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The present study aimed to evaluate the clinical and radiological 1-year outcomes of uterine artery embolization (UAE) performed in a selected population of women with symptomatic myomas and who do not wish to conceive. Between January 2004 and January 2018, a total of 62 patients with pre-menopausal status and with no wish to conceive in the future underwent UAE for the treatment of symptomatic fibroids. All the patients underwent magnetic resonance imaging (MRI) and/or transvaginal ultrasonography (TV-US) before and after the procedure at 1-year follow-up. Clinical and radiological parameters were recorded, stratifying the population into 3 groups according to the size of the dominant myoma (group 1: 80 mm). Mean fibroid diameter was significantly reduced (42.6% ± 21.6%) at 1-year follow-up, with excellent improvements in terms of both symptoms and quality of life. No significant difference was observed regarding baseline dimension and the number of myomas. No major complications were reported (2.5%). The present study confirms the safety and efficacy of UAE in the treatment of symptomatic fibroids in pre-menopausal women with no desire to conceive.

Purpose CT findings of hospitalized COVID-19 patients were analyzed during both the first and the second waves of the pandemic, in order to detect any significant differences between the two groups. Methods In this observational, retrospective, monocentric study, all hospitalized patients who underwent CT for suspected COVID-19 pneumonia from February 27 to March 27, 2020 (first wave) and from October 26 to November 24, 2020 (second wave) were enrolled. Epidemiological data, radiological pattern according to the RSNA consensus statement and visual score extension using a semi-quantitative score were compared. Results Two hundred and eleven patients (mean age, 64.52 years ± 15.14, 144 males) were evaluated during the first wave while 455 patients (mean age, 68.26 years ± 16.34, 283 males) were studied during the second wave. The same prevalence of patterns was documented in both the first and the second waves (p = 0.916), with non-typical patterns always more frequently observed in elderly patients, especially the “indeterminate” pattern. Compared to those infected during the first wave, the patients of the second wave were older (64.52 vs.68.26, p = 0.005) and presented a slightly higher mean semi-quantitative score (9.0 ± 2.88 vs. 8.4 ± 3.06, p = 0.042). Age and semi-quantitative score showed a positive correlation (r = 0.15, p = 0.001). Conclusions There was no difference regarding CT pattern prevalence between the first and the second waves, confirming both the validity of the RSNA consensus and the most frequent radiological COVID-19 features. Non-typical COVID-19 features were more frequently observed in older patients, thus should not be underestimated in the elderly population.

Introduction and Objectives Conventional transarterial chemoembolization (cTACE) has several limitations due to the lack of standardization. The aim of this study was to evaluate the chemical and physical characteristics and behaviors over time of emulsions for cTACE and to assess intra- and inter-operator variabilities in the preparation processes. Materials and Methods This in vitro study involved evaluation of emulsions for cTACE prepared using two methods: water-in-oil (WiO) and chemotherapeutic-in-oil (CiO). Three emulsions were prepared with each method and obtained after 20, 50, and 100 pumping exchanges. A drop from each final mixture was analyzed via light microscopy (time 1) and after 5, 10, 15, and 20 min since the end of preparation. After 20 min, all preparations were re-mixed and new drops were re-evaluated. The intra- and inter-operator variabilities were analyzed. Results The mean droplet diameter decreased non-significantly when the number of pumping exchanges increased and increased significantly over time for both WiO and CiO. The droplets returned to their initial diameters after re-mixing. There were no significant differences in the intra- and inter-operator variabilities (P > 0.01). Conclusions Any interventional radiologist, regardless of their experience, may prepare these emulsions. These data may represent a set of instructions to standardize cTACE.

Intravesical instillation of Bacillus Calmette-Guerin (BCG) is used as an adjuvant treatment of bladder cancer. Systemic BCG infection occurs in less than 1% of cases, and pulmonary involvement is even rarer (0.3% - 0.7%), with a favourable prognosis. A 78-year-old male developed miliary tuberculosis (TB) secondary to intravesical BCG treatment and subsequent coronavirus disease 2019 (COVID-19) superinfection that led to patient death. High awareness amongst clinicians is needed to proceed with immediate appropriate therapy in these patients, especially during the COVID-19 pandemic.

Introduction: Sarcopenia is defined as loss of skeletal muscle mass, strength, and function, and it is associated with increased morbidity and mortality in patients with chronic liver disease. Areas covered: The aim of this review is to provide a detailed report on the pathophysiological mechanisms underlying sarcopenia in cirrhotic patients, the several imaging methods available for the assessment of sarcopenia and the clinical studies evaluating the prognostic role of sarcopenia presence in cirrhotic patients. Expert opinion: Sarcopenia pathogenesis is complex and multifaceted, as chronic catabolic conditions, increased energy expenditure, reduced appetite, side effects of multiple therapies, alterations in circulating levels of hormones, low protein synthesis, presence of ascites or portosystemic shunts are all factors contributing to muscle atrophy in cirrhotic patients. Computed tomography scan is the most validated method to evaluate muscle mass and quality. Sarcopenia is associated with a higher rate waitlist mortality, hepatic encephalopathy, and lower quality of life in patients with liver cirrhosis. Future studies should make an effort to unify and validate liver disease-specific cutoffs for the definition of sarcopenia.

Aim: The present study evaluated the duration of chemoembolization in patients with hepatocellular carcinoma, analyzing possible factors affecting the procedural time. Methods: In total, 175 patients who underwent chemoembolization have been prospectively enrolled. The procedural length was considered the time between the insertion and the removal of the angiographic sheath. The features related to the tumor burden and angiographic procedures, which could be related to the procedural time, were recorded. Results: The chemoembolization time resulted in a mean of 58.1 min. The longer procedural time was associated with a number of nodules treated per patient ≥ 2 (P < 0.001), a number of segments with nodules ≥ 2 (P < 0.001), the presence of more than 1 nodule in the same segment (P < 0.001), the location of the tumor in the left lobe (P = 0.001), the exclusion from the Milan criteria (P < 0.001), and a number of segments treated ≥ 2 (P < 0.001). Only the number of nodules treated per patient resulted significantly in multivariate analysis (OR 2.927, 95%CI: 2.015-4.251, P < 0.001). Conclusion: The factors related to longer procedural time are the number of nodules treated ≥ 2, the number of segments with nodules ≥ 2, the involvement of the left lobe, the tumor burden outside the Milan criteria, and the number of segments treated ≥ 2. All these characteristics, known in the pre-procedural phase, represent useful tools for a correct planning of the angiographic room’s workflow during the pandemic era as well as in the future to reduce downtime and increase productivity.

The aim of the present study was to correlate laboratory data and postprocedural parameters after conventional transarterial chemoembolization (cTACE) for hepatocellular carcinoma (HCC) with the radiological response. The study consisted of a retrospective analysis of prospectively collected data from 70 consecutive patients who underwent cTACE. Laboratory parameters were assessed daily after cTACE and compared to pretreatment values. Post-treatment radiological response was assessed using mRECIST at one month from cTACE, and factors associated with treatment response (complete and objective response) were assessed by logistic regression analysis. The optimal cutoff points in predicting the complete response of target lesions were a 52% ALT and a 46% AST increase after cTACE compared to the pre-treatment values. Using multivariate analyses, &gt, 46% AST and &gt, 52% ALT increases with respect to the pre-treatment value were significantly correlated with the objective response (p = 0.03 and p = 0.04, respectively) and the complete response (p = 0.02 and p = 0.02, respectively). No patients experienced liver function deterioration after cTACE, and no specific treatment was required. This study showed that post-treatment transient transaminase elevation was predictive of objective response to superselective cTACE in clinical practice, representing a simple tool to guide treatment strategy of HCC patients in a tailored approach.

To investigate the feasibility of a study based on treatment with topiramate (TPM) added to moderate hypothermia in newborns with hypoxic ischemic encephalopathy (HIE).Multicenter randomized controlled trial. Term newborns with precocious metabolic, clinical and electroencephalographic (EEG) signs of HIE were selected according to their amplified integrated EEG pattern and randomized to receive either TPM (10 mg/kg once a day for the first three days of life) plus moderate hypothermia or hypothermia alone. Safety was assessed by monitoring cardiorespiratory parameters and blood samples collected to check renal, liver, metabolic balance and TPM pharmacokinetics. Efficacy was evaluated by the combined frequency of mortality and severe neurological disability as primary outcome. Incidence of magnetic resonance injury, epilepsy, blindness, hearing loss, neurodevelopment at 18-24 months of life was assessed as secondary outcomes.Forty-four asphyxiated newborns were enrolled in the study. Twenty one newborns (10 with moderate and 11 with severe HIE) were allocated to hypothermia plus TPM and 23 (12 moderate and 11 severe HIE) to hypothermia. No statistically or clinically significant differences were observed for safety, primary or secondary outcomes. However, a reduction in the prevalence of epilepsy was observed in newborns co-treated with TPM.Results of this pilot trial suggest that administration of TPM in newborns with HIE is safe but does not reduce the combined frequency of mortality and severe neurological disability. The role of TPM co-treatment in preventing subsequent epilepsy deserves further studies.

Background CareToy is an intelligent system, inspired by baby gyms, aimed to provide an intensive, individualized, home-based and family-centred early intervention (EI) program. Aims A pilot study was carried out to explore the feasibility of CareToy intervention in preterm infants, aged 3–9 months of corrected age. Methods Twenty low-risk preterm infants, without brain lesion or other clinical complications (14 allocated to CareToy intervention and 6 to Standard Care) were recruited. The Infant Motor Profile (IMP) was predefined as the primary outcome measure and Alberta Infant Motor Scale and Teller Acuity Cards as secondary measures. Moreover, 202 pre-programmed training scenarios were developed and instructions for the management of CareToy intervention were defined as general guidelines. Outcomes and results All infants received 4 weeks of their allocated intervention and were evaluated with the selected tests before and immediately after the 4 weeks. The mean difference changes in IMP total score and Teller Acuity Cards over the intervention period were higher in the CareToy group than in the Standard Care group. Conclusions and implications CareToy seems a feasible device for providing EI. An adequately powered randomized clinical trial is warranted.

CareToy system is an innovative tele-rehabilitative tool, useful in providing intensive, individualized, home-based, family-centred Early Intervention (EI) in infants. Our aim was to evaluate, through a Randomized Clinical Trial (RCT) study, the effects of CareToy intervention on early motor and visual development in preterm infants. 41 preterm infants (range age: 3.0-5.9 months of corrected age) were enrolled and randomized into two groups, CareToy and Standard Care. 19 infants randomized in CareToy group performed a 4-week CareToy program, while 22 allocated to control group completed 4 weeks of Standard Care. Infant Motor Profile (IMP) was primary outcome measure, Alberta Infant Motor Scale (AIMS) and Teller Acuity Cards were secondary ones. Assessments were carried out at baseline (T0) and at the end of CareToy training or Standard Care period (T1). T1 was the primary endpoint. After RCT phase, 17 infants from control group carried out a 4-week CareToy program, while 18 infants from the CareToy group continued with Standard Care. At the end of this phase, infants were re-assessed at T2. In RCT phase, delta IMP total score and variation and performance sub-domains were significantly higher (PTRIAL REGISTRATION: This trial has been registered at www.clinicaltrials.gov (Identifier NCT01990183).

Background: The clinical use of amplitude integrated electroencephalogram (aEEG) in the neonatal intensive care unit has largely increased. This method has been reported to have a very good predictive value for neurodevelopmental outcome in term neonates after perinatal asphyxia. Aim: The aim of this study was to assess the recovery of aEEG patterns during hypothermic treatment in full term asphyxiated neonates. Our working hypothesis is that children with aEEG recovery within 24 h of therapeutic hypothermia will have a normal development outcome (i.e., no or mild neurological impairment). Study design: We performed an observational prospective study on a group of asphyxiated patients admitted to our Neonatal Intensive Care Unit from April 2009 to April 2012. Results: 24 patients with moderate to severe perinatal asphyxia had an aEEG recorded for at least 72 h during hypotermia (at the beginning of the registration 13 patients presented moderate aEEG abnormalities and 11 severe aEEG abnormalities). Respectively 11 neonates with moderate aEEG abnormalities and 1 neonate with severe abnormalities normalized the aEEG pattern during the treatment. At the follow up 3 patients died during neonatal age, 5 babies developed cerebral palsy, 4 babies developed dyskinetic cerebral palsy and 12 babies did not develop any disability (babies with good outcome were those with normal aEEG pattern at 24 h). Conclusion: Recovery to a normal aEEG background pattern within the first 24 h of hypothermia after perinatal asphyxia predicts a normal outcome. Abnormal aEEG pattern persisting after 24 h correlates with poor outcome (death or cerebral palsy).

Autoimmune thyroid disorders (AITDs) are the result of a complex interplay between genetic and environmental factors, the former account for about 70-80% of liability to develop AITDs. However, at least 20-30% is contributed by environmental factors, which include certainly smoking (at least for Graves' disease and orbitopathy), probably stress, iodine and selenium intake, several drugs, irradiation, pollutants, viral and bacterial infections, allergy, pregnancy, and post-partum. Evidence for the intervention of these factors is often limited, and the mechanisms whereby environmental factors may concur to the onset of AITDs are in many instances unclear. Nevertheless, gene-environment interaction seems a fundamental process for the occurrence of AITDs.

In the last few decades, the survival rates of preterm babies and full-term babies with severe diseases have increased due to advances in perinatal care. Understandably however, higher survival rates have not been accompanied by an overall reduction of morbidity, so that limitation of long-term neurodevelopmental abnormalities remains a major challenge of early care (Plaisier et al., 2014). The possibility to better predict the outcome of newborns at neurodevelopmental risk is essential to inform early intervention, to allow best allocation of resources, and to minimize long-term consequences. Unfortunately, clinicians continue to possess limited ability to predict neurodevelopmental outcomes, mainly relying, in most settings, on early findings at cranial ultrasound (cUS). Recent studies (Smyser et al., 2012) have proven the power of magnetic resonance imaging (MRI) superior to other neuroimaging modalities, including cUS, in detecting cerebral injury. Neonatal MRI provides non-invasive, high-resolution images in less than 1 h; scans are performed without sedation eliminating the risk and the costs associated to it and are not associated to radiation exposure, as for computerized tomography (CT). The application of MRI in the neonatal population is rapidly increasing, making MRI one of the key diagnostic tools for the assessment of early brain development and injury. In specific clinical groups, such as for example very preterm infants, cerebral MRI should become part of standard clinical care and should be systematically performed at term equivalent age (TEA). Accurate assessment of cortical folding at TEA provides an important marker for structural brain growth and maturation. Myelination of the posterior limb of the internal capsule (PLIC) at around 36–38 weeks gestation, identifiable on T1 but also on T2-weighted images, is another important maturational hallmark, since its presence and symmetry are very powerful in predicting motor outcome. MR imaging is superior to cUS also in detecting diffuse white matter (WM) injury. Indeed, although cystic periventricular leukomalacia is seen less often, diffuse non-cystic types of WM injury, including punctate WM lesions and diffuse excessive high signal intensity, are most frequent and are considered the leading cause of disturbed brain growth, connectivity, and functionality. The predictive power of conventional MRI in this domain remains relatively low, as it is not sensitive enough to analyze changes in microstructure; however, it is greatly enhanced by the use of advanced MR techniques targeting the WM, such as diffusion tensor imaging (DTI), that can help analyzing brain growth in extremely preterm babies in the absence of evident WM abnormalities (Ramenghi et al., 2009). Diffusion tensor imaging (DTI) is a relatively new MR modality that assesses water diffusion in biological tissues at microstructural level. The diffusion tensor describes an ellipsoid in space characterized by the diffusion eigenvalues (λ1,λ2,λ3) in the three orthogonal directions and their corresponding eigenvectors. In brain WM, axial diffusivity (λ1) is oriented along the direction of the main tracts and radial diffusivity (λ2 and λ3) is oriented perpendicular to these tracts. Average diffusivity (Dav) reflects the mean of these eigenvalues and it is an indicator of brain maturation and/or injury. Dav decreases with increasing age probably for decreasing water content and increasing complexity of WM structures with myelination. Fractional anisotropy (FA) reflects the variance of the eigenvalues, ranging from 0 (isotropic diffusion) to 1 (anisotropic). The diffusion is mainly anisotropic because the water molecules preferentially move in the direction of fascicles of axons (Adams et al., 2010). In the white and gray matter, there is similar water content but different Dav value probably because the WM is less restrictive to water motion. Brain water content decreases with increasing gestational age and this mostly increases the WM anisotropy values. This increase has also been attributed to changes in WM structure associated with histologic maturation, and it takes place at different rates in different brain areas [the main areas analyzed are in commissural tracts, the corpus callosum (CC), and in projection tracts, the corticospinal tracts (CSTs)]. Developmental changes in anisotropy of cerebral cortex reflect changes in its microstructure, such as the arborization of basal dendrites of cortical neurons, the innervation of the cortical plate by thalamocortical and cortico-cortical fibers, all processes which are important basis of later functional connectivity (Huppi and Dubois, 2006). Because there are strongly preferred directions of diffusion, it is possible to create color maps of neonatal brain with diffusion tensor post-processing techniques. The color maps are based on major orientation with red representing right–left, green representing antero–posterior, and blue representing superior–inferior anatomical directions (De Bruine et al., 2013) (Figure ​(Figure11). Figure 1 Color anisotropy maps. Preterm birth can cause white matter injuries (WMIs) and consequently can cause change in FA and diffusivity. Decreased FA in the CC of preterm babies scanned at TEA is rather common and implies less efficient transmission between the hemispheres and may lead to language problems and cognitive dysfunctions. Regions with increased FA in a preterm baby may be attributed to a loss or to an impairment of WM instead of improved WM maturation (Li et al., 2014). Disorders of motor function can be tested in clinical practice with DTI. In children with congenital hemiparesis, there are different diffusion characteristics of CSTs compared to healthy one. There is an increasing FA asymmetry and a decrease in FA value in the affected pyramidal tract. A recent extension of DTI is tractography, which is a powerful tool that offers the possibility of non-invasive identification of specific WM pathways and connections in the brain. The general principle is to connect adjacent image voxels following water diffusion. Directional coherence of the fibers in a pathway is used to determine the presence or absence of connectivity between two regions of the brain. Tracking of the fiber-trajectories is terminated when they turn of too much degrees between two successive voxels. The main regions of interest include the CSTs, the CC, and optic radiations (OR). The primary goal should be to understand the normal relationship between structural and functional networks of these structures but there are few data in preterm babies (Brown et al., 2014). Preterm birth correlates with reduced connectivity, and it is very difficult to establish normal value for all gestational ages. Maturation does not occur simultaneously in the brain infact, for example, connectivity increases earlier in the occipital lobe and then in the frontal area. The postnatal age and WMI are additional confounding factors of diffusion metrics (Pannek et al., 2014). Nevertheless, the primary difference between DTI and conventional imaging is the capability of DTI to often detect injury earlier. This could anticipate the diagnosis of brain damage and might offer advantages in the future for deciding early intervention or administration of neuroprotective agents. Further studies will be needed to confirm whether these new techniques may predict neurodevelopmental outcome and whether they are equally applicable to all the pathways of the central nervous system.

Psychological tests based on visual information processing have shown to be promising in predicting neurodevelopmental outcome in infants at risk. In the present study we prospectively investigated the early development in a group of 20 high-risk preterm infants by means of i) the Fagan Test of Infant Intelligence at 7, 9, and 12 months postterm and ii) a detailed battery for the early assessment of visual functions at 6 and 10 months postterm. The results were then correlated to the Griffiths development scales at two years. At around 7 months no correlation was found in our infants between the Fagan test and neurodevelopmental outcome, possibly as a consequence of the influence of abnormal oculomotor behaviour. At around 9 months most of the visual abnormalities were no more present and the Fagan test was significantly correlated with the outcome. At 12 months postterm a decline of the predictive value of the FTII was observed. In conclusion, nine months postterm age appears to be the best age for the early assessment of neurodevelopmental outcome in high-risk preterm infants, as the maturation of the attentional and visual systems allows a more reliable evaluation.

Fukutin-related protein (FKRP) is a putative glycosyltransferase that mediate O-linked glycosylation of the α-dystroglycan. Mutations in the FKRP gene cause a spectrum of diseases ranging from a limb girdle muscular dystrophy 2I (LGMD2I), to severe Walker-Warburg or muscle-eye-brain forms and a congenital muscular dystrophy (with or without mental retardation) termed MDC1C. This article reports on a Moroccan infant who presented at birth with moderate floppiness, high serum creatine kinase (CK) levels, and brain ultrasonograph suggestive of widening of the posterior fossa. Muscle biopsy displayed moderate dystrophic pattern with complete absence of α-distroglycan and genetic studies identified a homozygous missense variant in FKRP. Mutations in FKRP should be looked for in forms of neonatal-onset hyperCKaemia with floppiness and small cerebellum.

Birth asphyxia is a cause of neonatal death or adverse neurological sequelae. Biomarkers can be useful to clinicians in order to optimize intensive care management and communication of prognosis to parents. During perinatal adverse events, increased cortisol secretion is due to hypothalamo-pituitary-adrenal axis activation. We aimed to investigate if cortisol variations during therapeutic hypothermia are associated with neurodevelopmental outcome. We compared 18 cases (neonates with birth asphyxia) with 18 controls (healthy term newborns) and confirmed increased serum cortisol concentrations following the peri-partum adverse event. Among cases, we stratified patients according to neurological outcome at 18 months (group A - good; group B - adverse) and found that after 24 h of therapeutic hypothermia serum cortisol concentration was significantly lower in group A vs group B (28.7 ng/mL vs 344 ng/mL, *p = 0.01). In group B serum, cortisol concentration decreased more gradually during therapeutic hypothermia. We conclude that monitoring serum cortisol concentration during neonatal therapeutic hypothermia can add information to clinical evaluation of neonates with birth asphyxia; cortisol values after the first 24 h of hypothermia can be a biomarker associated with neurodevelopmental outcome at 18 months of age.

OBJECTIVE The relationship between the method of treatment of hyperthyroidism due to Graves' disease and the course of Graves' ophthalmopathy is debated. Antithyroid drug therapy is associated with no change, or even amelioration, of ophthalmopathy. Although controversial, radioiodine may be followed by progression of eye disease, preventable by glucocorticoid administration. Whether thyroidectomy affects the course of ophthalmopathy is uncertain. DESIGN In a case control study, the course of non-severe Graves' ophthalmopathy after thyroidectomy was investigated and the results compared with those observed in patients treated with methimazole. PATIENTS Thirty patients with Graves' hyperthyroidism and non-severe/absent ophthalmopathy were treated with near-total thyroidectomy (Group 1, Tx), after achievement of euthyroidism with methimazole. After surgery, all patients started levothyroxine replacement therapy. Sixty patients treated with methimazole, matched for age, sex, duration of hyperthyroidism, degree of ocular involvement and smoking habits, were used as controls (Group 2, MMI). MEASUREMENTS Patients were seen every 1-2 months for 12 months for thyroid tests and ocular evaluation. RESULTS In Group 1, ocular parameters did not change in 17 of 18 patients with pre-existing ophthalmopathy, and in 12 patients without ophthalmopathy. Eye manifestations worsened only in one (3.3%) patient with pre-existing ophthalmopathy. In Group 2, ocular parameters did not change in 58 patients (33 with, and 25 without ophthalmopathy), while new ophthalmopathy occurred in two without pre-existing eye disease. One of the 30 patients treated by surgery (3.3%) had permanent hypoparathyroidism. CONCLUSIONS Treatment of Graves' hyperthyroidism with near-total thyroidectomy in patients with non-severe or absent pre-existing ophthalmopathy is not associated in the short term with significant effects on the course of ophthalmopathy.

The prevalence and natural history of Graves' orbitopathy (GO) are poorly documented.A large series of 346 patients with newly diagnosed and recent onset Graves' hyperthyroidism seen at a single (nontertiary referral) center over an 8-year period were enrolled in an observational prospective study and evaluated for GO activity and severity according to the EUGOGO (European Group on Graves' Orbitopathy) criteria. After excluding patients immediately treated for moderate-to-severe GO, patients undergoing total thyroidectomy or radioactive iodine treatment, and patients lost to follow-up, 237 patients were submitted to antithyroid drug (ATD) treatment, with ocular evaluation at 6, 12, and 18 months.Among the whole cohort, at presentation 255 (73.7%) had no ocular involvement, 70 (20.2%) had mild and inactive GO, 20 (5.8%) had moderate-to-severe and active GO, and 1 (0.3%) had sight-threatening GO with dysthyroid optic neuropathy. Of the 237 patients who completed the 18-month follow-up during or after ATD treatment, 194 (81.9%) had no GO at baseline. Progression to moderate-to-severe GO occurred in 5 (2.6%) of these patients. Of the 43 (18.1%) patients with mild and inactive GO at baseline, 1 (2.4%) progressed to moderate-to-severe GO, and 25 (58.1%) experienced complete remission.Most patients with newly diagnosed Graves' disease have no ocular involvement. Moderate-to-severe and active GO or sight-threatening GO are rare at presentation and rarely develop during ATD treatment. Most patients (80%) with no GO at baseline do not develop GO after an 18-month follow-up period. Remission of mild GO occurs in the majority of cases.

The aim of the study was to assess the prognostic value of maturational abnormalities in the electroencephalogram (EEG) of preterm infants. 63 subjects (mean gestational age: 32.7 weeks; range 28-34) were submitted to EEG recording within the first two weeks of life and subsequently followed up until at least 12 months of corrected age. Maturational features of background EEG were analysed and the occurrence of different degrees of maturational anomalies ("dysmaturity") was scored, according to standardised criteria. The results were compared to neurological outcome and to cranial ultrasound (US) findings. EEG maturational features significantly related to the outcome. When the EEG background activity was normal all but one patient showed a favourable outcome; the incidence of neurological sequelae became higher according to the degree of dysmaturity detected. However, some infants had a normal evolution, despite severe EEG dysmaturity in the early postnatal period. The correlation between EEG and US findings was low, although US also significantly related to the outcome. Background EEG maturational features seem to be a reliable prognostic tool in the early postnatal period of preterm infants, complementary to serial US scans.

Background Despite progresses in neonatal care, the mortality and the incidence of neuro-motor disability after perinatal asphyxia have failed to show substantial improvements. In countries with a high level of perinatal care, the incidence of asphyxia responsible for moderate or severe encephalopathy is still 2–3 per 1000 term newborns. Recent trials have demonstrated that moderate hypothermia, started within 6 hours after birth and protracted for 72 hours, can significantly improve survival and reduce neurologic impairment in neonates with hypoxic-ischemic encephalopathy. It is not currently known whether neuroprotective drugs can further improve the beneficial effects of hypothermia. Topiramate has been proven to reduce brain injury in animal models of neonatal hypoxic ischemic encephalopathy. However, the association of mild hypothermia and topiramate treatment has never been studied in human newborns. The objective of this research project is to evaluate, through a multicenter randomized controlled trial, whether the efficacy of moderate hypothermia can be increased by concomitant topiramate treatment. Methods/Design Term newborns (gestational age ≥ 36 weeks and birth weight ≥ 1800 g) with precocious metabolic, clinical and electroencephalographic (EEG) signs of hypoxic-ischemic encephalopathy will be randomized, according to their EEG pattern, to receive topiramate added to standard treatment with moderate hypothermia or standard treatment alone. Topiramate will be administered at 10 mg/kg once a day for the first 3 days of life. Topiramate concentrations will be measured on serial dried blood spots. 64 participants will be recruited in the study. To evaluate the safety of topiramate administration, cardiac and respiratory parameters will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. To evaluate the efficacy of topiramate, the neurologic outcome of enrolled newborns will be evaluated by serial neurologic and neuroradiologic examinations. Visual function will be evaluated by means of behavioural standardized tests. Discussion This pilot study will explore the possible therapeutic role of topiramate in combination with moderate hypothermia. Any favourable results of this research might open new perspectives about the reduction of cerebral damage in asphyxiated newborns. Trial registration Current Controlled Trials ISRCTN62175998; ClinicalTrials.gov Identifier NCT01241019; EudraCT Number 2010-018627-25

Increased serum interleukin-6 (IL-6) concentrations have recently been reported in patients with subacute thyroiditis and in some patients with amiodarone-induced thyrotoxicosis, possibly because of cytokine release from damaged thyroid cells. In this study, serum IL-6 levels were determined by an enzyme-linked immunosorbent assay method in 18 patients given percutaneous intranodular ethanol injection (PIEI) for autonomously functioning thyroid nodule, 12 patients treated with radioactive iodine (RAI) for Graves' disease or toxic adenoma, and 23 patients submitted to fine needle aspiration (FNA) for nonfunctioning thyroid nodules. Baseline serum IL-6 levels did not differ in the 3 groups. PIEI was followed by a dramatic increase in median IL-6 values from 42 fmol/L (range, < 25 to 84) to 381 fmol/L (range, 61-9870; P < 0.0001); the peak value was attained as little as 10 min after injection. RAI was also followed by a significant (P < 0.0001) increase in IL-6 from 52 fmol/L (range, < 25 to 84) to 189 fmol/L (range, 119-1417 fmol/L); the increase after RAI was lower than that after PIEI (P < 0.05), and the peak value was attained later (after 24 h). FNA was also followed by a slight, but significant, increase in the serum IL-6 concentration from 21 fmol/L (range, < 25 to 103) to 109 fmol/L (range, < 25 to 360; P < 0.0001 vs. baseline). The increase in IL-6 was correlated with the size of nodule or goiter (P < 0.0001), but not with the amount of injected ethanol or the dose of radioiodine delivered to the thyroid. Serum thyroglobulin also increased after PIEI, RAI, or FNA, but no significant correlation could be demonstrated with the increase in IL-6. The results of this study support the concept that in the absence of nonthyroidal illnesses, which are often associated with increased serum concentrations of the cytokine, IL-6 can be regarded as a useful marker of thyroid-destructive processes.

Variations in the serum concentration of interleukin-6 (IL-6) have been reported concomitantly with thyroid dysfunction: increased serum IL-6 levels have been found in patients with thyroidal destructive processes, such as subacute thyroiditis, some forms of amiodarone-induced thyrotoxicosis, or after percutaneous ethanol injection into "hot" thyroid nodules, as a result of the cytokine release from the damaged thyrocyte. In addition, recent in vitro evidence suggests that IL-6 might account, at least in part, for changes of thyroid economy found in nonthyroidal illness (NTI). In this cross-sectional study we addressed this problem by measuring serum IL-6 levels in 71 patients with NTI, due to neoplasia (n = 25), chronic liver disease (n = 9), chronic renal failure (n = 28), or other chronic nonthyroidal disorders (n = 9). These patients had reduced mean serum total T3 (TT3) and free T3 (FT3) concentrations, normal total and free T4 levels, normal TSH values, and increased serum reverse T3 (rT3) concentration (with the exception of chronic renal failure patients, who had normal rT3 levels). Serum IL-6 concentration was increased above normal (i.e. > 100 fmol/L) in almost all NTI patients, especially in those with low T3 values (median value: 258 fmol/L, range 73-3210, vs 152 fmol/L, range < 12.5-460, in patients with normal TT3 values, p < 0.001). Serum IL-6 values in NTI patients were negatively correlated with serum FT3 values (r = 0.56, p < 0.001), and positively correlated with serum rT3 values (r = 0.78, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Circadian variations in serum TSH, especially its nocturnal rise, are often blunted in nonthyroidal illness. We analyzed TSH secretion in 15 diabetic patients (7 with type I and 8 with type II diabetes mellitus). Patients were evaluated when diabetes was poorly controlled (fasting blood glucose ranging from 13.7-19.2 mmol/L with absence of ketoacidosis) and after achieving glycemic control. Before correction of hyperglycemia, the nocturnal serum TSH peak (2230-0200 h) was abolished in 11 of 15 patients (73%); the mean (+/- SE) night TSH/morning TSH x 100 was 109.0 +/- 9.5 (range, 66.7-166.7) vs. a mean of 216.5 +/- 27.0 (range, 139.8-462.5) in normal controls. The mean morning TSH value in diabetics (1.9 +/- 0.4 mU/L) did not differ from that in normal age- and sex-matched controls. The mean TSH increase after iv administration of TRH was only slightly reduced (8.4 +/- 1.2 mU/L pretreatment vs. 10.8 +/- 1.6 mU/L posttreatment), with the TRH test blunted in 3 cases. No differences were found between type I and type II patients. Correction of hyperglycemia was associated with the reappearance of a nocturnal TSH peak in all but 1 patient (mean TSH peak, 198.2 +/- 13.0; P = NS vs. controls). This change paralleled the normalization of serum total T3 and rT3, which were reduced and increased, respectively, when diabetes was poorly controlled. An inverse relationship was found between serum fructosamine levels and the nocturnal TSH peak, suggesting that metabolic decompensation accounts for the abolishment of the latter.

A high prevalence of antibodies to double-stranded DNA (AbDNAds) has been recently reported in serum of patients with autoimmune thyroid disorders, but the specificity of this finding has been questioned. For this reason, the prevalence of several antibodies to DNA-related nuclear antigens (AbDRENA) has been evaluated in sera of patients with autoimmune and non-autoimmune thyroid disease. The study group included: 46 Graves' disease patients, 28 Hashimoto's thyroiditis patients, 25 patients with toxic nodular goitre and 11 with non-toxic nodular goitre. Twenty-eight Graves' patients were retested during methimazole (MMI) therapy, and 5 after radioiodine administration. Twenty-two patients with systemic lupus erythematosus and 28 normal subjects served as positive and negative controls, respectively. AbDRENA included: AbDNAds by RIA or immunofluorescence (IF); antibodies to single-stranded DNA (AbDNAss) and antibodies to histone (AbHist) by ELISA methods; antibodies to nuclear antigens (ANA) by immunofluorescence. RIA values were considered to be abnormal when 2 SD above the mean of normal controls. In our study 13% of Graves' patients were positive for AbDNAds by RIA: all of them had negative tests by IF; 11% were positive for AbDNAss, 2% for AbHist and 7% for ANA. A comparable prevalence of positive results for AbDNAds by RIA, with negative IF tests, was found in Hashimoto's thyroiditis patients. No significant changes of antibody levels were observed in Graves' patients during MMI treatment or after radioiodine administration. A positivity for AbDNAds or AbDNAss was found in 8% of patients with toxic nodular goitre, but in none of those with non-toxic goitre.(ABSTRACT TRUNCATED AT 250 WORDS)

Graves' ophthalmopathy (GO), the most frequent extrathyroidal manifestation of Graves' disease, is a disorder of autoimmune origin, the pathogenic mechanisms of which are still incompletely understood. Although GO is severe in only 3-5% of affected individuals, quality of life is severely impaired even in patients with mild GO. Management of severe GO can be either medical or surgical (orbital decompression, eye muscle or lid surgery). Medical management relies on the use of high-dose systemic glucocorticoids or orbital radiotherapy, either alone or in combination. Studies carried out in the last 5 yr have shown that glucocorticoids are more effective through the i.v. route than through the oral route. However, particular attention should be paid to possible liver toxicity of i.v. glucocorticoids. Recent randomized clinical trials have, with one exception, confirmed that orbital radiotherapy is an effective and safe therapeutic procedure for GO. At variance with previous encouraging data, recent randomized clinical trials have shown that currently available SS analogs are not very effective in the management of GO. Antioxidants might have a role, at least in mild forms of GO. Particular attention should be paid to correction of risk factors (cigarette smoking, thyroid dysfunction, radioiodine therapy) involved in GO progression.

Pendred's syndrome is characterized by goiter, sensorineural deafness and impaired iodide organification. It is one of the most frequent causes of congenital deafness accounting for about 10% of hereditary hearing loss. It is caused by mutations in the pendrin (PDS) gene, which was postulated to be a sulfate transporter, because of its homology with other genes. We tested sulfate transport in mammalian COS-7 cells that were transiently transfected with PDS cDNA. 35SO4 uptake increased in a time-dependent manner, but this phenomenon was similar in cells transfected with PDS and in mock-transfected cells (450 and 360 cpm/beta-gal units at 10 min, respectively; 38,250 and 31,000 cpm/beta-gal units, at 12 h, respectively). There was no significant increase in 35SO4 uptake using increasing amounts of PDS-containing plasmid (up to 12 microg per dish). These data indicate that pendrin is not a sulfate transporter. Additional functional studies on this protein are warranted to clarify its role in thyroid pathophysiology and inner ear development.

We report the case of a 6-week-old female who presented an intracranial hemorrhage due to late vitamin K deficiency bleeding (VKDB). No other evident bleeding sites were present at the moment of diagnosis. Intramuscular vitamin K (1 mg) was administered at birth. She was exclusively breast-fed. No other risk factors for VKDB were detected. Low levels of vitamin K-dependent coagulation factors and their normalization after vitamin K administration confirmed the diagnosis of late VKDB. The present case suggests potential risks related to a single dose of intramuscular vitamin K at birth.

Thyrotoxicosis factitia, a syndrome due to the surreptitious ingestion of excess thyroid hormones, has generally been diagnosed in young or middle-aged women with psychopathological disturbances. We reviewed all the cases seen at our Institution over a 24-yr period, from 1973 to 1996. All 25 patients were women. Analysis was restricted to 17 patients who were born and lived in Tuscany (our region), since only these patients were distributed during the whole observation period. Diagnosis of thyrotoxicosis factitia was based on the following parameters: elevated serum total and/or free thyroid hormone levels, undetectable serum thyrotropin levels, low/undetectable serum thyroglobulin concentration, normal urinary iodine excretion, low/suppressed thyroidal radioactive iodine uptake (RAIU), absence of goiter, absence of circulating anti-thyroid antibodies. Surreptitious ingestion of thyroid hormone pill was eventually admitted by all patients. Age at diagnosis was >50 yr in 7/17 patients (41%): 6 of them were distributed in the period 1995-1996, and one in 1988. Patients older than 60 yr were 5/17 (29%), all in the last two years of the period under investigation. There was an increase in the age of patients with thyrotoxicosis factitia (p=0.02), which lost a statistical significance when the patients of the 1995-1996 period were excluded from analysis (p=0.88). This study provides evidence of an increased age of patients with thyrotoxicosis factitia in more recent years. From a practical standpoint, our study suggests that thyrotoxicosis factitia should be suspected and adequately looked for even in old patients with thyrotoxicosis of inexplicable origin, especially in the absence of goiter and thyroid autoimmune phenomena, and when common causes of low-RAIU hyperthyroidism, such as a load with iodine-containing drugs or subacute thyroiditis, have been excluded.

Following the incidental diagnosis of triventricular hydrocephalus in a fetus 34 weeks after the mother's last menstrual period, during an uneventful pregnancy, 1.5-T brain magnetic resonance (MR) was carried out. A subependymal hemorrhage, which had not been revealed by transabdominal ultrasound, was found; this finding was confirmed by neonatal brain ultrasound and MR. Fetal MR allowed identification of the hemorrhage as the cause of the hydrocephalus and also established its time of occurrence. Unexplained hydrocephalus should be included among the indications for fetal MR.

The aim of this study is to identify normal EEG patterns of preterm infants, characteristic of early postmenstrual ages (PMAs). Quantitative features of EEG background activity have been examined in records from 83 preterm infants within the first 2 weeks of life at a PMA of 27-34 weeks. These subjects presented different cranial ultrasound findings and different outcomes. EEG quantitative data have been compared to the subsequent neurological evolution. We supposed that the features of EEG background activity which were associated with a favourable outcome should be considered as indexes of "normality" of the tracing for that specific PMA. At 27-30 weeks of PMA a high incidence of "temporal sawtooth," a particular rhythmic theta activity detectable in temporal regions, relates to a favourable evolution, therefore it can be assumed that this activity is a normal feature of EEG tracings at this age. On the contrary, a significant correlation between a high incidence of "temporal sawtooth" and an abnormal outcome is observable at 33-34 weeks and leads us to deduce that this pattern should disappear at this time. After 31 weeks other parameters (such as the incidence of 8-20 Hz activities, the length of the intervals and burst duration) show a significant correlation with the outcome.

The somatostatin analogue, octreotide (OC) has commonly been used in the management of growth hormone- and thyrotropin-secreting pituitary tumors, and shown to be effective both on hormone production and tumor size. Because OC receptors may be expressed also in some nonfunctioning pituitary adenomas, it has been postulated that OC might play a role in the treatment of these tumors as well. In the present study, the morphological effects of OC administration, as assessed by computer tomography (CT) scan, were evaluated in 8 patients (5 men, 3 women, age range 25-79 yr) affected by non-functioning pituitary tumors. The drug was given sc at the dose of 100 micrograms tid for 3-6 months. No significant change in visual field or tumor size occurred after OC treatment in 7 patients, whereas one showed a significant improvement of visual field associated with a decreased tumoral mass. These data suggest that OC is not an effective drug in the management of nonfunctioning pituitary adenomas.

Interleukin-6 (IL-6) is the main mediator of the acute phase response. Increased serum concentrations of the cytokine have been found in patients with nonthyroidal inflammatory disorders and infections. In 18 patients with subacute thyroiditis (SAT) evaluated within 1-2 weeks after the onset of the disease, serum IL-6 values, as assessed by an ELISA method having a limit of detection of 25 fmol/L, ranged 139.2-543.9 fmol/L (mean +/- SE, 287.2 +/- 28.2 fmol/L). These values were significantly higher than those of 25 normal healthy controls (mean +/- SE, 26.2 +/- 5.5 fmol/L, range < 25-99.4), 18 of whom had serum IL-6 values below the detection limit. The increase in serum IL-6 levels in SAT patients appeared to be related to the inflammatory disorder and not to thyrotoxicosis, because 18 Graves' disease patients and 13 patients with toxic adenoma or toxic multinodular goiter had significantly lower serum IL-6 concentrations (101.7 +/- 35.2 fmol/L, range < 25-251, for Graves' disease, 79.6 +/- 41.4 fmol/L, range < 25-168.5, for toxic adenoma, p < 0.001 vs SAT for both groups) despite the markedly higher levels of total and free thyroid hormones. Neither free T4 nor free T3 values were correlated with serum IL-6 levels both in SAT and Graves' patients. Twelve SAT patients were reevaluated 3-4 months later, after remission of the disease and at least one month after glucocorticoid withdrawal. At the final observation, all SAT patients showed a normalization of IL-6 concentration, which was undetectable in 8/12 (mean +/- SE, 22.8 +/- 5.4 fmol/L, p < 0.001 vs acute phase values).(ABSTRACT TRUNCATED AT 250 WORDS)

Urinary iodine excretion was measured in 300 consecutive patients admitted to a general hospital for nonthyroidal disease. Iodine contamination (values greater than 300 micrograms l/g creatinine) was found in 29.3% of cases, mostly due to amiodarone and iodinated contrastographic agents. The source of iodine contamination was not detected in 23% of cases.

Leukomalacia is a major cause of neurological impairment in the high-risk newborn. It can be identified during the early postnatal period by means of ultrasound (US) imaging of the brain, through the anterior fontanel. Magnetic resonance imaging (MRI) permits an optimal differentiation of brain tissue and of its abnormalities, without resorting to ionizing radiation or intravenous contrast. It is particularly appropriate for following the evolution of leukomalacia, after fontanel closure. Ninety-five fullterm and preterm infants with cystic and non-cystic leukomalacia, documented by US, were clinically followed-up until at least 12 months of corrected age. Thirty-two had a severe neurological outcome (mainly cerebral palsy, sometimes associated with mental retardation and/or cerebral visual impairment). The prognosis was worse in cystic leukomalacia than in prolonged flare. Electroencephalogram (EEG) carried out in the first 2 weeks of life provided valuable indexes of further outcome, especially for US findings of more uncertain prognosis. MRI was carried out at around 12 months of corrected age, by means of an apparatus operating at 0.5 Tesla. The main categories of abnormalities observed were the following: cystic lesions, enlarged ventricles with irregular outlines, delayed myelination, high intensity areas in the long TR (repetition time) images within the white matter, cortical atrophy. MRI findings correlated well with the results of US imaging and often with motor, cognitive and visual impairments. Nevertheless, clinical features cannot be predicted by neuroimaging alone and a comprehensive approach, including longitudinal functional and electrophysiological testing, is highly recommended.

TSH secretion was evaluated in 10 patients with ACTH-dependent (pituitary microadenoma, n = 5) or ACTH-independent [adrenal adenoma (n = 4) or carcinoma (n = 1)] Cushing's syndrome, and in 12 normal controls matched for age and sex. Serum TSH concentration was assayed at night, from 2200-0200 h, and in the morning, both basally and 30 min after iv injection of 200 micrograms synthetic TRH. Patients with hypercortisolism showed significantly reduced serum total T4 and T3 and free T3 concentrations and increased serum reverse T3 levels. Their mean baseline serum TSH concentration in the morning, albeit slightly lower, did not significantly differ from those of controls. The mean peak TSH value after TRH was significantly reduced, and a blunted TSH response to TRH was found in 4 out of 10 patients. At variance with normal controls, who showed nighttime TSH values 63-228% higher than morning values, 9 out of 10 patients had nighttime levels not different from or even lower than those in the morning; the remaining patient had nighttime TSH values marginally (33%) higher than in the morning. An inverse relationship (r = 0.80, P less than 0.001) was found between serum cortisol and TSH values both at night and in the morning. No differences were found either in the pattern of TSH secretion or in the TSH response to TRH between patients with ACTH-dependent and those with ACTH-independent Cushing's syndrome. These results show a substantial impairment of TSH secretion, and in particular the loss of the nocturnal surge of the hormone, in patients with Cushing's syndrome. Although the origin of the nocturnal TSH rise is probably multifactorial, cortisol, at least when secreted in excess, appears to play an important role in its regulation.

TSH secretion, with particular regard to the nocturnal surge of the hormone, was evaluated in 15 women (age range, 35-66 yr; mean, 50 yr) with untreated major endogenous depression and 15 healthy women (age range, 32-67 yr; mean, 53 yr) using an ultrasensitive assay. Mean morning (0830 h) TSH values did not differ in the 2 groups (1.3 +/- 02 mU/L in depressives and 1.4 +/- 0.1 mU/L in controls), whereas mean nighttime (2400-0200 h) values were significantly reduced in depressives (1.5 +/- 0.3 vs. 3.1 +/- 0.3 mU/L; P less than 0.0005). At variance with the control group, morning and nighttime TSH values did not differ in the depressives. The nocturnal serum TSH surge was abolished in 14 of 15 depressed patients. The mean peak TSH value after TRH was slightly yet significantly lower in the depressives. Patients with subnormal (less than 0.4 mU/L) TSH values in the morning had a serum TSH increase after TRH less than 2 mU/L in 5 of 6 cases and a lack of the nocturnal TSH surge in 6 of 6. Among the 9 patients with normal TSH values in the morning, the nocturnal serum TSH surge was lost in 8 of 9, whereas the response to TRH was normal in all. The depressives, at variance with other reports, showed significantly lower values of total and free thyroid hormones. Mean serum sex hormone-binding globulin (SHBG) and ferritin were also significantly reduced. In conclusion, major endogenous depression is associated with a major impairment of TSH secretion, which baseline TSH measurements in the morning and the evaluation of the TSH response to TRH may not reveal. In this regard, the loss of the nocturnal serum TSH rise would appear to be a more sensitive indicator of hypothalamus-pituitary-thyroid axis alterations in depressives than the TRH test, which is commonly used in the evaluation of these patients. The lack of the nocturnal TSH surge may be responsible for the reduced thyroid hormone secretion and supports the case for some degree of central hypothyroidism in endogenous depression.

An ultrasensitive immunoradiometric assay (IRMA) using two monoclonal anti-TSH antibodies has been used for TSH measurements in basal conditions and after TRH stimulation. The results have been compared with those obtained by conventional radioimmunoassay (RIA). The IRMA method had very high sensitivity (0.07 microU/ml). Detectable serum TSH concentrations were found in all normal subjects by IRMA, but in only 76% by RIA. No overlap was observed with the results obtained by IRMA in untreated overtly hyperthyroid patients, in whom serum TSH was below the limit of detection. The relationship between basal and TRH-stimulated serum TSH concentrations by IRMA and RIA was evaluated in 176 subjects including normals and patients with untreated and treated hyperthyroidism, functioning thyroid adenoma, nontoxic goitre and patients on L-thyroxine therapy. A normal TSH response to TRH was observed in virtually all patients with detectable basal serum TSH by both methods. When patients with undetectable basal serum TSH levels were considered, all but one (98%) had no TSH response to TRH by IRMA. On the contrary using RIA, an absent response was found only in 47% of subjects, a blunted responses in 10% and a normal response in 42%. These data indicate that basal serum TSH measurements by IRMA allows a complete discrimination of normal from hyperthyroid patients and can avoid the need for TRH stimulation tests.

The ontogeny of nyctohemeral variations of hypothalamic TRH content was determined in male rats from 7-45 days after birth, exposed to a daily 12-h light, 12-h dark cycle (0600-1800 h light; 1800-0600 h dark) or maintained in complete darkness until 45 days. TRH was extracted from whole hypothalami with 90% methanol and assayed by specific RIA. Hypothalamic TRH extracted from rats at different ages showed immunological, chromatographic, and biological properties identical to those of synthetic TRH. No significant variations in hypothalamic TRH content during the day were observed in 7-, 10-, and 17-day-old rats; a significant change, with a maximal value at 1800 h, was observed in 23-day-old rats, while an adult pattern with a maximal value at 1200 h and a minimal value at 2400 h was found in rats of 31 days of age and became more evident in 45-day-old rats. In animals maintained in complete darkness for 45 days after birth, no significant changes in hypothalamic TRH content at 1200 and 2400 h were observed. These findings indicate that environmental cyclic light-dark exposure is required for the development of diurnal changes in hypothalamic TRH content. Furthermore, any study involving hypothalamic TRH determination should take into account the age of animals and the diurnal variations of TRH.