffolds coated or not with BME have a higher proliferation rate, higher production of bioactive nerve growth factor (NGF) and vascular endothelial growth factor (VEGF) compared to standard 2D conditions, lasting for at least 2 weeks. Due to the high mechanical flexibility of PLLA electrospun scaffolds, the PLLA/stem cell culture system offers an interesting potential for implantable neural repair devices.

Efficacy of vigabatrin intervention in a mild phenotypic expression of succinic semialdehyde dehydrogenase deficiency.

We report a patient with succinic semialdehyde dehydrogenase deficiency who presented a mild phenotype including developmental language delay, in association with the typical elevations of 4-hydroxybutyric acid (GHB) in biological fluids and MRI alterations. Two pathogenic mutations were identified one transversion (c.278 G>T) in exon 1 and another (c.1557 T>G) in exon 10. Both parents are carriers of one of the mutations, confirming compound-heterozygosity in their affected child. To reduce the GHB levels in body fluids, a treatment with vigabatrin at low dose (25 mg/kg per day) was started, monitoring its efficacy by clinical and neurochemical follow-up. After 9 months of therapy with vigabatrin, a significant reduction of GHB concentrations in urine and CSF was observed; after 36 months, a significant improvement of communicative skills, not previously reported, was referred. These results support the hypothesis that the clinical improvement is correlated to the reduction in the GHB levels and the importance of considering the SSADH deficiency in the differential diagnosis of patients with mental retardation and language delay.

Isolation of rat embryonic stem-like cells: a tool for stem cell research and drug discovery.

The establishment of rat embryonic stem cells constitutes a precious tool since rat has been extensively used in biomedical research, in particular for the generation of human neurodisease animal models. Up to now only a few studies have described the isolation of rat embryonic stem-like cells. One out of 9 isolated rat embryonic stem-like cell lines (B1-RESC) obtained from a 4.5-day post-coitum blastocyst were extensively characterized and kept in culture for up to 80 passages on feeders with LIF. The stable growth of these cells and the expression of pluripotent markers were confirmed up to a high number of passages in culture, also in the absence of feeders and LIF. B1-RESC expresses the three germ layers markers both in vitro, within differentiating embryoid bodies, and in vivo through teratoma formation. Collectively, the B1-RESC line with a stable near-diploid karyotype can be used as a highly sensitive tool for testing anti-proliferative molecules.

Language disorder with mild intellectual disability in a child affected by a novel mutation of SLC6A8 gene.

We describe the clinical and molecular features of a child harboring a novel mutation in SLC6A8 gene in association with a milder phenotype than other creatine transporter (CT1) deficient patients (OMIM 300352) [1-7]. The mutation c.757 G>C p.G253R in exon 4 of SLC6A8 was hemizygous in the child, aged 6 years and 6 months, who showed mild intellectual disability with severe speech and language delay. His carrier mother had borderline intellectual functioning. Although the neurochemical and biochemical parameters were fully consistent with those reported in the literature for subjects with CT1 deficit, in our patient within a general cognitive disability, a discrepancy between nonverbal and verbal skills was observed, confirming the peculiar vulnerability of language development under brain Cr depletion.

Rapid identification of graphene flakes: alumina does it better.

We report a systematic investigation of the colour contrast (CC) of graphene (one, two and three layers) on 50, 72 and 80 nm thick Al(2)O(3)/Si(100) and 100 and 300 nm thick SiO(2)/Si(100). The CC is determined by the analysis of optical microscopy images taken under white light illumination. A corresponding assignment of graphene in the single-layer, double-layer and trilayer phases is made using micro-Raman spectroscopy. A quantitative evaluation allows us to conclude that the colour contrast between 72 nm alumina and graphene is significantly larger than that between 300 nm silicon oxide and graphene (by factors of 2.2, 2.0 and 3.3 for the single-layer, double-layer and trilayer graphene flakes respectively). Moreover, data indicate that, to increase visibility, the use of a red or a green light is preferable.

Diagnostic accuracy of rhTSH test with neck ultrasonography in differentiated thyroid cancer follow-up.

Serum thyroglobulin levels measurement after injection of recombinant human thyrotropin (rh-TSH) represents the most important advance in the follow-up of patients with differentiated thyroid cancer, obtaining TSH elevation without L-thyroxine withdrawal, avoiding marked hypothyroidism symptoms. During a 4-yr period (2004-2008), 66 consecutive patients with DTC (59 papillary and 7 follicular carcinomas) were examined after rh-TSH Tg test and neck ultrasonography. In all patients basal Tg was <0.25 ng/ml. In twelve (18.5%) examined patients rh-TSH Tg was >0.25 ng/ml, and in seven (58.3%) of these was demonstrated persistent or recurrent disease. These data indicate that rhTSH-Tg>0.25 ng/ml should be considered diagnostic for persistent or recurrent disease and suggests further exams (neck ultrasonography, whole body scan or cytology) to localize the disease. Furthermore, neck ultrasonography has demonstrated high accuracy in detecting lymph nodal metastases and should be always combined with rh-TSH test.

Treatment with L-arginine improves neuropsychological disorders in a child with creatine transporter defect.

Creatine transporter deficit (CT1) is an inherited metabolic disorder that causes mental retardation, epilepsy, speech, language and behavioral deficits. Until now, no treatment has been proven to be successful for this condition. We describe 1-year follow-up study of a child, aged 9.6 years, with CT1 defect, on oral supplementation with L-arginine, a precursor of creatine synthesis. Under supplementation, he showed a noticeable improvement of neurological, language and behavioral status and an increase of brain creatine and phosphocreatine documented with magnetic resonance spectroscopy. The results suggest that children with CT1 disorder show some residual adaptive plasticity for certain functions even at quite an advanced age. Further trials with higher L-arginine dosages and more protracted treatment are encouraged.

Mental retardation and verbal dyspraxia in a new patient with de novo creatine transporter (SLC6A8) mutation.

We report on a 9.5-year-old Italian boy affected by creatine transporter deficit (CT1), due to a de novo mutation in SLC6A8 gene. The patient was investigated by means of a comprehensive neuropsychological protocol and presented with an unusual alteration of speech and expressive-language function, associated with mental retardation, that differed from CT1 patients described to date. In particular, he exhibited a developmental apraxia of speech (DAS) with motor planning and execution deficit, while receptive language was consistent with his mental age.

Treatment monitoring of brain creatine deficiency syndromes: a 1H- and 31P-MR spectroscopy study.

BACKGROUND AND PURPOSE: Brain creatine (Cr) deficiencies (BCr-d) are rare disorders of creatine biosynthesis and transport. We performed consecutive measures of total Cr (tCr) and of its phosphorylated fraction, phosphocreatine (PCr), in the brains of children affected by Cr synthesis defects during a long period of therapy. The aim was to identify the optimal treatment strategy for these disorders. MATERIALS AND METHODS: Two patients with guanidinoacetate methyltransferase defect (GAMT-d) were treated with different amounts of Cr and with diet restrictions aimed at reducing endogenous guanidinoacetate (GAA) synthesis. Three patients with arginine:glycine amidinotransferase defect (AGAT-d) were treated with different Cr intakes. The patients' treatments were monitored by means of (1)H- and (31)P-MR spectroscopy. RESULTS: Cr and PCr replenishment was lower in GAMT-d than in AGAT-d even when GAMT-d therapy was carried out with a very high Cr intake. Cr and especially PCr replenishment became more efficient only when GAA blood values were reduced. Adenosine triphosphate (ATP) was increased in the baseline phosphorous spectrum of GAMT-d, and it returned to a normal value with treatment. Brain pH and brain P(i) showed no significant change in the AGAT-d syndrome and at any Cr intake. However, 1 of the 2 GAMT-d patients manifested a lower brain pH level while consuming the GAA-lowering diet. CONCLUSIONS: AGAT-d treatment needs lower Cr intake than GAMT-d. Cr supplementation in GAMT-d treatment should include diet restrictions aimed at reducing GAA concentration in body fluids. (1)H- and especially (31)P-MR spectroscopy are the ideal tools for monitoring the therapy response to these disorders.

[Epidemiology of work-related diseases in ULSS 12 Venice (Italy)]. / Epidemiologia delle malattie professionali nella ULSS 12 Veneziana.

In Veneto, like in Italy, in the last years the course of the professional diseases shown a trend in reduction. This trend has had to the difficulty to recognize the professional aetiology of multifactorial diseases. In the Venice the analysis of the course of the professional diseases in last the 4-5 years has demonstrated an increase of the communications of diseases from the doctors who operate in hospital to the SPISAL for the active search for pathologies asbestos and CVM correlated; moreover it has been a reduction of the hearing loss from noise from 2000 and it has been increment of cancer of lung and mesothelioma from 2001. Emergent diseases, like the allergy, the back diseases and those tied to the organizational constriction, are sottostimate. They have been a collaboration with the doctors of hospital, the doctors of factories, the INAIL and the court.

Plasma changes of calcitonin gene-related peptide and substance P in patients with dialysis headache.

Little is known of mechanism of dialysis headache (DH). As suggested for migraine, a role for neuropeptides has been investigated. Twenty-four patients under haemodialysis were studied. Twelve of them suffered from DH. The remaining patients were headache free. Blood samples for radioimmunoassay of calcitonin gene-related peptide (CGRP) and substance P (SP) were collected from the arteriovenous fistula before and after dialysis treatment. Basal plasma concentrations of CGRP were found to be higher in headache patients. Dialysis significantly decreased CGRP concentrations in both groups. No difference in basal plasma concentrations of SP was observed between groups. At the end of the treatment plasma SP concentrations were reduced in headache-free patients but increased in headache patients. Elevated plasma concentrations of CGRP in patients with DH could represent a biochemical factor contributing to susceptibility to headache. Because of the disputable role of SP in migraine, the significance of the increase of the peptide in plasma during DH remains to be elucidated.

Arginine:glycine amidinotransferase (AGAT) deficiency in a newborn: early treatment can prevent phenotypic expression of the disease.

Arginine:glycine amidinotransferase deficiency is a treatable inborn error of creatine synthesis, characterized by mental retardation, language impairment, and behavioral disorders. We describe a patient in whom arginine:glycine amidinotransferase was diagnosed at birth and treated at 4 months with creatine supplementation. In contrast with his 2 older sisters, he had normal psychomotor development at 18 months.

[Can we cure autism? From outcome to intervention]. / Podemos curar el autismo? Del desenlace clinico a la intervención.

Outcome in autism is variable but with a significant trend toward a poor prognosis and despite reports that outcome in individuals with autism may be improving secondary to early intensive interventions there is still much to be learned about the natural history and the effects of intervention in autism spectrum disorders. While there may not be a known cure for autism, there are a number of viable treatment options available. The primary models of treatment are non pharmacological interventions that include intervention models such as applied behavior analysis and developmental and structured teaching. The role of pharmacological interventions is limited to treating specific symptoms that may be interfering with a child's ability to learn or function within a particular environment. The question of whether or not we can cure autism needs to be discussed in terms of the need to overcome the as of yet poorly understood fundamental disturbance in autism and the need to develop treatment protocols specifically targeting social deficits. At the present time, it is more appropriate to speak of our quest to understand autism than it is to speak of a cure.