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Myopathy is a well-known complication of hypercortisolism and commonly involves proximal lower-limb girdle. We report a rare case of Cushing's syndrome in a 60-year-old female presenting with significant respiratory muscle weakness and respiratory failure. She had history of rheumatoid arthritis, primary biliary cirrhosis and primary hypothyroidism and presented with weight gain and increasing shortness of breath. Investigations confirmed a restrictive defect with impaired gas transfer but with no significant parenchymatous pulmonary disease. Respiratory muscle test confirmed weakness of respiratory muscles and diaphragm. Biochemical and radiological investigations confirmed hypercortisolaemia secondary to a left adrenal tumour. Following adrenalectomy her respiratory symptoms improved along with an objective improvement in the respiratory muscle strength, diaphragmatic movement and pulmonary function test. LEARNING POINTS: Cushing's syndrome can present in many ways, a high index of suspicion is required for its diagnosis, as often patients present with only few of the pathognomonic symptoms and signs of the syndrome.Proximal lower-limb girdle myopathy is common in Cushing's syndrome. Less often long-term exposure of excess glucocorticoid production can also affect other muscles including respiratory muscle and the diaphragm leading to progressive shortness of breath and even acute respiratory failure.Treatment of Cushing's myopathy involves treating the underlying cause that is hypercortisolism. Various medications have been suggested to hinder the development of GC-induced myopathy, but their effects are poorly analysed.

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One of the major issues in graphene-based optoelectronics is to scale-up high-performing devices. In this work, we report an original approach for the fabrication of efficient optoelectronic devices from scalable tungsten disulfide (WS2)/graphene heterostructures. Our approach allows for the patterned growth of WS2 on graphene and facilitates the realization of ohmic contacts. Photodetectors fabricated with WS2 on epitaxial graphene on silicon carbide (SiC) present, when illuminated with red light, a maximum responsivity R ∼220 A W-1, a detectivity D* ∼2.0 × 109 Jones and a -3 dB bandwidth of 250 Hz. The retrieved detectivity is 3 orders of magnitude higher than that obtained with graphene-only devices at the same wavelength. For shorter illumination wavelengths we observe a persistent photocurrent with a nearly complete charge retention, which originates from deep trap levels in the SiC substrate. This work ultimately demonstrates that WS2/graphene optoelectronic devices with promising performances can be obtained in a scalable manner. Furthermore, by combining wavelength-selective memory, enhanced responsivity and fast detection, this system is of interest for the implementation of 2d-based data storage devices.

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We demonstrate high-fidelity electron spin read-out of a precision placed single donor in silicon via spin selective tunneling to either the D(+) or D(-) charge state of the donor. By performing read-out at the stable two electron D(0)↔D(-) charge transition we can increase the tunnel rates to a nearby single electron transistor charge sensor by nearly 2 orders of magnitude, allowing faster qubit read-out (1 ms) with minimum loss in read-out fidelity (98.4%) compared to read-out at the D(+)↔D(0) transition (99.6%). Furthermore, we show that read-out via the D(-) charge state can be used to rapidly initialize the electron spin qubit in its ground state with a fidelity of F(I)=99.8%.

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Vitamin D deficiency is highly prevalent in India. This has set off a trend among medical practitioners to prescribe vitamin D supplements empirically. Whilst this approach is generally safe, in predisposed individuals it may lead to hypervitaminosis D. Here we present a case where empirical use of high dose vitamin D supplementation had serious consequences highlighting the need to use vitamin D therapy judiciously and to remain vigilant for side-effects in high-risk individuals.

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The spin states of an electron bound to a single phosphorus donor in silicon show remarkably long coherence and relaxation times, which makes them promising building blocks for the realization of a solid-state quantum computer. Here we demonstrate, by high-fidelity (93%) electrical spin readout, that a long relaxation time T1 of about 2 s, at B=1.2 T and T≈100 mK, is also characteristic of electronic spin states associated with a cluster of few phosphorus donors, suggesting their suitability as hosts for spin qubits. Owing to the difference in the hyperfine coupling, electronic spin transitions of such clusters can be sufficiently distinct from those of a single phosphorus donor. Our atomistic tight-binding calculations reveal that when neighbouring qubits are hosted by a single phosphorus atom and a cluster of two phosphorus donors, the difference in their electron spin resonance frequencies allows qubit rotations with error rates ≈10(-4). These results provide a new approach to achieving individual qubit addressability.

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A 58-year-old white woman presented with sudden onset of diplopia, headache and vomiting with a history of tiredness and lethargy over the past four to six months. She had smooth, pale, hairless skin and on examination she was found to have left-sided third and sixth nerve palsy. Laboratory tests confirmed pan-anterior hypopituitarism. Computerized tomography scan of head and magnetic resonance imaging appearances were consistent with those of a sphenoid sinus mucocoele. Following adequate replacement with hydrocortisone and thyroxine she underwent sphenoid mucocoele drainage and endoscopic left sphenoethmoidectomy. Her symptoms were relieved over the next few days and she had a near-total recovery of ophthalmoplegia over the following three months. Pituitary function tests showed partial resolution of hypopituitarism with recovery of hypothalamic-pituitary-adrenal axis and hydrocortisone therapy was withdrawn, but she continued to require thyroxine.

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This study explored the variation between examiners in the orthodontic treatment need assessments of fifth-grade children with a borderline orthodontic treatment need. Each of three groups of children with borderline treatment need (n = 18, 19, and 19, respectively) were examined by one of three groups of orthodontists (33 in each group), whereby each of 56 children had 33 orthodontic treatment need assessments based on a clinical examination. This treatment need determination exercise was subsequently repeated with treatment need determined based on study casts and extraoral photographs. The proportion of positive treatment decisions based on the clinical examination was 49.3, 49.6, and 52.5 per cent, respectively, and 45.7, 46.3, and 50.5 per cent, based on the model assessments. There was a considerable disagreement between examiners in the treatment need assessments, whether assessments were based on a clinical examination or on a model-based case presentation. The average percentage agreement between two orthodontists for the treatment need based on clinical examination was 69, 66, and 61, respectively, corresponding to mean kappa values of 0.38, 0.32, and 0.22. When the model-based assessments were considered, the average percentage agreement between two orthodontists was 62, 58, and 69, respectively, corresponding to mean kappa values of 0.25, 0.16, and 0.37. Linear regression analysis of the orthodontists' treatment propensity as a function of their gender, place of education, years of orthodontic treatment experience, type of workplace, and place of work showed that only the orthodontic experience was influential for the model-based treatment propensity [ß = 0.34 per cent/year (95 per cent confidence interval = 0.01-0.66)].

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Panic disorder (PD) is an anxiety disorder characterized by recurrent panic attacks with a lifetime prevalence of 4.7%. Genetic factors are known to contribute to the development of the disorder. Several lines of evidence point towards a major role of the norepinephrine system in the pathogenesis of PD. The SLC6A2 gene is located on chromosome 16q12.2 and encodes the norepinephrine transporter (NET), responsible for the reuptake of norepinephrine into presynaptic nerve terminals. The aim of the present study was to analyze genetic variants located within the NET gene for association with PD. The case-control sample consisted of 449 patients with PD and 279 ethnically matched controls. All cases fulfilled the ICD-10 diagnostic criteria for PD. Genotyping was performed using the Sequenom platform (Sequenom, Inc, San Diego, USA). To test for allelic and haplotypic association, the PLINK software was used, and COMBASSOC was applied to test for gene-wise association. After quality control 29 single nucleotide polymorphisms (SNPs) spanning the gene-region were successfully analyzed. Seven SNPs located within the 5' end of the gene were significantly associated with PD. Furthermore, the NET gene showed overall evidence for association with the disease (P = 0.000035). In conclusion, the present study indicates that NET could be a susceptibility gene for PD.

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BACKGROUND: Patients with diabetes have increased frequency of hospital admissions and longer lengths of stay compared to patients without diabetes. Our specialist diabetes inpatient service was reconfigured to deliver a proactive diabetes outreach service to improve the overall care of this population. AIMS: To ascertain the effect of a structured diabetes outreach service to acutely admitted patients with diabetes on avoidable admissions, delayed discharges and appropriate diabetes related follow-up plans. METHODS: Audits were carried out before and 4 months after the introduction of a diabetes outreach service. The proportion of patients under care of the diabetes team, avoidable admissions, delayed discharges and existence of effective follow-up plans were compared pre- and post-implementation of this outreach service. RESULTS: The number of inpatients with diabetes fell by 35% (83 on a typical day pre-outreach vs. 53 post-outreach) despite a similar number of total medical admissions in that month (1449 vs.1459). This was due to a reduction in those admitted with diabetes related (13 vs. 5) and general medical (29 vs. 10) problems whilst numbers requiring other specialist care (41 vs. 39) remained unchanged. The proportion of patients under the care of diabetes team rose (23% vs. 73%) while those with avoidable admissions (18% vs. 7%), delayed discharges (17% vs. 2%) and inappropriate discharge plans (65% vs. 11%) all fell. CONCLUSION: This reformatted service was associated with a marked improvement in a number of parameters relevant to inpatient care.

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Adrenal incidentalomas are adrenal masses discovered incidental to imaging studies performed for reasons unrelated to adrenal pathology. Although most adrenal incidentalomas are non-functioning benign adenomas, their increasing prevalence presents diagnostic and therapeutic challenges. The assessment of adrenal incidentalomas is aimed at deciding whether or not the tumour should be surgically removed. Adrenalectomy is indicated for phaeochromocytoma, other symptomatic hormone-secreting tumours and those with a high risk of malignancy. Biochemical screening for tumour hypersecretion is mandatory in all adrenal incidentalomas, since hormone secreting tumours may be clinically silent. The diagnosis of phaeochromocytoma is of paramount importance because of its life-threatening complications. Non-functioning adrenal incidentalomas need assessment for risk of malignancy, and this is based on the size of the tumour and its imaging characteristics. An observational policy with periodic radiological and biochemical reassessment is pursued in patients with non-functioning incidentalomas with low malignancy risk. The duration and frequency of reassessment remains unclear, as the natural history of adrenal incidentalomas has yet to be clearly defined, and there is a lack of controlled studies comparing surgical intervention with observation. However, the possibility of acquiring autonomous hypersecretion or conversion to malignancy in an incidentaloma diagnosed to be a benign non-functioning lesion is very low, and most patients may be safely discharged after an initial follow-up period of 2 years.

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AIMS: To assess the coverage of the diabetes retinopathy screening service (DRSS) in North Staffordshire, to identify patient characteristies associated with non-attendance and to assess the proportion of patients with diabetic retinopathy who achieved glycaemic and blood pressure (BP) control targets. METHODS: Data for all patients who underwent annual retinal screening between 1 May 2000 and 30 April 2001 were obtained from the North Staffordshire Diabetes Register. Age, gender, ethnicity, socio-economic status, type and duration of diabetes were compared between patients who underwent eye screening and those who did not. Frequencies of patients who achieved glycaemic and BP targets in these groups of patients were compared to the remaining patients. RESULTS: 5646 of the 11682 (48%) patients on the diabetes register underwent retinal screening during the year. Patients with Type 2 diabetes, older patients, patients belonging to ethnic minorities and those wholly managed in primary care were less likely to attend for eye screening (P < 0.05 for all groups) with ethnic minority or primary care management demonstrating independent influence (P < 0.001). The percentage of patients with retinopathy achieving HbA1c and systolic BP targets was significantly lower than in their unaffected counterparts (chi2 = 63, P < 0.001 and chi2 = 71, P < 0.001 respectively). CONCLUSIONS: The efficacy of the DRSS in North Staffordshire is low and might be improved by targeting specific patient groups. Glycaemic control and systolic BP control needs to be improved in patients with diabetic retinopathy.

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OBJECTIVE: Adult GH deficiency (GHD) is linked to endothelial dysfunction and vascular disease. We examined the effect of 12 months of GH therapy on endothelial function, C-reactive protein (CRP) and coronary risk. DESIGN: Open-design intervention study. PATIENTS: Fourteen GH-deficient patients (nonsmokers, without diabetes, hypertension or vascular disease) studied before, 6 months and 12 months after GH therapy. MEASUREMENTS: Flow-mediated dilatation (FMD), carotid intima-media thickness (IMT) thrombomodulin (TM), E-selectin, CRP, lipid profile, blood pressure and anthropometric data were recorded. We used the Framingham equation to calculate coronary risk. RESULTS: FMD improved (7.5 +/- 1.62 vs. 11.93 +/- 1.52, P = 0.038). Overall there was no change in IMT, TM, E-selectin or CRP. The correlation between TM and FMD showed a trend for statistical significance (r = -0.54, P = 0.056). Changes in CRP correlated with change in IGF-1 (r = -0.67, P = 0.012); E-selectin correlated with high density lipoprotein (HDL)-cholesterol (r = -0.60, P = 0.028), triglycerides (r = 0.68, P = 0.01) and waist-to-hip ratio (WHR) (r = 0.71, P = 0.006). Systolic (127.36 +/- 4.47 vs. 120.36 +/- 3.50, P = 0.017) and diastolic (84.71 +/- 2.73 vs. 76.93 +/- 2.03, P = 0.005) blood pressure decreased. HDL-cholesterol increased (0.70 +/- 0.05 vs. 0.93 +/- 0.06, P = 0.001). WHR decreased (0.90 +/- 0.02 to 0.88 +/- 0.02, P = 0.043) without changes in weight or body mass index (BMI). Ten-year absolute (P = 0.009) and relative (P = 0.002) cardiac risk decreased. CONCLUSION: Biophysical test of endothelial function (FMD) improved after 12 months of GH therapy but there was no significant change in biochemical endothelial or inflammatory markers. Calculated coronary risk decreased mainly due to reduction in systolic and diastolic blood pressure and increase in HDL-cholesterol.

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BACKGROUND: Postsurgical regrowth or recurrence of nonfunctioning pituitary adenomas (NFAs) is not uncommon and often requires further surgery or radiotherapy (DXT). Routine postoperative DXT increases the incidence of hypopituitarism, which is associated with increased morbidity and mortality. Identification of genetic abnormalities in the tumour tissue, which can predict recurrence, may allow targeting DXT to the most appropriate patients. DESIGN AND METHODS: We have performed loss of heterozygosity (LOH) analysis on 96 NFAs of which 43 (45%) were recurrent and 53 (55%) were nonrecurrent tumours. Analysis of all tumours was performed on the surgical specimen obtained at the time of first surgery. All tumours underwent allelotyping across nine highly informative microsatellite markers selected on the basis of high LOH frequency in an earlier study involving genome-wide allelotyping. LOH frequency across all microsatellite markers as well as across individual markers was compared between the two cohorts of tumours. RESULTS: LOH frequency in tumours that subsequently recurred was significantly higher across all microsatellite markers as compared to tumours that did not recur (P < 0.05). Allelic loss across one or more microsatellite marker was significantly higher in recurrent tumours (30/43) as compared to their nonrecurrent counterparts (17/53) (P < 0.01). On Poisson regression analysis, the higher LOH frequency in recurrent tumours was independent of the invasiveness of tumours determined radiologically. In addition, LOH at the microsatellite markers D1S215 and D1S459 was significantly higher in tumours that recurred as compared to tumours that did not (32%vs. 3% and 27%vs. 2%, respectively; P < 0.01 for both). No significant difference in LOH frequency between the two tumour groups was evident at the other markers. No association could be demonstrated between the frequency and pattern of LOH and the time to manifest recurrence. CONCLUSIONS: We have shown that it may be possible to predict recurrence of NFAs by LOH analysis of the initial tumour specimen at predefined microsatellite markers, especially on chromosome 1q. This merits further prospective study.

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Through the use of a candidate gene approach, several previous studies have identified loss of heterozygosity (LOH) at putative tumor-suppressor gene (TSG) loci in sporadic pituitary tumors. This study reports a genome-wide allelotyping by use of 122 microsatellite markers in a large cohort of tumors, consisting of somatotrophinomas and non-functioning adenomas. Samples were first subject to prior whole genome amplification by primer extension pre-amplification (PEP) to circumvent limitations imposed by insufficient DNA for whole-genome analysis with this number of microsatellite markers. The overall mean frequency of loss in invasive tumors was significantly higher than that in their non-invasive counterparts (7 vs. 3% somatotrophinomas; 6 vs. 3% non-functioning adenomas, respectively). Analysis of the mean frequency of LOH, across all markers to individual chromosomal arms, identified 13 chromosomal arms in somatotrophinomas and 10 in non-functioning tumors, with LOH greater than the 99% upper confidence interval calculated for the rate of overall random allelic loss. In the majority of cases, these losses were more frequent in invasive tumors than in their non-invasive counterparts, suggesting these to be markers of tumor progression. Other regions showed similar frequencies of LOH in both invasive and non-invasive tumors, implying these to be early changes in pituitary tumorigenesis. This genome-wide study also revealed chromosomal regions where losses were frequently associated with an individual marker, for example, chromosome arm 1q (LOH > 30%). In some cases, these losses were subtype-specific and were found at a higher frequency in invasive tumors than in their non-invasive counterparts. Identification of these regions of loss provides the first preliminary evidence for the location of novel putative TSGs involved in pituitary tumorigenesis that are, in some cases, subtype-specific. This investigation provides an unbiased estimate of global aberrations in sporadic pituitary tumors as assessed by LOH analysis. The identification of multiple "hotspots" throughout the genome may be a reflection of an unstable chromatin structure that is susceptible to a deletion or epigenetic-mediated gene-silencing events.

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AIMS: To assess the process of clinical care and outcomes of young patients with diabetes attending clinics at a large district general hospital. METHODS: Retrospective analysis of data obtained from 106 case notes of patients aged 12-22 years attending the paediatric, combined adolescent or adult diabetes clinics between 1998 and 2000. The frequency of follow-up, rate of admission, glycaemic control, systolic blood pressure, weight change and screening for complications were assessed. RESULTS: The mean attendance rate was 78%. The admission rate was 91 admissions per 1000 patient years. Overall, the mean HbA1c was 9.1% with only 15% of paediatric and adolescent patients having mean HbA1c

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AIMS: To evaluate the influence of addition of rosiglitazone to insulin therapy over a 24-week period in massively obese patients with poorly controlled Type 2 diabetes taking large doses of insulin. METHODS: Eight massively obese patients (median body mass index (BMI) 42 kg/m2) with Type 2 diabetes who were on large doses of insulin (median daily dose of 204 U) and/or had poor glycaemic control (median HbA1c of 8.1% (upper limit for normal 5.5%)) were treated over a 24-week period with the combination of insulin and maximum doses of rosiglitazone. Outcomes monitored were changes in weight, BMI, HbA1c, dose of insulin and development of side-effects. RESULTS: At the end of 24 weeks there was a median weight gain of 3 kg (P < 0.01), a fall in median HbA1c from 8.1% to 6.7% (16% reduction from baseline) (P < 0.01) and a reduction in median insulin dose from 204 U/day to 159 U/day (P < 0.01) (23% reduction from baseline). Peripheral oedema was the only significant side-effect and was seen in five patients. CONCLUSIONS: Combination of insulin and rosiglitazone is effective in massively obese patients with Type 2 diabetes, though there is a high incidence of peripheral oedema.

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In 1992 a 54-year-old man underwent transsphenoidal adenomectomy to remove a clinically nonfunctioning pituitary adenoma during which there was a transient cerebrospinal fluid (CSF) leak. He received radiotherapy to a small residual remnant. Follow-up magnetic resonance imaging (MRI) scan in 1997 showed an increase in the tumour in the pituitary stalk region and an additional intradural lesion at C1 level. In the absence of neurological symptoms and signs, an observational policy was followed. By 1999 the cervical dural lesion had enlarged and laminectomy was performed, during which three intradural lesions were removed. Histology and immunohistochemistry of the metastases were identical to those of the initial pituitary adenoma. Follow-up MRI scan showed extension of the pituitary remnant above the chiasma, requiring transfrontal surgery. Operation was complicated by secondary brain haemorrhage from which the patient died. Autopsy revealed a small amount of residual tumour at the top of the stalk and several small intradural tumour nodules at the level of the foramen magnum. Genetic analysis of the initial pituitary tumour identified significant allelic losses in keeping with its invasive nature, while that of the metastases indicated a separate clone as shown by retention of alleles lost in the primary tumour. The regrown pituitary tumour also appeared to be of a different clone to the initial tumour and the same as two of three of the first metastases (C1 level). The foramen magnum metastasis showed the same loss of heterozygosity (LOH) pattern as one of the original C1 metastases and the pituitary tumour tissue obtained at autopsy. We speculate that at the initial pituitary surgery, cells seeded into the CSF and grew in the dura. These cells were from a different clone, implying that the original pituitary tumour contained at least two clones, possibly three, providing evidence for the contemporaneous oligoclonality of the original pituitary tumour.

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