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F Tassone

Publications and source records attributed to F Tassone.

At least 19 recordsLinked to original sources
PubMed2006

Tremor/ataxia syndrome and fragile X premutation: diagnostic caveats.

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a newly discovered late-onset neurodegenerative disorder caused by a premutation in the FMR1 X-linked gene. We present examples of a discrepancy between obvious brain changes observed on MRI, and minimal clinical neurological manifestations in three older carriers of this premutation. This discrepancy occurred in three of nine carriers ascertained in an unbiased manner. If the systematic follow-up studies of adult carriers confirm this trend, this will have an impact on early diagnosis of neurological involvement and possible prevention. If MRI changes precede clinical manifestation of FXTAS this may explain the low detection rate of fragile X carriers among patients with neurological syndromes associated with tremor/ataxia.

Aged↗
PubMed2006

Molecular and imaging correlates of the fragile X-associated tremor/ataxia syndrome.

OBJECTIVES: To assess changes in regional brain volumes associated with the fragile X-associated tremor/ataxia syndrome (FXTAS) and the molecular correlates of these changes. METHODS: We administered molecular, MRI, and neurocognitive tests to 36 male premutation carriers (ages 51 to 79), 25 affected and 11 unaffected with FXTAS, and to 21 control subjects of similar age and education. RESULTS: We found differences among the three groups in whole brain, cerebrum, cerebellum, ventricular volume, and whole-brain white matter hyperintensity, with the affected group showing significantly more pathology than the control and unaffected groups. Brainstem volume was significantly smaller in the unaffected group vs controls but did not differ from the affected group. Within the premutation sample, CGG repeat length correlated with reductions in IQ and cerebellar volume and increased ventricular volume and whole-brain white matter hyperintensity. CONCLUSIONS: The current findings, coupled with recent evidence linking the degree of neuropathology (numbers of intranuclear inclusions) to the size of the premutation allele, provide evidence that the neurodegenerative phenotype in the fragile X-associated tremor/ataxia syndrome is a consequence of the CGG repeat expansion.

Aged↗
PubMed2005

Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS).

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects carriers, principally males, of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Clinical features of FXTAS include progressive intention tremor and gait ataxia, accompanied by characteristic white matter abnormalities on MRI. The neuropathological hallmark of FXTAS is an intranuclear inclusion, present in both neurons and astrocytes throughout the CNS. Prior to the current work, the nature of the associations between inclusion loads and molecular measures (e.g. CGG repeat) was not defined. Post-mortem brain and spinal cord tissue has been examined for gross and microscopic pathology in a series of 11 FXTAS cases (males, age 67-87 years at the time of death). Quantitative counts of inclusion numbers were performed in various brain regions in both neurons and astrocytes. Inclusion counts were compared with specific molecular (CGG repeat, FMR1 mRNA level) and clinical (age of onset, age of death) parameters. In the current series, the three most prominent neuropathological characteristics are (i) significant cerebral and cerebellar white matter disease, (ii) associated astrocytic pathology with dramatically enlarged inclusion-bearing astrocytes prominent in cerebral white matter and (iii) the presence of intranuclear inclusions in both brain and spinal cord. The pattern of white matter pathology is distinct from that associated with hypertensive vascular disease and other diseases of white matter. Spongiosis was present in the middle cerebellar peduncles in seven of the eight cases in which those tissues were available for study. There is inclusion formation in cranial nerve nucleus XII and in autonomic neurons of the spinal cord. The most striking finding is the highly significant association between the number of CGG repeats and the numbers of intranuclear inclusions in both neurons and astrocytes, indicating that the CGG repeat is a powerful predictor of neurological involvement in males, both clinically (age of death) and neuropathologically (number of inclusions).

Age of Onset↗
PubMed2005

Protein composition of the intranuclear inclusions of FXTAS.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by premutation expansions (55-200 CGG repeats) in the fragile X mental retardation 1 (FMR1) gene. The pathologic hallmark of FXTAS is the ubiquitin-positive intranuclear inclusion found in neurons and astrocytes in broad distribution throughout the brain. The pathogenesis of FXTAS is likely to involve an RNA toxic gain-of-function mechanism, and the FMR1 mRNA has recently been identified within the inclusions. However, little is known about the proteins that mediate the abnormal cellular response to the expanded CGG repeat allele. As one approach to identify the protein mediators, we have endeavoured to define the protein complement of the inclusion itself. Fluorescence-activated flow-based methods have been developed for the efficient purification of inclusions from the post-mortem brain tissue of FXTAS patients. Mass spectrometric analysis of the entire protein complement of the isolated inclusions, combined with immunohistochemical analysis of both isolated nuclei and tissue sections, has been used to identify inclusion-associated proteins. More than 20 inclusion-associated proteins have been identified on the basis of combined immunohistochemical and mass spectrometric analysis, including a number of neurofilaments and lamin A/C. There is no dominant protein species in the inclusions, and ubiquitinated proteins represent only a minor component; thus, inclusion formation is not likely to reflect a breakdown in proteasomal degradation of nuclear proteins. The list of proteins includes at least two RNA binding proteins, heterogeneous nuclear ribonucleoprotein A2 and muscle blind-like protein 1, which are possible mediators of the RNA gain-of-function in FXTAS.

Aged↗
PubMed2005

Evidence for, and a spectrum of, neurological involvement in carriers of the fragile X pre-mutation: FXTAS and beyond.

A neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), occurs in some older men carrying a small CGG repeat expansion (pre-mutation) in the FMR1 gene. We surveyed a sample of older pre-mutation males to estimate the prevalence and spectrum of neurological involvement. Twelve pre-mutation males aged 50-82 years and 11 age-matched normal controls ascertained in an unbiased manner were included in a neurological assessment that also used standard scales for tremor (Clinical Rating Scale for Tremor), ataxia (International Cooperative Ataxia Rating Scale, ICARS) and parkinsonian signs (Unified Parkinson's Disease Rating Scale). Axial FLAIR images of the brain, and neuropsychological and molecular tests were also conducted in pre-mutation carriers. The neurological disorder meeting all the criteria for diagnosis of 'definite' to 'possible' FXTAS occurred in five of 12 pre-mutation carriers (41.7%), and this prevalence was significantly higher compared with normal controls (0%). The ataxia (ICARS) score and the sum of all three tremor/ataxia scores were significantly higher in pre-mutation carriers than in controls, and mRNA was elevated in all but one carrier, but did not correlate with the degree of neurological involvement. In conclusion, the findings provide further evidence that the pre-mutation allele of FMR1 is a significant cause of late-onset neurodegeneration, presenting with a broad spectrum of clinical manifestations.

Age of Onset↗
PubMed2004

Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation.

We describe five female carriers of the FMR1 premutation who presented with symptoms of tremor and ataxia and who received a diagnosis of definite or probable fragile-X-associated tremor/ataxia syndrome (FXTAS). Unlike their male counterparts with FXTAS, none of the women had dementia. Females had not been reported in previous studies of FXTAS, suggesting that they may be relatively protected from this disorder. Brain tissue was available from one of the five subjects, a women who died at age 85 years; microscopic examination revealed intranuclear neuronal and astrocytic inclusions, in accord with the findings previously reported in males with FXTAS. The work-up of families with the FMR1 mutation should include questions regarding neurological symptoms in both older male and female carriers, with the expectation that females may also manifest the symptoms of FXTAS, although more subtly and less often than their male counterparts.

Adult↗
PubMed2004

A rare case of adulthood-onset growth hormone deficiency presenting as sporadic, symptomatic hypoglycemia.

Symptomatic hypoglycemia is described in children with severe GH deficiency (GHD), but is rare in adults with GHD. We describe the case of a 62- yr-old man, referred for recurrent hypoglycemic events. He reported a previous head trauma at the age of 20 yr and a diagnosis of reactive hypoglycemia at the age of 50 yr. In the last months, during a period of job-related stress, the hypoglycemic episodes became more frequent and severe (glucose <2.2 mmol/l), finally requiring hospitalization. On admission, the patient was in good general health, with normal renal and hepatic function. During hospitalization, no hypoglycemic episodes were recorded, also during a 72-h fasting test. Biochemical data and abdominal computed tomography (CT) excluded insulinoma. A tumor-induced hypoglycemia was ruled out. The 4-h oral glucose tolerance test (OGTT) showed an impaired glucose tolerance with a tendency toward asymptomatic hypoglycemia. Hormonal study disclosed low levels of GH (0.2 ng/ml) and IGF-I (51 ng/ml); the response of GH to GHRH plus arginine confirmed a severe GHD (GH peak 2.7 ng/ml). Other pituitary and counterregulation hormones were within the normal range and magnetic resonance imaging (MRI) of the pituitary gland was normal. Replacement therapy with a low dose of rhGH induced an increase of IGF-I up to low-normal values, accompanied by lasting regression of hypoglycemic events. In conclusion, hypoglycemia was the main clinical symptom of isolated adult onset GHD, in the present case. The possible pathogenesis of isolated adult onset GHD and the association of GHD with conditions predisposing to hypoglycemia are considered and discussed.

Age of Onset↗
PubMed2004

Obese patients with obstructive sleep apnoea syndrome show a peculiar alteration of the corticotroph but not of the thyrotroph and lactotroph function.

OBJECTIVE: Obstructive sleep apnoea syndrome (OSAS) is strongly associated with obesity (OB) and is characterized by several changes in endocrine functions, e.g. GH/IGF-I axis, adrenal and thyroid activity. It is still unclear whether these alterations simply reflect overweight or include peculiar hypoxia-induced hormonal alterations. Hormonal evaluations have been generally performed in basal conditions but we have recently reported that OSAS is characterized by a more severe reduction of the GH releasable pool in comparison to simple obesity. We aimed to extend our evaluation of anterior pituitary function to corticotroph, thyrotroph and lactotroph secretion under dynamic testing in OSAS in comparison with simply obese and normal subjects. SUBJECTS AND METHODS: In 15 male patients with OSAS [age, mean +/- SEM 43.5 +/- 1.6 years; body mass index (BMI) 39.2 +/- 3.1 kg/m2; apnoea/hypopnoea index, (AHI) 53.4 +/- 8.7], 15 male patients with simple obesity (OB, age 39.7 +/- 1.2 years; BMI 41.2 +/- 2.0 kg/m2; AHI 3.1 +/- 1.2 events/h of sleep) and in 15 normal lean male subjects (NS, age 38.2 +/- 1.4 years; BMI 21.2 +/- 0.8 kg/m2; AHI 1.9 +/- 0.8 events/h of sleep) we evaluated: (a) the ACTH and cortisol responses to CRH [2 microg/kg intravenously (i.v.)] and basal 24 h UFC levels; (b) the TSH and PRL responses to TRH (5 microg/kg iv) as well as FT3 and FT4 levels. RESULTS: Twenty-four-hour UFC levels in OSAS and OB were similar and within the normal range. Basal ACTH and cortisol levels were similar in all groups. However, the ACTH response to CRH in OSAS (Deltapeak: 30.3 +/- 3.8 pmol/l; DeltaAUC: 682.8 +/- 128.4 pmol*h/l) was markedly higher (P < 0.001) than in OB (Deltapeak: 9.3 +/- 1.4 pmol/l; DeltaAUC 471.5 +/- 97.3 pmol*h/l), which, in turn, was higher (P < 0.05) than in NS (Deltapeak: 3.3 +/- 0.9 pmol/l; DeltaAUC 94.7 +/- 76.7 pmol*h/l). On the other hand, the cortisol response to CRH was not significantly different in the three groups. Basal FT3 and FT4 levels as well as the TSH response to TRH were similar in all groups. Similarly, both basal PRL levels and the PRL response to TRH were similar in the three groups. CONCLUSIONS: With respect to patients with simple abdominal obesity, obese patients with OSAS show a more remarkable enhancement of the ACTH response to CRH but a preserved TSH and PRL responsiveness to TRH. These findings indicate the existence of a peculiarly exaggerated ACTH hyper-responsiveness to CRH that would reflect hypoxia- and/or sleep-induced alterations of the neural control of corticotroph function; this further alteration is coupled to the previously described, peculiar reduction of somatotroph function.

Adrenocorticotropic Hormone↗
PubMed2004

Aging in individuals with the FMR1 mutation.

Individuals with fragile X mental retardation 1 (FMR1) premutation (55 to 200 CGG repeats) are typically unaffected by fragile X syndrome. However, a subgroup of older males with the premutation have developed a neurological syndrome, which usually begins between 50 and 70 years and is associated with a progressive intention tremor and/or ataxia manifested by balance problems, frequent falling, and Parkinsonian symptoms, such as masked facies, intermittent resting tremor, and mild rigidity. This finding has been termed the fragile X-associated tremor/ataxia syndrome (FXTAS) and has brought focus to the aging process in individuals with the FMR1 mutation. The premutation is associated with elevated messenger RNA levels leading to the formation of intranuclear inclusions in neurons and astrocytes associated with FXTAS. This review is a summary of our experience with FXTAS in male carriers of the premutation.

Aged↗
PubMed2003

Both fasting-induced leptin reduction and GH increase are blunted in Cushing's syndrome and in simple obesity.

BACKGROUND: Simple obesity and Cushing's syndrome (CS) are two clinical models of leptin hypersecretion coupled with GH hyposecretion. Fasting inhibits leptin while stimulating GH secretion in normal human subjects. OBJECTIVES: To clarify the effect of fasting on leptin and GH secretion in obesity and CS. PATIENTS AND PROTOCOL: We studied six women with CS [age 17-66 years; body mass index (BMI) 28.6 kg/m2], seven women with visceral obesity (OB; 20-41 years; BMI 42.9 kg/m2) and seven normal women (NS; 25-31 years; BMI 19.3 kg/m2). The effects of 36-h fasting on 8-h diurnal mean leptin, GH, insulin and glucose concentrations (mLEPTc, mGHc, mINSc and mGLUc) as well as on the IGF/IGFBP system were studied. RESULTS: Before fasting, mLEPTc in OB and in CS were similar and both were higher (P < 0.01) than in NS. OB and CS showed similar mGHc, which were lower (P < 0.05) than in NS. Fasting induced a reduction in mLEPTc that was significant in NS and CS (P < 0.04) but not in OB. The mLEPTc in OB and CS after fasting remained higher (P < 0.05) than in NS. After fasting, OB and CS showed no increase in mGHc, although this clearly increased (P < 0.02) in NS. IGF-I but not IGFBP-3 levels decreased in all groups (P < 0.05). Fasting reduced mINSc and mGLUc while increasing IGFBP-1 in all groups. After fasting, mINSc in OB and CS remained higher (P < 0.03) than in NS. CONCLUSIONS: Short-term fasting has less inhibitory effect on leptin and no stimulatory effect on GH secretion in patients with Cushing's syndrome as well as simple obesity. After fasting, insulin levels in hypercortisolaemic and also in obese patients remained higher than in normal subjects suggesting that hyperinsulinism could play a role in the altered response of leptin and GH to starvation in these conditions.

Adolescent↗
PubMed2003

Expression of the FMR1 gene.

Fragile X syndrome is a trinucleotide repeat disorder in which a (CGG)n element located within the 5' untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene expands to more than 200 copies (full mutation) and becomes hypermethylated. Such expansions are accompanied by the failure to produce FMR1 protein (FMRP), resulting in the fragile X phenotype. For smaller (premutation) expansions (approximately 55-200 repeats), FMR1 mRNA and FMRP levels had been assumed to be normal; however, our group and others have recently demonstrated that FMR1 mRNA levels are elevated in cells harboring premutation alleles. Moreover, mRNA levels remain elevated in fragile X males with partially methylated full mutation alleles. Finally, some fragile X males with hypermethylated, full mutation alleles continue to produce FMR1 mRNA, despite the expectation that those genes should be silent. These observations all point to a complex mechanism of expression of the FMR1 gene, one that provides a more consistent foundation for the spectrum of clinical involvement. An FMRP deficit is observed in all categories of fragile X individuals, including carriers of the premutation and partially methylated full mutation alleles. These results demonstrate that lowered FMRP levels, in the absence of methylation-coupled silencing of the FMR1 gene, are not caused by reduced transcriptional activity, but rather by a reduced efficiency of translation.

DNA Methylation↗
PubMed2003

Neuroendocrine and metabolic effects of acute ghrelin administration in human obesity.

Ghrelin stimulates appetite and plays a role in the neuroendocrine response to energy balance variations. Ghrelin levels are inversely associated with body mass index (BMI), increased by fasting and decreased by food intake, glucose load, insulin, and somatostatin. Ghrelin levels are reduced in obesity, a condition of hyperinsulinism, reduced GH secretion, and hypothalamus-pituitary-adrenal axis hyperactivity. We studied the endocrine and metabolic response to acute ghrelin administration (1.0 microg/kg i.v.) in nine obese women [OB; BMI (mean +/- SD) 36.3 +/- 2.3 kg/m(2)] and seven normal women (NW; BMI 20.3 +/- 1.7 kg/m(2)). Basal ghrelin levels in NW were higher than in OB (P < 0.05). In NW, ghrelin increased (P < 0.05) GH, prolactin (PRL), ACTH, cortisol, and glucose levels but did not modify insulin. In OB, ghrelin increased (P < 0.01) GH, PRL, ACTH, and cortisol levels. The GH response to ghrelin in OB was 55% lower (P < 0.02) than in NW, whereas the PRL, ACTH, and cortisol responses were similar. In OB, ghrelin increased glucose and reduced insulin (P < 0.05). Thus, obesity shows remarkable reduction of the somatotroph responsiveness to ghrelin, suggesting that ghrelin hyposecretion unlikely explains the impairment of somatotroph function in obesity. On the other hand, in obesity ghrelin shows preserved influence on PRL, ACTH, and insulin secretion as well as in glucose levels.

Adrenocorticotropic Hormone↗
PubMed2003

Effect of journey time and environmental condition on bull behaviour and beef quality during road transport in northern Italy.

Response to a transport time of 1 and 3 hours on the road carried out under different environmental conditions was evaluated on 60 pure-breed Charolaise bulls. Temperature and relative humidity from loading to slaughter were expressed as THI (Temperature-Humidity Index). Regardless of journey time or environmental conditions, the most common standing orientation was either perpendicular or parallel to the direction of travel. Diagonal orientation increased with THI class. Cortisol and glucose plasma concentrations increased because of transport but they were not influenced by journey time or THI class. The CK plasma concentration, instead, increased according to THI class. The incidence of carcass bruising was not affected by the journey time or by the environmental conditions. Journey time also had a negligible effect on beef quality while, meat lightness increased and water holding capacity slightly decreased depending on THI.

Animals↗
PubMed2002

Glucagon administration elicits blunted GH but exaggerated ACTH response in obesity.

Reduction in both spontaneous and stimulated GH secretion in obesity has been clearly demonstrated. Mild hyperactivity of hypothalamus-pituitary-adrenal (HPA) axis has been also reported. Glucagon, at least after im administration, induces clear increase in either GH or ACTH and F levels but its effect on somatotroph and corticotroph secretion in obesity has never been studied. In 7 patients with abdominal obesity (OB, aged 24-42 yr, BMI: 29.1-43.9 kg/m2, waist/hip ratio [WHR]: 0.86-1.00) we studied the GH, ACTH and F responses to the im administration of glucagon (0.017 mg/kg at 0 min). The results in OB were compared with those in a group of 6 age-matched controls normal subjects (Ns aged 26-32 yr, BMI 19.7-22.5 kg/m2). In Ns glucagon administration induced clear increase in GH (peak vs baseline, mean+/-SE: 11.6+/-3.4 vs 3.3+/-0.7 microg/l, p<0.02), and ACTH (52.9+/-15.2 vs 19.0+/-1.5 pg/ml, p<0.02) levels which peaked at +150 and +165 min, respectively. Increase in F levels (222.3+/-23.8 vs 158.3+/-7.0 ng/ml, p<0.05) was also recorded but peaked at +180 min. In OB glucagon administration induced GH response (7.4+/-2.3 vs 0.8+/-0.6 microg/l) lower (p<0.05) than that recorded in Ns; when the GH responses were evaluated by co-variance analysis, a significant difference between the 2 groups was recorded in term of peaks but not of AUCs. On the other hand, the ACTH response to glucagon in OB was higher than that in Ns (11452.6+/-2447.7 vs 4892.2+/-719.4 pg/ml x min, p<0.05). The F response to glucagon in OB and Ns was, however, similar (24057.9+/-4109.1 vs 29835.9+/-1566.0 ng/ml x min). In conclusion, this study demonstrates that in obese patients the im administration of glucagon elicits blunted GH response but exaggerated ACTH increase which is uncoupled with the adrenal response. These findings agree with the existence of concomitant GH insufficiency and altered corticotroph function in obesity.

Adrenocorticotropic Hormone↗
PubMed2002

Blood glucose pre-prandial baseline decreases from morning to evening in type 2 diabetes: role of fasting blood glucose and influence on post-prandial excursions.

BACKGROUND: To know the relationships between pre- and postprandial blood glucose (BG), i.e. BG profile shape, is a requisite for an appropriate therapy for type 2 diabetic patients. In non diabetic subjects, pre-breakfast, pre-lunch and pre-dinner BG are similar, so that BG postprandial excursions are superimposed on a stable BG preprandial baseline. We aimed to clarify: (a) whether BG preprandial baseline is stable also in type 2 diabetes and (b) whether fasting BG (FBG) influences the slope of BG preprandial baseline and the relationships between pre- and postprandial BG. DESIGN: We evaluated self-measured BG profiles of 237 type 2 diabetic patients on diet alone (M/F, 152/85; age 58.6 +/- 0.7 years; years from diagnosis 4.8 +/- 0.6; BMI 28.0 +/- 0.3 kg m-2): 536 profiles containing preprandial BG (corresponding HbA1c 6.8 +/- 0.06%) and 208 profiles containing both pre- and postprandial BG (corresponding HbA1c 6.8 +/- 0.09%). The profiles, measured by nurses, of 866 type 2 diabetic patients on diet alone were also considered (corresponding HbA1c 6.7 +/- 0.04%). RESULTS: In self-measured profiles containing only preprandial BG: (i) FBG (6.77 +/- 0.07 mmol L(-1)) is higher than pre-lunch BG (6.09 +/- 0.07 mmol L(-1)), P = 0.0001) and pre-dinner BG (5.84 +/- 0.06 mmol L(-1)), P =0.0001); (ii) the delta value between FBG and pre-dinner BG is correlated with FBG (r = 0.57, P = 0.0001), the highest FBG, the steepest the fall of BG preprandial baseline throughout the day. This trend is confirmed in profiles measured by nurses. In profiles containing both pre- and postprandial BG: (i) there is a trend to preprandial BG fall (P = 0.0001) and to postprandial BG increase (P = 0.0001) from morning to evening; (ii) postprandial excursions are influenced and sometimes masked by the slope of BG preprandial baseline, thus, in profiles with FBG < or = 6.7 mmol L(-1), all postprandial values are higher than FBG (P = 0.0001), whereas in profiles with FBG > 7.8 mmol L(-1), postprandial values are not significantly higher than FBG. CONCLUSION: In type 2 diabetes, the shape of BG profiles changes in relation to FBG, because it deeply influences the slope of BG preprandial baseline on which postprandial excursions are superimposed. Thus, before planning treatment policies, not only the extent of fasting and postprandial hyperglycaemia, but also the shape of profiles should be considered, to safely correct hyperglycaemia without inducing hypoglycaemia.

Blood Glucose↗