Use of a free proximal ulnar autograft for ipsilateral radial lengthening in a dog with a short radius and subsequent elbow incongruity.

OBJECTIVE: To report the technique and outcome of proximal ulnar autograft transplantation to achieve ipsilateral radial lengthening in a dog with premature closure of both proximal and distal radial physes. STUDY DESIGN: Case report. ANIMALS: An 8-month-old female spayed Border Collie. METHODS: The dog was presented for a grade III/IV left thoracic limb lameness localized to the elbow. Orthogonal radiographs of both forelimbs revealed a 7% length deficit of the left radius and elbow subluxation indices indicative of left elbow incongruity due to suspect premature closure of both radial physes. Radial lengthening consisted of a proximal ulnar ostectomy, a radial osteotomy, and transplantation of the ulnar autograft into the radial osteotomy site secured with an eight-hole dynamic compression plate. Orthopedic examinations were conducted at 2 weeks, 4 weeks, and 3 years postoperatively. Radiographic examinations were completed preoperatively, immediately postoperatively, and at 4 weeks and 3 years postoperatively. RESULTS: Lameness improved with a grade II/IV lameness at 4 weeks postoperatively and complete resolution at 3 years postoperatively. Radiographic examination at 4 weeks showed persistent radial lengthening of 1 cm, and a decreased humeroradial index (HRI), humeroulnar index (HUI), and radioulnar index (RUI) compared with preoperative values. At the 3 year examination, the HRI and HUI had increased indicating progression of elbow incongruity. The patient remained clinically unaffected. CONCLUSION: In dogs with radial shortening and elbow incongruity, use of an ipsilateral proximal ulnar autograft with rigid internal fixation can be an effective treatment for radial lengthening to improve elbow congruity and resolve lameness.

Canonical Approach To Generate Multidimensional Potential Energy Surfaces.

A new force-based canonical approach for the accurate generation of multidimensional potential energy surfaces is demonstrated. Canonical transformations previously developed for diatomic molecules are used to construct accurate approximations to the 3-dimensional potential energy surface of the water molecule from judiciously chosen (adopting the right coordinate system) 1-dimensional planar slices that are shown to have the same canonical shape as the classical Lennard-Jones potential curve. Spline interpolation is then used to piece together the 1-dimensional canonical potential curves, to obtain the full 3-dimensional potential energy surface of a water molecule with a relative error less than 0.01. This work provides an approach to greatly reduce the computational cost of constructing potential energy surfaces in molecules from ab initio calculations. The canonical transformation techniques developed in this work illuminate a pathway to deepening our understanding of chemical bonding.

Morbidity and mortality in patients with hyperprolactinaemia: the PROLEARS study.

PURPOSE: High serum prolactin concentrations have been associated with adverse health outcomes in some but not all studies. This study aimed to examine the morbidity and all-cause mortality associated with hyperprolactinaemia. METHODS: A population-based matched cohort study in Tayside (Scotland, UK) from 1988 to 2014 was performed. Record-linkage technology was used to identify patients with hyperprolactinaemia that were compared to an age-sex-matched cohort of patients free of hyperprolactinaemia. The number of deaths and incident admissions with diabetes mellitus, cardiovascular disease, cancer, breast cancer, bone fractures and infectious conditions were compared by the survival analysis. RESULTS: Patients with hyperprolactinaemia related to pituitary tumours had no increased risk of diabetes, cardiovascular disease, bone fractures, all-cause cancer or breast cancer. Whilst no increased mortality was observed in patients with pituitary microadenomas (HR = 1.65, 95% CI: 0.79-3.44), other subgroups including those with pituitary macroadenomas and drug-induced and idiopathic hyperprolactinaemia demonstrated an increased risk of death. Individuals with drug-induced hyperprolactinaemia also demonstrated increased risks of diabetes, cardiovascular disease, infectious disease and bone fracture. However, these increased risks were not associated with the degree of serum prolactin elevation (Ptrend > 0.3). No increased risk of cancer was observed in any subgroup. CONCLUSIONS: No excess morbidity was observed in patients with raised prolactin due to pituitary tumours. Although the increased morbidity and mortality associated with defined patient subgroups are unlikely to be directly related to the elevation in serum prolactin, hyperprolactinaemia might act as a biomarker for the presence of some increased disease risk in these patients.

Is there any fundamental difference between ionic, covalent, and others types of bond? A canonical perspective on the question.

The concept of chemical bonding is normally presented and simplified through two models: the covalent bond and the ionic bond. Expansion of the ideal covalent and ionic models leads chemists to the concepts of electronegativity and polarizability, and thus to the classification of polar and non-polar bonds. In addition, the intermolecular interactions are normally viewed as physical phenomena without direct correlation to the chemical bond in any simplistic model. Contrary to these traditional concepts of chemical bonding, recently developed canonical approaches demonstrate a unified perspective on the nature of binding in pairwise interatomic interactions. This new canonical model, which is a force-based approach with a basis in fundamental molecular quantum mechanics, confirms much earlier assertions that in fact there are no fundamental distinctions among covalent bonds, ionic bonds, and intermolecular interactions including the hydrogen bond, the halogen bond, and van der Waals interactions.

Influence of in-house rehabilitation on the postoperative outcome of dogs with intervertebral disk herniation.

OBJECTIVE: To determine the influence of in-house rehabilitation on the postoperative outcome of dogs with intervertebral disk herniation (IVDH). DESIGN: Retrospective cohort study. ANIMALS: Dogs (n = 248) under 20 kg of weight, with single site, thoracolumbar, Hansen Type I IVDH. PROCEDURES: Medical records of non-ambulatory dogs with IVDH treated via hemilaminectomy were reviewed. Dogs were classified in 2 groups depending on whether their postoperative management included an in-house rehabilitation program. Preoperative and sequential postoperative modified Frankel scores (MFSs) were recorded. Time to ambulation, time to normal conscious proprioception, final MFS, and complications were compared between the groups. RESULTS: More dogs returned to full neurologic function (final MFS of Grade 5) when in-house rehabilitation was included in the postoperative management (33% compared to 9%). Normal conscious proprioception and ambulation returned earlier in the control group (42 days and 14 days, respectively) compared to the group with rehabilitation (49 days and 28 days, respectively). The complication rate was higher in the control group (29%) compared with the group with rehabilitation (16%). CONCLUSIONS AND CLINICAL RELEVANCE: In-house rehabilitation should be included in the postoperative management in dogs after surgical treatment of IVDH to improve neurologic function and reduce postoperative complications.

The epidemiology of hyperprolactinaemia over 20 years in the Tayside region of Scotland: the Prolactin Epidemiology, Audit and Research Study (PROLEARS).

OBJECTIVE: To estimate the prevalence and incidence of hyperprolactinaemia. Hyperprolactinaemia is a common problem in endocrine practice, but its epidemiology has not been accurately established. STUDY DESIGN: A population-based retrospective follow-up study in Tayside, Scotland (population 400,000), from 1993 to 2013. PATIENTS: Record linkage technology (biochemistry, prescribing, hospital admissions, radiology, mortality and maternity data) was used to identify all patients with a serum prolactin measurement. From these, cases were defined as those with a prolactin greater than 1000 mU/L (47·2 ng/ml) or at least three prescriptions for a dopamine agonist. MEASUREMENTS: Number of prevalent and incident cases of hyperprolactinaemia per calendar year by age, sex and cause of hyperprolactinaemia. RESULTS: A total of 32289 patients had a serum prolactin assay undertaken, of which 1301 had hyperprolactinaemia not related to pregnancy: 25·6% patients had pituitary disorder, 45·9% were drug-induced, 7·5% had macroprolactin and 6·1% had hypothyroidism, leaving 15·0% idiopathic. Over the 20 years, there was a fourfold increase in the number of prolactin assays performed, and prevalence of hyperprolactinaemia was initially 0·02%, but rose to 0·23% by 2013. Overall incidence was 13·8 cases per 100000 person-years (20·6 in 2008-13) and was 3·5 times higher in women than in men. The highest rates were found in women aged 25-44 years. Drug-induced causes tripled during the 20 years. CONCLUSIONS: Rising prevalence of hyperprolactinaemia is probably due to an increased ascertainment and increased incidence of psychoactive drug-related causes. Rates are higher in women than in men but only before the age of 65 years.

Glucose and lipid levels with lanreotide autogel 120 mg in treatment-naïve patients with acromegaly: data from the PRIMARYS study.

OBJECTIVE: Impaired glycaemic control, characteristic of acromegaly, can be exacerbated by treatment with somatostatin analogues (SSAs), particularly those with multireceptor activity. We present data from the PRIMARYS study on the impact of the SSA lanreotide, associated with tumour volume and hormonal improvements, on glucose and other metabolic parameters in acromegaly. DESIGN: PRIMARYS was a 48-week open-label single-arm phase 3b study of lanreotide autogel 120 mg/4 weeks. A priori and post hoc metabolic profile data are reported for the overall population, patients with/without diabetes and patients achieving/not achieving hormonal control. PATIENTS: Treatment-naïve adults with pituitary macroadenoma, mean growth hormone >1 µg/l and elevated insulin-like growth factor-1 levels (n = 90). MEASUREMENTS: Glycaemic parameters [glycated haemoglobin (HbA1c ) and fasting plasma glucose (FPG) levels] assessed at baseline and weeks 12, 24 and 48. Lipid-profile data (triglycerides, total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol) collected at baseline and study end. RESULTS: In patients with diabetes (n = 24), HbA1c showed a clinically relevant decrease during treatment [mean change from baseline to week 48, -1·44% (95% CI: -2·52, -0·36)]. In the overall population, in patients without diabetes, or in patients with/without hormonal control, HbA1c did not significantly change by week 48. Mean FPG levels showed no significant change by week 48 in all populations. Individually, increases and decreases in glycaemic parameters affected some patients in all populations. Glycaemic status as a composite measure of HbA1c and FPG (classification as normal, mild or diabetic) was stable from baseline to study end in most patients (overall, 70%; patients with diabetes, 50%; patients without diabetes, 76%), but worsened by week 48 in nine (15%) patients [seven (50%) with diabetes at baseline] and improved in nine (15%) patients (none with diabetes). Changes in lipid profiles were not considered clinically meaningful. CONCLUSIONS: Glucose and lipid levels were not detrimentally affected in most patients, while only a relatively small proportion showed deterioration in glucose control.

Morse, Lennard-Jones, and Kratzer Potentials: A Canonical Perspective with Applications.

Canonical approaches are applied to classic Morse, Lennard-Jones, and Kratzer potentials. Using the canonical transformation generated for the Morse potential as a reference, inverse transformations allow the accurate generation of the Born-Oppenheimer potential for the H2+ ion, neutral covalently bound H2, van der Waals bound Ar2, and the hydrogen bonded one-dimensional dissociative coordinate in a water dimer. Similar transformations are also generated using the Lennard-Jones and Kratzer potentials as references. Following application of inverse transformations, vibrational eigenvalues generated from the Born-Oppenheimer potentials give significantly improved quantitative comparison with values determined from the original accurately known potentials. In addition, an algorithmic strategy based upon a canonical transformation to the dimensionless form applied to the force distribution associated with a potential is presented. The resulting canonical force distribution is employed to construct an algorithm for deriving accurate estimates for the dissociation energy, the maximum attractive force, and the internuclear separations corresponding to the maximum attractive force and the potential well.

A Follow-Up Study of the Prevalence of Valvular Heart Abnormalities in Hyperprolactinemic Patients Treated With Cabergoline.

CONTEXT: Uncertainty exists whether the long-term use of ergot-derived dopamine agonist (DA) drugs for the treatment of hyperprolactinemia may be associated with clinically significant valvular heart disease and whether current regulatory authority guidelines for echocardiographic screening are clinically appropriate. OBJECTIVE: Our objective was to provide follow-up echocardiographic data on a previously described cohort of patients treated with DA for lactotrope pituitary tumors and to explore possible associations between structural and functional valve abnormalities with the cumulative dose of drug used. DESIGN: Follow-up echocardiographic data were collected from a proportion of our previously reported cohort of patients; all had received continuous DA therapy for at least 2 years in the intervening period. Studies were performed according to British Society of Echocardiography minimum standards for adult transthoracic echocardiography. Generalized estimating equations with backward selection were used to determine odds ratios of valvular heart abnormalities according to tertiles of cumulative cabergoline dose, using the lowest tertile as the reference group. SETTING: Thirteen centers of secondary/tertiary endocrine care across the United Kingdom were included. RESULTS: There were 192 patients (81 males; median age, 51 years; interquartile range [IQR], 42-62). Median (IQR) cumulative cabergoline doses at the first and second echocardiograms were 97 mg (20-377) and 232 mg (91-551), respectively. Median (IQR) duration of uninterrupted cabergoline therapy between echocardiograms was 34 months (24-42). No associations were observed between cumulative doses of dopamine agonist used and the age-corrected prevalence of any valvular abnormality. CONCLUSION: This large UK follow-up study does not support a clinically significant association between the use of DA for the treatment of hyperprolactinemia and cardiac valvulopathy.

Canonical Force Distributions in Pairwise Interatomic Interactions from the Perspective of the Hellmann-Feynman Theorem.

Force-based canonical approaches have recently given a unified but different viewpoint on the nature of bonding in pairwise interatomic interactions. Differing molecular categories (covalent, ionic, van der Waals, hydrogen, and halogen bonding) of representative interatomic interactions with binding energies ranging from 1.01 to 1072.03 kJ/mol have been modeled canonically giving a rigorous semiempirical verification to high accuracy. However, the fundamental physical basis expected to provide the inherent characteristics of these canonical transformations has not yet been elucidated. Subsequently, it was shown through direct numerical differentiation of these potentials that their associated force curves have canonical shapes. However, this approach to analyzing force results in inherent loss of accuracy coming from numerical differentiation of the potentials. We now show that this serious obstruction can be avoided by directly demonstrating the canonical nature of force distributions from the perspective of the Hellmann-Feynman theorem. This requires only differentiation of explicitly known Coulombic potentials, and we discuss how this approach to canonical forces can be used to further explain the nature of chemical bonding in pairwise interatomic interactions. All parameter values used in the canonical transformation are determined through explicit physical based algorithms, and it does not require direct consideration of electron correlation effects.

Canonical Approaches to Applications of the Virial Theorem.

Canonical approaches are applied for investigation of the extraordinarily accurate electronic ground state potentials of H2(+), H2, HeH(+), and LiH using the virial theorem. These approaches will be dependent on previous investigations involving the canonical nature of E(R), the Born-Oppenheimer potential, and F(R), the associated force of E(R), that have been demonstrated to be individually canonical to high accuracy in the case of the systems investigated. Now, the canonical nature of the remaining functions in the virial theorem [the electronic kinetic energy T(R), the electrostatic potential energy V(R), and the function W(R) = RF(R)] are investigated and applied to H2, HeH(+), and LiH with H2(+) chosen as reference. The results will be discussed in the context of a different perspective of molecular bonding that goes beyond previous direct applications of the virial theorem.

Effects of lanreotide Autogel primary therapy on symptoms and quality-of-life in acromegaly: data from the PRIMARYS study.

PURPOSE: To evaluate the effects of lanreotide Autogel on patient-reported outcomes and association with biochemical control, using PRIMARYS data. METHODS: PRIMARYS was a 1-year, open-label study of lanreotide Autogel (Depot in USA) 120 mg every 4 weeks in 90 treatment-naïve patients with acromegaly. Symptoms were assessed using Patient-assessed Acromegaly Symptom Questionnaire (PASQ) and health-related quality of life (HRQoL) using the AcroQoL questionnaire. Correlations between PASQ and AcroQoL scores, and between PASQ/AcroQoL and growth hormone (GH)/insulin-like growth factor-1 (IGF-1) levels were also evaluated (post hoc). RESULTS: Acromegaly symptoms and HRQoL significantly improved from week 12 to week 48, with modest correlations at week 48 between PASQ total score (R = -0.55, p < 0.0001) and AcroQoL global and physical scores (R = -0.67, p < 0.0001). Approximately 60% of patients achieved a minimal important difference (MID; improvement >50% of baseline standard deviation) in PASQ total score and >40% achieved a MID in AcroQoL global score (post hoc). Changes in PASQ scores were similar in biochemically controlled (GH levels ≤2.5 µg/L and normal IGF-1 levels) and uncontrolled groups, while changes in global and psychological AcroQoL scores were greater in the controlled group. There was no correlation between changes in PASQ or AcroQoL scores and changes in GH or IGF-1 levels. CONCLUSIONS: Primary treatment with lanreotide Autogel over 1 year was associated with rapid and sustained improvements in clinical signs and symptoms and HRQoL in patients with acromegaly. Improvements in HRQoL, but not symptoms, were greater in those achieving biochemical control (ClinicalTrials.gov: NCT00690898; EudraCT: 2007-000155-34).

SAGIT®: clinician-reported outcome instrument for managing acromegaly in clinical practice--development and results from a pilot study.

PURPOSE: The SAGIT instrument is a comprehensive clinician-reported outcome instrument assessing key features of acromegaly: signs and symptoms, associated comorbidities; growth hormone levels; insulin-like growth factor-1 levels; and tumor profile. The SAGIT instrument has been designed to assist endocrinologists managing acromegaly in practice. Here, we report on pre-testing (to assess ease of understanding and acceptability) and a pilot study (to assess relevance, ease of use, and utility in real-life conditions) (NCT02231593). METHODS: For pre-testing, 11 endocrinologists completed the SAGIT instrument using patient medical records and were also interviewed. They subsequently completed a PRAgmatic Content and face validity Test (PRAC-Test(©)) to report their experiences using SAGIT, and feedback was used to revise the instrument. In the pilot study, nine endocrinologists completed the SAGIT instrument in real-time with patients belonging to three different categories (stable/controlled, active/uncontrolled acromegaly, treatment-naïve), while four completed the instrument based on medical-record review. All participants then completed the PRAC-Test(©) and their feedback was used to update the instrument. RESULTS: The SAGIT instrument was well accepted by endocrinologists, with most indicating that it was concise, practical, easy to understand, useful for assessing treatment response, and valuable as a component of the patient's medical record. The pilot study confirmed the instrument's acceptability, utility, and ease of use, and indicated its potential for distinguishing acromegaly clinical stages. CONCLUSIONS: The SAGIT instrument is promising as a tool for use by endocrinologists in everyday practice to assess the status and evolution of disease in patients with acromegaly and to guide treatment decision-making.

Canonical Potentials and Spectra within the Born-Oppenheimer Approximation.

A generalized formulation of canonical transformations and spectra are used to investigate the concept of a canonical potential strictly within the Born-Oppenheimer approximation. Data for the most accurate available ground electronic state pairwise intermolecular potentials in H2, HD, D2, HeH(+), and LiH are used to rigorously evaluate such transformations. The corresponding potentials are generated explicitly using parameters calculated with algebraic functions from that of the single canonical potential of the simplest molecule, H2(+). The efficacy of this approach is further tested by direct comparison of the predicted eigenvalues of all vibrational states in the selected molecular systems considered with the corresponding most accurately known Born-Oppenheimer eigenvalues currently available. Deviations are demonstrated to be less than 2 cm(-1) for all vibrational states in H2, HD, D2, HeH(+), and LiH, with an average standard deviation of 0.27 cm(-1) for the 87 states considered. The implications of these results for molecular quantum chemistry are discussed.

A general transformation to canonical form for potentials in pairwise interatomic interactions.

A generalized formulation of explicit force-based transformations is introduced to investigate the concept of a canonical potential in both fundamental chemical and intermolecular bonding. Different classes of representative ground electronic state pairwise interatomic interactions are referenced to a chosen canonical potential illustrating application of such transformations. Specifically, accurately determined potentials of the diatomic molecules H2, H2(+), HF, LiH, argon dimer, and one-dimensional dissociative coordinates in Ar-HBr, OC-HF, and OC-Cl2 are investigated throughout their bound potentials. Advantages of the current formulation for accurately evaluating equilibrium dissociation energies and a fundamentally different unified perspective on nature of intermolecular interactions will be emphasized. In particular, this canonical approach has significance to previous assertions that there is no very fundamental distinction between van der Waals bonding and covalent bonding or for that matter hydrogen and halogen bonds.

Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort.

CONTEXT: Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence. OBJECTIVE: The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL. DESIGN: Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX, FH) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples. SETTING: The study was conducted at university hospitals. PATIENTS: Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL participated in the study. OUTCOME: Outcomes included genetic screening and clinical characteristics. RESULTS: Eleven germline mutations (five SDHB, one SDHC, one SDHD, two VHL, and two MEN1) and four variants of unknown significance (two SDHA, one SDHB, and one SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and loss of heterozygosity at the MEN1 locus in two pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have a unique histological feature not previously described in this context. CONCLUSIONS: Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, whereas mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma.

Factors contributing to high levothyroxine doses in primary hypothyroidism: an interventional audit of a large community database.

BACKGROUND: While few hypothyroid patients require more than the expected weight-related dose of levothyroxine, the underlying causes of larger-than-expected dosing requirements have not been studied in a single cohort. Our aim was to determine and quantify the multiple factors contributing to high-dose levothyroxine requirements in a cohort of patients with hypothyroidism. METHODS: The Grampian Automated Follow-Up Register (GAFUR) monitors around 17,500 hypothyroid patients. In 2008, 190 (1%) patients took >225 µg of levothyroxine daily. A questionnaire was sent to 174 patients (16 were untraceable) to assess causes and to offer blood tests for endomysial, parietal cell (PCA), and thyroid peroxidase (TPO) autoantibodies. Primary care practices were contacted for medication details. All patients with positive endomysial autoantibodies were referred to a gastroenterologist. Thyroid function tests and levothyroxine doses were re-evaluated in 2011. RESULTS: A total of 125 questionnaires (72%) were returned. Mean levothyroxine dose was 248 µg daily. Twenty-six patients (20.8%) took medication known to interfere with levothyroxine absorption, and 21 patients (16.8%) admitted to compliance issues. Seven patients had positive anti-endomysial antibodies on initial screening, with four being new diagnoses of celiac disease, and PCA were positive in 27 (21.6%) patients. At follow-up in 2011, the mean levothyroxine dose had decreased in patients on interfering medications and in the four new cases of celiac disease. CONCLUSIONS: Causes of patients needing high-dose levothyroxine replacement include poor compliance, medication interference, PCA (as a marker of atrophic/autoimmune gastritis), and celiac disease. Doses can be decreased following advice regarding medication or after management of underlying conditions.

Should all patients with acromegaly receive somatostatin analogue therapy before surgery and, if so, for how long?

Current guidelines do not recommend the routine use of somatostatin analogue pretreatment prior to surgery in patients with growth hormone-secreting pituitary tumours. In theory, presurgical use of somatostatin analogues should improve metabolic control and reduce soft tissue swelling, leading to improved anaesthetic outcomes. Shrinkage of tumours prior to surgery might also improve surgical remission rates. Hence, this article addresses the question: Should all patients with acromegaly receive a somatostatin analogue prior to surgery? Clinical trials published before December 2013 were reviewed, although literature in this area remains relatively deficient. We conclude: (i) On the basis of limited data available, somatostatin analogue pretreatment does not improve anaesthetic or immediate postoperative outcomes (i.e. hospital stay, rates of surgical complications and postoperative pituitary dysfunction). (ii) Somatostatin analogues should be considered in all patients with growth hormone-secreting macroadenomas, including invasive macroadenomas, when the overall surgical remission rate for macroadenomas at the treating centre is below 50%. Four recent RCTs have demonstrated increased rates of surgical remission using such an approach. (iii) When deemed appropriate, patients should be treated with somatostatin analogues for at least 3 months before surgery; there is currently no evidence that treatment beyond 6 months provides any additional benefit. Patients with minimally invasive macroadenomas are those most likely to benefit in terms of improved surgical remission.

Mutational analysis of the adaptor protein 2 sigma subunit (AP2S1) gene: search for autosomal dominant hypocalcemia type 3 (ADH3).

CONTEXT: Autosomal dominant hypocalcemia (ADH) types 1 and 2 are due to calcium-sensing receptor (CASR) and G-protein subunit-α11 (GNA11) gain-of-function mutations, respectively, whereas CASR and GNA11 loss-of-function mutations result in familial hypocalciuric hypercalcemia (FHH) types 1 and 2, respectively. Loss-of-function mutations of adaptor protein-2 sigma subunit (AP2σ 2), encoded by AP2S1, cause FHH3, and we therefore sought for gain-of-function AP2S1 mutations that may cause an additional form of ADH, which we designated ADH3. OBJECTIVE: The objective of the study was to investigate the hypothesis that gain-of-function AP2S1 mutations may cause ADH3. DESIGN: The sample size required for the detection of at least one mutation with a greater than 95% likelihood was determined by binomial probability analysis. Nineteen patients (including six familial cases) with hypocalcemia in association with low or normal serum PTH concentrations, consistent with ADH, but who did not have CASR or GNA11 mutations, were ascertained. Leukocyte DNA was used for sequence and copy number variation analysis of AP2S1. RESULTS: Binomial probability analysis, using the assumption that AP2S1 mutations would occur in hypocalcemic patients at a prevalence of 20%, which is observed in FHH patients without CASR or GNA11 mutations, indicated that the likelihood of detecting at least one AP2S1 mutation was greater than 95% and greater than 98% in sample sizes of 14 and 19 hypocalcemic patients, respectively. AP2S1 mutations and copy number variations were not detected in the 19 hypocalcemic patients. CONCLUSION: The absence of AP2S1 abnormalities in hypocalcemic patients, suggests that ADH3 may not occur or otherwise represents a rare hypocalcemic disorder.