Establishing a valid cohort of patients with acromegaly by combining the National Patient Register with the Swedish Pituitary Register.

PURPOSE: The aim of this study was to establish a valid national cohort of patients diagnosed with acromegaly by combining data from the general National Patient Register (NPR) and the disease-specific Swedish Pituitary Register (SPR). METHODS: Patients ≥ 18 years of age at diagnosis of acromegaly reported from 1991 to 2018 who were registered in the NPR and/or SPR were included. The diagnosis of acromegaly was considered correct for patients identified in both registers or confirmed through chart review. Medical records were reviewed in two of Sweden´s six health care regions if the patient was reported only in the NPR. An algorithm for the NPR, with criteria requiring multiple diagnosis registrations and tumour and/or surgery codes, was constructed to reduce the number of patients to review in the remaining four regions. RESULTS: A total of 1866 patients were identified. Among these, 938 were reported in both registers. After application of the algorithm and chart review, the diagnosis was confirmed for 83 of the 906 patients found only in the NPR. Among 22 patients only registered in the SPR, a review of medical records confirmed acromegaly in 13. This resulted in a total of 1034 cases with acromegaly during the study period. The incidence rate of acromegaly in Sweden 1991-2018 was calculated to 4.0/million/year in the entire population and 5.1/million/year among subjects ≥ 18 years of age. CONCLUSION: The combination of the SPR and NPR established a valid cohort of patients diagnosed with acromegaly and increased the estimated incidence in Sweden.

Performance of BOADICEA and BRCAPRO genetic models and of empirical criteria based on cancer family history for predicting BRCA mutation carrier probabilities: a retrospective study in a sample of Italian cancer genetics clinics.

PURPOSE: To evaluate in current practice the performance of BOADICEA and BRCAPRO risk models and empirical criteria based on cancer family history for the selection of individuals for BRCA genetic testing. PATIENTS AND METHODS: The probability of BRCA mutation according to the three tools was retrospectively estimated in 918 index cases consecutively undergone BRCA testing at 15 Italian cancer genetics clinics between 2006 and 2008. RESULTS: 179 of 918 cases (19.5%) carried BRCA mutations. With the strict use of the criteria based on cancer family history 173 BRCA (21.9%) mutations would have been detected in 789 individuals. At the commonly used 10% threshold of BRCA mutation carrier probability, the genetic models showed a similar performance [PPV (38% and 37%), sensitivity (76% and 77%) and specificity (70% and 69%)]. Their strict use would have avoided around 60% of the tests but would have missed approximately 1 every 4 carriers. CONCLUSION: Our data highlight the complexity of BRCA testing referral in routine practice and question the strict use of genetic models for BRCA risk assessment.

Long-path second-harmonic interferometer with nanosecond time resolution: reliable diagnostic tool for electron density measurement in pulsed plasma devices.

We describe the performance of a second-harmonic interferometer (SHI) to measure, on an optical path exceeding 12 m, the electron plasma density of two plasmoids formed in separate theta-pinch chambers and then merged in a central compression chamber after undergoing acceleration and compression. The excellent mechanical stability and a time resolution better than 50 ns suggest the application of SHI, especially in pulsed plasma devices with limited optical accesses.

Contribution of germline mutations in the BRCA and PALB2 genes to pancreatic cancer in Italy.

Pancreatic adenocarcinoma (PC) is the third most common cancer associated with BRCA mutations. Most notice has been given to BRCA2, while the association between BRCA1 and PC is less widely reported. Recently, PALB2 has been implicated in both PC and breast cancer (BC) susceptibility. We selected 29 Italian PC patients from a case-control study of PC according to their personal and family history of both PC and breast/ovarian cancer (BC/OC) and tested them for presence of germline mutations in BRCA1, BRCA2 and PALB2. We identified no germline mutations or deletions in PALB2, but detected 7 BRCA mutations (4 in BRCA1 and 3 in BRCA2). These findings suggest that PALB2 does not play a major role in PC susceptibility in our population. As we found an almost equal frequency of germline mutations in BRCA1 and BRCA2, germline alterations in either of these genes may explain a subset of Italian families presenting both PC and BC/OC. Moreover, as we began the observation of these families from probands who are affected by PC, we provide here a direct assessment of the role of PALB2 and BRCA mutations in PC susceptibility.

Multicentre observational study of the natural history of left-sided acute diverticulitis.

BACKGROUND: The natural history of acute diverticulitis (AD) is still unclear. This study investigated the recurrence rate, and the risks of emergency surgery, associated stoma and death following initial medical or surgical treatment of AD. METHODS: The Italian Study Group on Complicated Diverticulosis conducted a 4-year multicentre retrospective and prospective database analysis of patients admitted to hospital for medical or surgical treatment of AD and then followed for a minimum of 9 years. The persistence of symptoms, recurrent episodes of AD, new hospital admissions, medical or surgical treatment, and their outcome were recorded during follow-up. RESULTS: Of 1046 patients enrolled at 17 centres, 743 were eligible for the study (407 recruited retrospectively and 336 prospectively); 242 patients (32·6 per cent) underwent emergency surgery at accrual. After a mean follow-up of 10·7 years, rates of recurrence (17·2 versus 5·8 per cent; P < 0·001) and emergency surgery (6·9 versus 1·3 per cent; P = 0·021) were higher for medically treated patients than for those treated surgically. Among patients who had initial medical treatment, age less than 40 years and a history of at least three episodes of AD were associated with an increased risk of AD recurrence. There was no association between any of the investigated parameters and subsequent emergency surgery. The risk of stoma formation was below 1 per cent and disease-related mortality was zero in this group. The disease-related mortality rate was 0·6 per cent among patients who had surgical treatment. CONCLUSION: Long-term risks of recurrent AD or emergency surgery were limited and colectomy did not fully protect against recurrence.

A state observer for the Virgo inverted pendulum.

We report an application of Kalman filtering to the inverted pendulum (IP) of the Virgo gravitational wave interferometer. Using subspace method system identification techniques, we calculated a linear mechanical model of Virgo IP from experimental transfer functions. We then developed a Kalman filter, based on the obtained state space representation, that estimates from open loop time domain data, the state variables of the system. This allows the observation (and eventually control) of every resonance mode of the IP mechanical structure independently.

Doppler spectroscopy and D-alpha emission diagnostics for the C-2 FRC plasma.

Two Doppler spectroscopy diagnostics with complementary capabilities are developed to measure the ion temperatures and velocities of FRC plasmas in the C-2 device. First, the multichord ion doppler diagnostic can simultaneously measure 15 chords of the plasma using an image intensified camera. Second, a single-chord fast-response ion Doppler diagnostic provides much higher faster time response by using a 16-channel photo-multiplier tube array. To study the neutral density of deuterium under different wall and plasma conditions, a highly sensitive eight-channel D-alpha diagnostic has been developed and calibrated for absolute radiance measurements. These spectroscopic diagnostics capabilities, combined with other plasma diagnostics, are helping to understand and improve the field reversed configuration plasmas in the C-2 device.

In-vacuum Faraday isolation remote tuning.

In-vacuum Faraday isolators (FIs) are used in gravitational wave interferometers to prevent the disturbance caused by light reflected back to the input port from the interferometer itself. The efficiency of the optical isolation is becoming more critical with the increase of laser input power. An in-vacuum FI, used in a gravitational wave experiment (Virgo), has a 20 mm clear aperture and is illuminated by an almost 20 W incoming beam, having a diameter of about 5 mm. When going in vacuum at 10(-6) mbar, a degradation of the isolation exceeding 10 dB was observed. A remotely controlled system using a motorized lambda=2 waveplate inserted between the first polarizer and the Faraday rotator has proven its capability to restore the optical isolation to a value close to the one set up in air.

Dynamic formation of a hot field reversed configuration with improved confinement by supersonic merging of two colliding high-ß compact toroids.

A hot stable field-reversed configuration (FRC) has been produced in the C-2 experiment by colliding and merging two high-ß plasmoids preformed by the dynamic version of field-reversed θ-pinch technology. The merging process exhibits the highest poloidal flux amplification obtained in a magnetic confinement system (over tenfold increase). Most of the kinetic energy is converted into thermal energy with total temperature (T{i}+T{e}) exceeding 0.5 keV. The final FRC state exhibits a record FRC lifetime with flux confinement approaching classical values. These findings should have significant implications for fusion research and the physics of magnetic reconnection.

Neuroendocrine effects of citalopram, a selective serotonin re-uptake inhibitor, during lifespan in humans.

OBJECTIVE: Serotonergic system contributes to the regulation of hypothalamus-pituitary-adrenal axis. In humans, serotonergic agonists increase PRL, ACTH, and cortisol, while serotonin (5HT) influence on GH is controversial. Central 5HT activity and neuroendocrine function change during lifespan. DESIGN: To clarify the neuroendocrine response to 5HT across lifespan, we assessed ACTH, cortisol, DHEA, PRL, and GH responses to citalopram (CT) in young adults (YA) (no.=12, 29.2±1.7 yr mean±SEM), middle aged (MA) (no.=12, 54.3±0.9 yr), and elderly (ES) (no.=12, 69.3±0.9 yr) males. All the subjects received placebo (saline iv over 120 min) or CT (20 mg iv over 120 min). Blood samples were taken every 15 min up to 240 min. RESULTS: During placebo, ACTH, cortisol, GH, and PRL were similar in all groups while DHEA showed an age-dependent reduction from middle age (p<0.001). During CT, ACTH, and cortisol were higher than during placebo in YA (p<0.05) and even more in MA (p<0.01 vs placebo, p<0.05 vs YA); in ES, the increase of both ACTH and cortisol (p<0.05 vs placebo) was lower than in MA (p<0.05) and higher than in YA (p<0.05 for cortisol only). No changes were observed for DHEA, GH, and PRL in any group. CONCLUSIONS: Corticotrope response to CT is age-dependent in normal men, being amplified starting from middle age, suggesting precocious changes in the serotonergic neuroendocrine control during lifespan. CT is a useful tool to evaluate the age-dependent serotonergic function in humans.

Germline MLH1 and MSH2 mutations in Italian pancreatic cancer patients with suspected Lynch syndrome.

Lynch syndrome is an inherited cancer syndrome caused by germline mutations in mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. LS predisposes to high risk of early-onset colorectal, endometrial and other tumors. Patients with Lynch syndrome have also been shown to have an elevated risk for pancreatic cancer (PC). In this study, we aimed to estimate the frequency of suspected Lynch syndrome among a series of 135 PC patients. Further, we wanted to determine the frequency of MMR gene mutations in the suspected Lynch syndrome cases. We also aimed to verify the pathogenicity of any novel non-truncating variants we might detect with a functional assay. Based on personal and/or familial cancer history, 19 patients were classified as suspected Lynch syndrome cases. DNA material for mutation analysis was available for eleven of them. Four patients were found to carry a total of five MLH1 or MSH2 variants. Of these, MSH2-Q402X, MSH2-G322D, and MLH1-K618A had been previously reported, while the MSH2-E205Q and MSH2-V367I variants were novel. MSH2-Q402X is a known stop mutation and reported here for the first time here in association with PC. MLH1-K618A was found in the unaffected branch of a kindred, suggesting that it may be a polymorphism or a low penetrance variant. MSH2-G322D likely does not cause a MMR defect, although this variant has also been associated with breast cancer as indeed seen in our patient. The novel variants MSH2-E205Q and MSH2-V367I were found in the same patient. Both novel variants were however functional in the applied MMR assay. Our findings suggest that only a small subset of pancreatic cancer patients carry pathogenic MMR mutations.

CDKN2A mutations and MC1R variants in Italian patients with single or multiple primary melanoma.

We evaluated the contribution of germline CDKN2A mutations and MC1R variants to the development of melanoma in a hospital-based study of single (SPM, n = 398) and multiple primary melanoma (MPM, n = 95). The overall frequency of CDKN2A mutations was 15.2%, and four-fold higher in MPM than in SPM cases (OR = 4.27; 95% CI 2.43-7.53). The likelihood of identifying a CDKN2A mutation increased with family history of melanoma and younger age at diagnosis in MPM cases. Compared to SPM patients, the risk of harboring a CDKN2A mutation rose as the number of primary melanomas increased and was not influenced by family history. The G101W and E27X founder mutations were the most common. Several other mutations (W15X, Q50X, R58X, A68L, A127P and H142R) were detected for the first time in Italian patients. One novel mutation, T77A, was identified. Several non-coding variants with unknown functional significance were also found (5'UTR -25C > T, -21C > T, -67G > C, IVS1 +37G > C); the novel 5'UTR -21C > T variant was not detected in controls. The CDKN2A A148T polymorphism was more frequent in MPM patients than in the control population (15.7% versus 6.6%). Compared to the SPM patients, MPM cases had a 2-fold increased probability of being MC1R variant carriers and a higher probability of carrying two or more variants. No specific association was observed between the type of variant and the number of melanomas, suggesting that the number rather than the type of MC1R variant increases the risk of MPM. We observed no interaction between CDKN2A status and the presence of MC1R variants. The high frequency of CDKN2A mutations in our MPM cases, independent of their family history, is of relevance to genetic counseling and testing in our population.

Diode-pumped passively mode-locked Yb:YLF laser.

We demonstrate passive mode-locking by means of a semiconductor saturable-absorber mirror in a diode-pumped Yb:YLF laser. We present crystal growth process, spectroscopic measurements, and investigation of mode-locking performance. Pulse trains with minimum duration of 196 fs, average power of 54 mW and a repetition rate of 55 MHz were obtained. The optical spectrum, centered at 1028 nm, has a 7.1-nm bandwidth leading to nearly transform-limited pulses.

Hypothalamus-pituitary-adrenal axis evaluation in patients with hypothalamo-pituitary disorders: comparison of different provocative tests.

BACKGROUND: The insulin tolerance test (ITT) is the gold standard test to evaluate hypothalamic-pituitary-adrenal (HPA) axis in suspected ACTH insufficiency. When contraindicated, alternative tests have been proposed such as metyrapone and ACTH stimulation test. 250 microg ACTH is a supramaximal dose and unreliable in this setting. The diagnostic reliability of 1.0 microg ACTH test is controversial and very low doses have been proposed. DESIGN: In 31 patients with hypothalamo-pituitary disorders and normal basal cortisol, we compared the diagnostic sensitivity, specificity and accuracy of metyrapone [metyrapone test (MET) 30 mg/kg p.o.], high (HDT, 250 microg i.v.), low (LDT, 1.0 microg i.v.) and very-low (VLDT, 0.06 microg i.v.) dose ACTH tests. Receiver operator curve (ROC) analysis was applied with ITT as reference test. RESULTS: MET approached the best pairs of values for highest sensitivity (71.4% and 64.3%) and highest specificity (100% and 82.4%) using ACTH and 11-deoxycortisol (11-DOC) cut-off of 17.3 pmol/l and 144.3 nmol/l. Either HDT or LDT sensitivity approached 71.4% with a specificity of 82.4% or 73.3% with a specificity of 80% for cortisol cut-off of 582.1 or 477.3 nmol/l. VLDT approached the highest sensitivity (57.1%) and highest specificity (88.2%) for a cortisol cut-off of 364.2 nmol/l. CONCLUSION: Neither MET nor ACTH test can be considered completely reliable for the diagnosis of secondary hypoadrenalism, when compared with ITT that remains the best test. Either MET or ACTH stimulation test, at both high and low dose, show an overall similar reliability, provided that appropriated cut-off values were considered; testing with very low ACTH doses seems to be misleading.

Primary hyperaldosteronism is associated with derangement in the regulation of the hypothalamus-pituitary-adrenal axis in humans.

Hippocampal mineralocorticoid receptors (MR) play a major role in the control of hypothalamus- pituitary-adrenal (HPA) axis. The functional profile of HPA axis and the impact of MR blockade under chronic exposure to mineralocorticoid excess are unknown. To clarify this issue, ACT H, cortisol, and aldosterone secretions were studied in 6 patients with primary hyperaldosteronism (HA) and 8 controls (NS) during placebo, placebo+human CR H (hCR H) (2 microg/kg iv bolus at 22:00 h), potassium canrenoate (CAN, 200 mg iv bolus at 20:00 h followed by 200 mg infused over 4 h) or CAN+hCR H. During placebo, both aldosterone and ACT H levels were higher (p<0.01) in HA than in NS, while cortisol levels were not significantly different. Both HA and NS showed significant ACT H and cortisol responses to hCR H (p<0.004), although the hormonal responses in HA were higher (p<0.02) than in NS. CAN infusion did not modify aldosterone levels in both HA and NS. Under CAN infusion, ACT H showed progressive rise in NS (p<0.05) but not in HA, while cortisol levels showed a significant (p<0.05) but less marked and delayed increase in HA compared to NS. CAN enhanced hCRH-induced ACTH and cortisol responses in NS (p<0.05), but not in HA. In conclusion, in humans primary hyperaldosteronism is associated with deranged function of the HPA axis. In fact, hyperaldosteronemic patients show basal and hCR H-stimulated HPA hyperactivity that is, at least partially, refractory to further stimulation by mineralocorticoid blockade with canrenoate. Whether this hormonal alteration can influence the clinical feature of hypertensive patients with primary hyperaldosteronism needs to be clarified.

The activation of somatostatinergic receptors by either somatostatin-14 or cortistatin-17 often inhibits ACTH hypersecretion in patients with Cushing's disease.

OBJECT: Somatostatin (SS) is known to inhibit GH and insulin, while its effect on corticotrope secretion is controversial: inhibition of ACTH secretion by agonists activating somatostatinergic receptors (sst)-2 and sst-5 was reported in vitro. Cortistatin (CST) not only binds all sst receptor subtypes but also possesses central actions that are not shared by SS. DESIGN: In nine patients with Cushing's disease (CD), ACTH, cortisol, GH, insulin, and glucose levels were studied during 120-min i.v. infusion of SS-14 (2.0 microg/kg per h), CST-17 (2.0 microg/kg per h) or saline. RESULTS: Both SS or CST significantly affected the hypothalamic-pituitary-adrenal axis. Cortisol was decreased to the same extent by either SS or CST (P < 0.05). Both SS and CST decreased ACTH, although statistical difference was reached only during CST (P < 0.05). Analyzing the individual responses as areas under curve (AUCs), a clear and consensual inhibition of ACTH and cortisol under either SS or CST was recorded in five out of nine patients. Both SS or CST inhibited (P < 0.05) insulin, that even showed a rebound (P < 0.01) at the end of infusion. GH was not modified by either peptide. CONCLUSION: SS and CST often display similar inhibitory effects on the HPA axis in CD. The activation of sst receptors by both peptides is followed in almost 50% of patients by a remarkable inhibition of ACTH and cortisol hypersecretion. These findings reinforce the view that sst receptors are involved in the control of the secretory activity of tumoral corticotropic cells.

Somatopause reflects age-related changes in the neural control of GH/IGF-I axis.

This paper will focus on the hypofunction of GH/IGF-I axis in aging, as the most impressive example of decreased activity as function of age-related changes in the neural control of somatotroph cells. GH secretion undergoes clear age-related variations that are generally mirrored by IGF-I levels, the best marker of GH status. Given the well known positive influence of GH/IGF-I on body composition, structure functions and metabolism, this paper discusses the potential clinical implications, also taking into account evidence showing that, at least in animals, deficiency in GH/IGF-I is somewhat associated to prolonged life. Although somatopause is likely to contribute to age-related changes in body composition, structure functions and metabolism, we are now in front of the paradox of lifelong GH/IGF-I deficiency or resistance resulting in prolonged life expectancy and GH replacement at advanced age, probably exerting anti-aging effects. This evidence questions whether GH deficiency is or not a beneficial adaptation to aging. By answering this question one is not simply finding new phylosophical paradigm but also the rational basis for anti-aging drug interventions.

Treatment of thyroid associated ophthalmopathy with periocular injections of triamcinolone.

AIM: To evaluate the efficacy of periocular triamcinolone acetonide for the treatment of thyroid associated ophthalmopathy (TAO), and the presence of ocular or systemic adverse effects. METHODS: A multicentre prospective pilot study was performed on patients diagnosed with Graves' ophthalmopathy less than 6 months before entry to the study. Patients were admitted to the study and were randomised into two groups: treatment and control. The treatment group received four doses of 20 mg of triamcinolone acetate 40 mg/ml in a peribulbar injection to the inferolateral orbital quadrant. Both groups were evaluated by measuring the area of binocular vision without diplopia on a Goldmann perimeter and the size of the extraocular muscles on computed tomography (CT) scans. Ophthalmological and systemic examinations were done to rule out ocular and systemic adverse effects. Follow up was 6 months for both groups. RESULTS: 50 patients were eligible for the study. 41 patients completed the study. There was an increase in the area of binocular vision without diplopia in the treatment group (Sigma initial: mean 231.1 (SD 99.9) and final absolute change, mean 107.1 (SD 129.0)) compared to the control group (Sigma initial: mean 350.7 (SD 86.5) and final absolute change, mean -4.5 (SD 67.6)). The sizes of the extraocular muscles were reduced in the treatment group (mean (inferior rectus initial values): 1.3 (0.7), final percentage change: -13.2 (25.7), medial rectus initial values: 1.2 (0.6), final percentage change: -8.2 (20.7), superior rectus-levator palpebrae initial values: 1.2 (0.6), final percentage change: -9.5 (29.1), lateral rectus initial values: 1.0 (0.4), final percentage change: -11.5 (20.6)) compared to the control group (inferior rectus initial values: 0.9 (0.3), final percentage change: -4.0 (21.5), medial rectus initial values: 0.9 (0.3), final percentage change: 0.6 (22.4), superior rectus-levator palpebrae initial values: 0.9 (0.3), final percentage change: 12.5 (37.5), lateral rectus initial values: 0.9 (0.4), final percentage change: -0.5 (31.6)). Both measurements (degree of diplopia and muscle thickness) were statistically significant between groups (initial - final). No systemic or ocular adverse effects were found. CONCLUSIONS: Triamcinolone administered as a periocular injection is effective in reducing diplopia and the sizes of extraocular muscles in TAO ophthalmopathy of recent onset. This form of treatment is not associated with systemic or ocular side effects.

Predictive value of rectal bleeding for distal colonic neoplastic lesions in a screened population.

The aim of this study was to determine the diagnostic value of rectal bleeding for distal colorectal cancer (CRC), or large (> or =10 mm) adenomas among an average-risk population. A cross-sectional survey was conducted among individuals aged 55-64 years, who attended sigmoidoscopy (FS) screening in the context of a multicentre randomised trial of FS screening for CRC. Sensitivity, specificity and positive predictive value (PPV) of rectal bleeding for large distal adenomas or CRC were calculated. Rectal bleeding was reported by 8.8% of 8507 patients examined (15% of those with large adenomas and 29% of those with CRC). The risk of CRC was increased when bleeding was associated with an altered bowel habit: odds ratio (OR)=10.42; 95% Confidence Interval (CI): 4.08-26.59; the corresponding OR for isolated bleeding was 5.29 (95% CI: 2.28-12.30). Rectal bleeding carries an increased risk of distal neoplastic lesions. However, most lesions are detected among asymptomatic subjects. This finding suggests that screening represents the optimal strategy to detect CRC or large adenomas in the distal colon in the targeted age range.