Diagnosis by Serendipity: Cushing Syndrome Attributable to Cortisol-Producing Adrenal Adenoma as the Initial Manifestation of Multiple Endocrine Neoplasia Type 1 Due to a Rare Splicing Site Men1 Gene Mutation

ObjectiveTo report a case that highlights the potential for Cushing syndrome to be the first manifestation of multiple endocrine neoplasia type 1 (MEN 1) syndrome and to describe the rare underlying genetic mutation and the heterogeneous manifestations of the syndrome within the same family.MethodsWe present a case report including biochemical and radiologic findings, review family data, and discuss the results of genetic analyses.ResultsA 16-year-old girl who was not known to have any medical illness and had no known family history of MEN 1 syndrome presented with Cushing syndrome attributable to a cortisol-producing adrenal adenoma. During her evaluation, she was found to have primary hyperparathyroidism and a pituitary microprolactinoma. These findings raised the possibility of MEN 1 syndrome. She did not have clinical, biochemical, or radiologic evidence of islet cell pancreatic tumors. Family screening showed that her father had evidence of primary hyperparathyroidism, mild hyperprolactinemia, normal findings on magnetic resonance imaging of the pituitary, and a 1.2- cm nodule in the tail of the pancreas in conjunction with slight elevation of serum insulin and normal gastrin levels. The patient’s 5 siblings had evidence of primary hyperparathyroidism, and 2 of them also had mild hyperprolactinemia. Genetic screening confirmed the presence of a MEN1 gene missense G to A mutation in the patient, her father, and her siblings at the splicing site of intron 6 (IVS6 + 1G > A). This mutation leads to frameshift and truncation of the MEN1 gene.ConclusionIn MEN 1, Cushing syndrome is an extremely rare and usually late manifestation. Most cases are due to corticotropin-producing pituitary adenomas. Although Cushing syndrome generally develops years after the more typical manifestations of MEN 1 appear, it may be the primary manifestation of MEN 1 syndrome. There is considerable heterogeneity in the manifestations of MEN 1, even within a family having the same genetic mutation. (Endocr Pract. 2008;14:595-602)     

Serum Monocyte Chemokine Protein-1 Levels Before and After Parathyroidectomy in Patients with Primary Hyperparathyroidism

ObjectiveTo investigate the effects of parathyroidectomy on serum monocyte chemokine protein-1 (MCP- 1) levels in patients with primary hyperparathyroidism (PHPT).MethodsForty-three PHPT patients, age 56 ± 12 years, underwent minimally invasive parathyroidectomy. Serum samples were collected at 0 and 15 to 20 minutes after parathyroid adenoma removal. Serum samples were stored at -70°C until time of assay.ResultsIn 40 PHPT patients with a single adenoma, MCP-1 levels decreased from 342 ± 103 to 250 ± 77 pg/ mL (P < .001) 15 to 20 minutes after parathyroid adenoma removal. MCP-1 levels were positively correlated with intact parathyroid hormone (PTH) levels (R = 0.47; P < .01). In 3 PHPT patients with double parathyroid adenoma, MCP-1 levels did not decrease after removal of the first adenoma but decreased 15 to 20 minutes after second adenoma removal.ConclusionOur results provide evidence that the decrease in serum intact PTH due to minimally invasive parathyroidectomy results in an immediate decrease in serum MCP-1 levels. (Endocr Pract. 2014;20:1165-1169)     

HRPT2- (CDC73) Related Hereditary Hyperparathyroidism: A Case Series From Western India

Objective: To describe a case series of HRPT2- (CDC73) related hereditary primary hyperparathyroidism (PHPT) from western India.Methods: We present a case series of 4 families (7 patients) with PHPT caused by CDC73 gene mutations.Results: The mean age of presentation of the 4 index cases was 27.25 ± 9.8 years. Two family members were identified through biochemical screening (Cases 1b and 2b), while 1 mutation-positive family member did not manifest any features of PHPT or hyperparathyroidism jaw tumor syndrome (HPT-JT) syndrome (Case 2c). Biochemistry showed increased serum calcium (mean: 13.21 ± 1.24 mg/dL), low serum phosphorus (mean: 1.78 ± 0.44 mg/dL), and high parathyroid hormone (PTH, mean: 936 ± 586.9 pg/mL).All patients had a uniglandular presentation and underwent single adenoma excision initially except Cases 2a and 2b, who underwent subtotal parathyroidectomy at baseline. Two cases experienced PHPT recurrence (Cases 3 and 4), while 1 remained uncured due to parathyroid carcinoma (Case 1a). Other associated syndromic features like ossifying jaw fibromas were present in 2 patients, renal cysts in 3 patients, and uterine involvement in 2 patients. Two families had novel germline CDC73 mutations (Families 1 and 3), while the other 2 had reported mutations. Family 2 had familial isolated PHPT without any other features of HPT-JT syndrome.Conclusion: Our findings reaffirm the need for genetic analysis of patients with PHPT, especially those with younger age of disease onset; recurrent disease; and associated features like polycystic kidneys, endometrial involvement, ossifying jaw tumors, or parathyroid carcinoma.Abbreviations: FIHP = familial isolated hyperparathyroidism HPT-JT = hyperparathyroidism jaw tumor syndrome PHPT = primary hyperparathyroidism PTH = parathyroid hormone ⁹⁹Tc = ⁹⁹Technetium     

Primary Hyperparathyroidism During Pregnancy: A Case Series of 8 Patients

Objective: Due to a lack of typical clinical manifestations and physiologic changes in calcium metabolism during pregnancy, primary hyperparathyroidism (PHPT) during pregnancy is commonly underdiagnosed, and treatment during this unique period presents a clinical challenge. Hence, the aim of the present study was to summarize the cases of 8 pregnant patients with PHPT who were treated at our center to provide better clinical insight into this condition.Methods: Our study comprised a retrospective analysis of 8 pregnant PHPT patients and a control group of 22 age-matched, nonpregnant PHPT patients during the same period. Clinical manifestations, biochemical indices, pathologic types, therapeutic strategies, and pregnancy outcomes were compiled, and 25 patients were screened for germline mutations in the MEN1, CDC73, and CaSR genes.Results: The most-common symptoms in the pregnancy group involved the gastrointestinal tract (GIT) in 7/8 cases (87.5%), followed by urinary system involvement (50%) and joint pain (50%). In contrast, GIT symptoms in the control group were significantly less common (31.82%; P = .012). There was a trend of more-severe elevation of serum parathyroid hormone levels in the control group compared to that in the pregnancy group (P = .053). No differences were found in blood-ionized calcium, phosphate, or alkaline phosphatase levels between the two groups. In the pregnancy group, the serum albumin-corrected calcium level was reduced from 3.42 ± 0.66 mmol/L to 2.89 ± 0.46 mmol/L (P = .025) after hydration and medical treatment. Six patients, three of whom were in the second trimester of pregnancy, underwent parathyroidectomy, and 3 patients were after childbirth or had induced labor. Postoperative serum calcium levels were reduced to within the normal range. Fetal/neonatal complications were observed in 4 of 5 patients who had not received surgical treatment during pregnancy. In addition, 2 of 5 pregnant PHPT patients were found to carry MEN1 mutations, whereas no mutations were detected in any of the 20 nonpregnant patients.Conclusion: In this case series of PHPT during pregnancy, the most-common complaint of GIT symptoms may be easily confused with pregnancy reactions, which might contribute to the under- or misdiagnosis of this clinical entity. Patients who did not receive surgical treatment during pregnancy had high incidences of fetal/neonatal complications and worse pregnancy outcomes.Abbreviations: CaSR = calcium-sensing receptor; CDC73 = cell division cycle 73; GIT = gastrointestinal tract; MEN = multiple endocrine neoplasia; PHPT = primary hyperparathyroidism; PTH = parathyroid hormone; SCa = serum calcium     

Evaluation of Vitamin D Repletion Regimens to Correct Vitamin D Status in Adults

ObjectiveTo determine the efficacy and safety of commonly prescribed regimens for the treatment of vitamin D insufficiency.MethodsWe performed a retrospective analysis of 306 consecutive patients who were prescribed ergocalciferol (vitamin D₂) for correction of vitamin D insufficiency at the Atlanta Veterans Affairs Medical Center between February 2003 and May 2006. Serum levels of parathyroid hormone, 25-hydroxyvitamin D (25-OHD), and calcium were compared before and after treatment with ergocalciferol. Patients who did not have a 25-OHD determination (n = 41) were excluded from analysis. Vitamin D deficiency, insufficiency, and sufficiency were defined as a serum 25-OHD level of < 20 ng/mL, 21 to 29 ng/mL, and > 30 ng/mL, respectively.ResultsWe identified 36 discrete prescribing regimens. The 3 most common regimens were ergocalciferol 50,000 IU once weekly for 4 weeks followed by 50,000 IU once monthly for 5 months (n = 48); ergocalciferol 50,000 IU once monthly for 6 months (n = 80); and ergocalciferol 50,000 IU 3 times weekly for 6 weeks (n = 27). Each of these 3 treatments significantly increased serum 25-OHD (P < .01), but vitamin D sufficiency was achieved in only 38%, 42%, and 82% of study subjects, respectively. Regimens with > 600,000 IU of ergocalciferol given for a mean of 60 ± 40 days achieved sufficiency in 64% of cases, without vitamin D toxicity.ConclusionIn this study, regimens that contained at least 600,000 IU of ergocalciferol appeared to be the most effective in achieving vitamin D sufficiency. Guidelines for the treatment of vitamin D insufficiency in healthy adults should be developed. (Endocr Pract. 2009;15:95-103)     

Deterioraron of Ovarian Function After Total Abdominal Hysterectomy with Preservaron of Ovaries

Objective: To evaluate ovarian function after total abdominal hysterectomy in premenopausal women.Methods: In the present cross-sectional study, we enrolled 52 healthy female subjects having normal menstrual cycle as controls and 37 female patients (age <45 years) who had undergone total abdominal hysterectomy (TAH) with preservation of at least one ovary for the evaluation of ovarian function. Serum antimüllerian hormone (AMH) and follicle-stimulating hormone (FSH) were measured by enzyme-linked immunosorbent assay in both groups. Transvaginal Doppler ultrasonography was done to measure ovarian stromal blood flow indices (resistive index [RI] and pulsatility index [PI]). The means obtained from different sample groups were compared using the nonparametric Mann-Whitney U test, and correlations between two variables were evaluated using the Spearman nonparametric correlation test. A value of P<.05 was considered statistically significant.Results: Mean postoperative duration of patients who had undergone hysterectomy was 2.5 years. Mean serum AMH level was 7.68 ± 6.70 ng/mL in the cases, significantly lower than the level in controls (10.98 ± 7.83 ng/mL) (P = .016). Serum FSH level in controls was 12.01 ± 6.27 μIU/mL, which was significantly higher in the cases (20.27 ± 12.91 μIU/mL) (P = .001). An inverse correlation between serum AMH and FSH was observed (P = .0006; r = -0.4583). However, the ovary RI and PI values in both groups were similar.Conclusion: TAH affects ovarian function, despite normal ovarian blood supply.Abbreviations:AMH = antimüllerian hormoneFSH = follicle-stimulating hormoneRI = resistive indexPI = pulsatility indexTAH = total abdominal hysterectomy     

Intérêt de l’imagerie hybride TEMP/TDM pour la détection de l’ectopie parathyroïdienne. Expérience du service de médecine nucléaire – CHU Mohammed VI,Marrakech

IntroductionHyperparathyroidism due to a parathyroid ectopia is a rare disease; it is the most common cause of persistent or recurrent hyperparathyroidism. Its treatment is exclusively surgical and the results of the surgery benefit from the contribution of preoperative imaging techniques. The aim of this work is to illustrate the interest of the single photon emission computed tomography/computed tomography (SPECT/CT) in the detection and treatment of ectopic parathyroid orientation.Case reportClinical case 1: a 41-year-old patient was followed for persistent primary hyperparathyroidism revealed by brown tumors at the level of the lower extremity of the right femur and tibia. The rate of parathormone was 1987.4 pg/mL. The cervical echography and the scanning were not decisive. The SPECT/CT, performed during a ^99mTc-MIBI scintigraphy and the same for the 2nd clinical case, has showed an area of high uptake projecting behind the left sternoclavicular joint. The diagnosis of ectopic parathyroid localization was retained. Resection and pathologic examination of the surgical specimen revealed parathyroid adenoma tissue. The evolution was marked by a normalization of the rate of parathormone. Clinical case 2: a 71-year-old patient who presents a clinico-biological board of primitive persistent hyperparathyroidism. A first scintigraphy (^99mTc-MIBI) realized in 2010 was negative. The rate of parathormone was 969 ng/L, the rate of calcium was 2.90 mmol/L. Two cervical ultrasound were normal. The SPECT/CT has objectified an area of high uptake in projection at the upper floor of the middle mediastinum. The diagnosis of ectopic parathyroid localization was retained. Surgical resection and histological study revealed a parathyroid adenoma tissue. The evolution was marked by a normalization of the rate of parathormone.DiscussionThe SPECT/CT has an important role in the management of patients with persistent or recurrent hyperparathyroidism. It can usually visualize ectopic parathyroid injury, specify its size and anatomic relationships to optimize surgical management.     

Vascularity-Targeted Percutaneous Ethanol Injection of Toxic Thyroid Adenomas: Outcomes of A Feasibility Study Performed in the USA

Objective: The recommended treatment options for toxic adenoma (TA) in the USA are radioactive iodine ablation and surgical resection, with continued observation for pre-toxic adenoma (PTA). Percutaneous ethanol ablation (PEI) has proven efficacy in the treatment of TA and is widely available in Europe but not in the USA.Methods: Retrospective analysis was performed of all patients who underwent PEI for TA/PTA at the University of Utah, from January 2010 to 2018. Ultrasound-guided PEI, with injections targeting power Doppler–mapped blood vessels within the adenomas, was conducted. Functionality was confirmed using thyroid scintigraphy prior to PEI.Results: Eighteen adults (15 female) underwent PEI. Mean age was 41 ± 13.7 years. Baseline thyroid-stimulating hormone (TSH) was suppressed (0.06 ± 0.09 mU/L), with normal free thyroxine (FT4) 1.43 ± 0.39 ng/dL. Median nodule volume was 5.7 cm³ (interquartile range &lsqb;IQR], 4.8 to 7.7 cm³). Seventy-eight percent (n = 14) underwent two or less PEI sessions. Median volume of ethanol used was 0.46 mL/mL nodule volume (IQR, 0.3 to 0.6 mL). There was a significant increase in TSH concentrations within the first 3 months after PEI (0.06 ± 0.09 mU/L vs. 1.22 ± 1.88 mU/L; P = .02), with a concomitant significant decrease in FT4 concentrations (1.43 ± 0.39 ng/day vs. 1.13 ± 0.25 ng/day; P<.01). Significant nodular volume reduction was observed following PEI (median 5.7 cm³ &lsqb;IQR 4.8–7.7 cm³] vs. 2.5 cm³ &lsqb;IQR 2.0–7.8 cm³]; P<.01).Conclusion: Vascularity-targeted PEI is safe and effective for treating PTA and TA. This unique approach required lower injected alcohol volume and fewer injections for therapeutic success.Abbreviations: ATA = American Thyroid Association; FT4 = free thyroxine; IQR = interquartile range; PD = power Doppler; PEI = percutaneous ethanol injection; PTA = pre-toxic adenoma; RAI = radioactive iodine ablation; RFA = radiofrequency ablation; TA = toxic adenoma; TT3 = total triiodothyronine; US = ultrasound     

Association of First-Trimester Thyroid Function Test Values with Thyroperoxidase Antibody Status,Smoking, and Multivitamin Use

ObjectiveTo determine first-trimester thyroid function values and associations with thyroperoxidase antibody (TPO-Ab) status, smoking, emesis, and iodine-containing multivitamin use.MethodsWe collected information by interview, questionnaire, and blood draw at the initial obstetric visit in 668 pregnant women without known thyroid disease. We compared thyroid-stimulating hormone (TSH), total thyroxine (T₄), and free T₄ index (FT₄I) values by TPO-Ab status. Multiple regression was used to identify characteristics associated with thyroid function values.ResultsThe following median (range containing 95% of the data points) thyroid function test values were obtained in 585 TPO-Ab–negative women: TSH, 1.1 mIU/L (0.04-3.6); FT₄I, 2.1 (1.5-2.9); and T₄, 9.9 μg/dL (7.0-14.0). The following median (range containing 95% of the data points) thyroid function test values were obtained in 83 TPO-Ab–positive women: TSH, 1.8 mIU/L (0.3-6.4) (P < .001); FT₄I, 2.0 (1.4-2.7) (P = .06); and T₄, 9.3 μg/dL (6.8-13.0) (P = .03) (P values denote statistically significant differences between TPO-Ab–positive and negative participants). Among TPO-Ab–negative participants, TSH level was not associated with use of iodine-containing multivitamins, smoking, or race. TSH increased 0.03 mIU/L for every year of maternal age (P = .03) and decreased by 0.3 mIU/L for every increase in parity (P < .001). T₄ decreased 0.04 μg/dL for every year of maternal age (P = .04). Mean FT₄I was 2.05 in smokers and 2.20 in nonsmokers (P < .01). There were no relationships between T₄ or FT₄I and parity, race, or iodine-containing multivitamin use.ConclusionTPO-Ab status of pregnant women should be considered when constructing trimester-specific reference ranges because elevated serum TPO-Ab levels are associated with higher TSH and lower T₄ values. (Endocr Pract. 2008;14:33-39)     

Differencesin-Vitamin-D3-Dosing-Regimens in a Geriatric Community-Dwelling Population

ObjectiveThe adequate dose of vitamin D supple mentation for community-dwelling elderly people has not been thoroughly investigated. This study aims to determine the efficacy of a low-dose and a higher dose of vitamin D₃ in maintaining 25-hydroxyvitamin D [25(OH)D] levels at or above 30 ng/mL.MethodsThis was a single site, double-blind, ran domized exploratory clinical trial that enrolled adults 65 years of age and older. Within strata of baseline 25(OH) D levels (< 30 versus ≥ 30 ng/mL) subjects were random ized in a 1:2 ratio to receive either 400 or 2,000 IU vitamin D₃ daily for 6 months. The main outcome measures were changes in serum 25(OH)D levels according to baseline 25(OH)D levels and dose of vitamin D3.ResultsAt baseline, 41 of 105 participants (39%) had low 25(OH)D levels (< 30 ng/mL). After 6 months of vitamin D₃ supplementation, 21 of 32 participants (66%) receiving 400 IU and 14 of 59 participants (24%) receiving 2,000 IU of vitamin D₃ still had low 25(OH)D levels. Thelargest increases in serum 25(OH)D levels were observed in subjects with baseline levels < 30 ng/mL who received 2,000 IU of vitamin D daily.ConclusionRegardless of baseline 25(OH)D level, in persons 65 years of age and older, 6-month vitamin D₃ supplementation with 400 IU daily resulted in low 25(OH) D in most individuals, while 2,000 IU daily maintained 25(OH)D levels within an acceptable range in most people on this regimen. (Endocr Pract. 2012;18:847-854)     

Utility of Ultrasound-Guided Fine-Needle Aspiration of Parathyroid Adenomas for Localization Before Minimally Invasive Parathyroidectomy

ObjectiveTo determine the sensitivity and specificity of ultrasound (US)-guided fine-needle aspiration (FNA) and measurement of parathyroid hormone (PTH) in the aspirate (FNA/PTH) as a preoperative localization procedure.MethodsThe study group consisted of 34 consecutive patients with primary hyperparathyroidism. The FNA/PTH estimations in these patients were compared with those from 13 proven thyroid nodules. All patients underwent US study of the neck, which suggested the presence of a solitary adenoma in 30 patients and of hyperplasia in 2; no adenoma or hyperplasia could be visualized in 2 patients. Thirty-two patients underwent FNA/PTH, which yielded a mean PTH level of 22,060.0 ± 6,653.0 pg/mL. This result was significantly different (P < 0.001) from the mean PTH level in 13 thyroid nodules (9.0 ± 1.0 pg/mL).ResultsOn the basis of the FNA/PTH results, 28 patients with suspected adenomas underwent minimally invasive parathyroidectomy (MIP), and 2 patients are awaiting a surgical procedure. Of these 28 patients, 27 had more than a 50% decline in intraoperative PTH level after removal of the suspected adenoma, confirming surgical success. In 1 patient, multigland hyperplasia was discovered during the operation. The 2 study subjects with US findings of suspected hyperplasia underwent 4-gland surgical procedures. All patients treated surgically continued to have normal serum calcium levels 6 to 18 months post-operatively.ConclusionPrimary hyperparathyroidism is caused most commonly by a solitary adenoma and less commonly by multigland hyperplasia of the parathyroid glands. Surgical resection is the only curative therapy. MIP has become a frequently used strategy, but there are limitations to current preoperative localization techniques. We conclude that US-guided FNA is a useful technique that facilitates MIP, with a high degree of specificity (95%) and sensitivity (91%). (Endocr Pract. 2007;13:333-337)     

Higher Growth Hormone Levels are Associated with Erectile Dysfunction in Male Patients With Acromegaly

Objective: To investigate in vivo correlates of erectile dysfunction (ED) in male patients with acromegaly.Methods: Fifty-one male patients with acromegaly were assessed by the International Index of Erectile Function-5 and Acromegaly Quality of Life (Acro-QoL) questionnaires. The measurement of serum nitric oxide (NO) were performed in patients and age-matched nonacromegalic controls.Results: Among 51 patients analyzed, 32 (62.7%) had ED. Patients with ED showed lower Acro-QoL scores regarding global (69.8 ± 17.7 versus 79.4 ± 11.2; P = .035) and personal relationship dimensions (59.6 ± 22.1 versus 76.8 ± 17.6; P = .012) than non-ED patients. ED patients were older (44.5 ± 11.2 years versus 33.2 ± 8.5 years; P = .04) and showed higher growth hormone (GH) levels (15.5 μg/L &lsqb;interquartile range of 9.5 to 34.5 μg/L] versus 5.9 μg/L &lsqb;interquartile range of 3.4 to 13.9 μg/L]; P = .001) compared to non-ED patients. The cutoff values for identifying ED were 7.9 μg/L for random GH and 5.3 μg/L for GH nadir after oral administration of 75 g of glucose. There was no significant difference in total testosterone levels between the two groups (6.36 ± 4.24 nmol/L versus 9.54 ± 5.50 nmol/L; P = .299). The NO levels in patients with acromegaly were significantly lower than those in nonacromegalic controls (8.77 ± 1.78 μmol/L versus 19.19 ± 5.02 μmol/L, respectively; P = .049). Furthermore, the NO levels were even lower in ED patients than those in non-ED patients (5.14 ± 0.98 μmol/L versus 12.09 ± 3.44 μmol/L; P = .027).Conclusion: Our study showed that ED is prevalent in male acromegalic patients and may be associated with systemic endothelial dysfunction induced by excessive GH. Further studies investigating the mechanism of GH and ED are required.Abbreviations: Acro-QoL = Acromegaly Quality of Life; ED = erectile dysfunction; FSH = follicle-stimulating hormone; GH = growth hormone; IGF-1 = insulin-like growth factor 1; IIEF-5 = international index of erection function-5; LH = luteinizing hormone; MRI = magnetic resonance imaging; NO = nitric oxide; OGTT = oral glucose tolerance test; QoL = quality of life; ROC = receiver operating characteristic     

Optimal Free Thyroxine Levels for Thyroid Hormone Replacement in Hypothyroidism

ObjectiveTo determine whether a difference exists in the free thyroxine level required to achieve a normal thyrotropin (thyroid-stimulating hormone or TSH) level between patients with primary hypothyroidism and euthyroid control subjects and compare the free thyroxine levels in patients with primary and secondary hypothyroidism receiving thyroid hormone replacement.MethodsWe retrospectively assessed TSH and free thyroxine values in 58 patients with primary hypothyroidism and 78 euthyroid control subjects for whom screening thyroid function tests had been performed. From the medical records, we also obtained free thyroxine values for 23 patients with central hypothyroidism receiving stable levothyroxine replacement therapy.ResultsThe mean free thyroxine level was significantly higher in patients with primary hypothyroidism than in euthyroid control subjects (1.36 ± 0.201 ng/dL versus 1.10 ± 0.155 ng/dL, respectively, P < .0001), whereas the corresponding mean TSH concentrations did not differ significantly (1.60 ± 1.183 mlU/L versus 1.73 ± 0.792 mlU/L, P = .46). The mean free thyroxine value was also significantly higher in the patients with central hypothyroidism in comparison with that in the euthyroid control subjects (1.31 ± 0.278 ng/dL versus 1.10 ± 0.155 ng/dL, respectively, P < .0001), and no significant difference was noted between the patients with primary and central hypothyroidism (1.36 ng/dL versus 1.31 ng/dL, P = .60).ConclusionPatients with hypothyroidism require a higher level of serum free thyroxine to achieve a normal TSH value in comparison with euthyroid control subjects. This finding suggests that patients with central hypothy-roidism should be treated to achieve free thyroxine levels in the upper part of the reference range. (Endocr Pract. 2008;14:550-555)     

Surgeon-Performed Ultrasonography as an Adjunct to Minimally Invasive Radio-Guided Parathyroidectomy in 100 Consecutive Patients with Primary Hyperparathyroidism

ObjectiveTo examine whether surgeon-performed ultrasonography (SPU) in patients with primary hyperparathyroidism and negative preoperative sestamibi scans improves adenoma localization, increases the directed unilateral exploration rate, and reduces operative time and length of hospital stay.MethodsWe retrospectively analyzed 100 consecutive patients with primary hyperparathyroidism encountered between January 1, 2005, and March 31, 2007. Patients underwent preoperative sestamibi scanning and SPU. Minimally invasive radio-guided parathyroidectomy (MIRP) was performed on patients with positive sestamibi scans. In sestamibi scan–negative patients, unilateral exploration was performed with removal of the adenoma, which was submitted for frozen section. Accuracy, operative time, hospital length of stay, mortality, and morbidity were assessed.ResultsOf 100 patients, 79 had positive sestamibi scans and underwent MIRP. Twenty-one had negative sestamibi scans, 18 of whom underwent SPU. Parathyroid adenoma was localized in 17 (94%) of the 18 patients. Operative time and length of hospital stay were not significantly different between sestamibi scan–negative patients who underwent SPU with directed unilateral exploration and sestamibi scan–positive patients who underwent MIRP (operative time: 46 minutes vs 38 minutes, respectively; length of hospital stay: 17.8 hours vs 16.1 hours, respectively). Operative time and length of hospital stay were significantly shorter in sestamibi scan–negative patients who underwent SPU with directed unilateral exploration and in patients who underwent MIRP than in historical controls who underwent 4-gland exploration (P < .01 for both outcomes). No morbidity or mortality was documented.ConclusionSPU localizes 94% of adenomas in sestamibi scan–negative patients, which allows for directed unilateral exploration and results in operative time and length of hospital stay not significantly different from patients undergoing MIRP. (Endocr Pract. 2008;14:28-32)     

The effect of molecular packing on the occurrence of spin crossover phenomena in one-dimensional Fe(II)-bis-Schiff base complexes

Two new one-dimensional Fe(II)-bis-Schiff base complexes, [Fe(L1)(pyz)] · CH₂Cl₂ (1) and [Fe(L2)(pyz)] · 2CH₂Cl₂ (2) (H₂L1 = bis(O-vanillin)-O-phenylenediimine, H₂L2 = bis(O-vanillin)-2,3-naphthalenediimine, pyz = pyrazine) are reported with their crystal structures and magnetic property. Compound 1 shows a two-step SCO behavior while 2 shows HS at all the temperature range measured. Although the extension of aromatic moiety from benzene (L1) to naphthalene (L2) was introduced for the purpose of strengthening the cooperativity, it leads to the absence of SCO, due to the unanticipated π–π interaction, which leads to the longer Fe–N bond lengths and a weak ligand field around Fe(II) ion.     

Increased Atherogenic Low-Density Lipoprotein Cholesterol in Untreated Subclinical Hypothyroidism

ObjectiveTo evaluate the effects of physiologic doses of levothyroxine replacement on the lipoprotein profile in patients with subclinical hypothyroidism (SCH).MethodsIn a prospective, double-blind, placebo- controlled study, we enrolled 120 patients—mostly, but not exclusively, premenopausal women—with SCH. Patients were randomly assigned to either a levothyroxine- treated group (n = 60) or a placebo (control) group (n = 60). Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were measured before and 52 weeks after assignment to either group.ResultsIn the levothyroxine-treated group, the lipoprotein mean values before and after the 52-week study were as follows: TC, 5.05 ± 0.98 mmol/L versus 4.74 ± 0.87 mmol/L (P < .0001); LDL-C, 3.30 ± 0.90 mmol/L versus 2.89 ± 0.59 mmol/L (P < .01); TG, 1.18 ± 0.71 mmol/L versus 0.95 ± 0.53 mmol/L (P < .002); and HDL-C, 1.20 ± 0.33 mmol/L versus 1.19 ± 0.32 mmol/L (P = .29). In the control group, TC, HDL-C, and TG values remained unchanged after 52 weeks in comparison with baseline, but LDL-C mean values increased from 2.79 ± 0.60 mmol/L to 3.11 ± 0.77 mmol/L, a change that was statistically significant (P < .001). At the end of the study, the lipid profile changes between levothyroxine- treated and control groups were compared. Total cholesterol and LDL-C were significantly lower in the levothyroxine-receiving group (P < .029 and P < .0001, respectively) in comparison with the control group. The difference did not reach statistical significance for TG and HDL-C values.ConclusionIn premenopausal women, SCH has a negative effect on the lipoprotein profile and may translate into a sizable cardiovascular risk if left untreated. (Endocr Pract. 2008;14:570-575)     

An oligothiophene compound neutralized influenza A viruses by interfering with hemagglutinin

Background and ObjectivesRecently influenza pandemic outbreaks were caused by emerging H5N1, H7N9 and H1N1 viruses. However, virucidal disinfectants are mainly unspecific and toxic. It is tactical to discover specific virucidal compounds.MethodsThe inhibitory potency was determined in H5N1 pseudovirus system; Interactions of compounds with hemagglutinin (HA) were detected with surface plasmon resonance (SPR) and further calculated with molecular docking. Virucidal effect was also estimated in influenza virus A/Puerto Rico/8/34(H1N1). Prevention efficacy was further estimated in mice model.ResultsOligothiophene compound 4sc was potently virucidal against H5N1 pseudovirus with selective index > 1169 (IC₅₀ = 0.17 ± 0.01 μM). Pseudovirus assay revealed 4sc may interact with HA. However, HA inhibition test indicated 4sc did not interact with receptor pocket in HA. SPR detection revealed 4sc interacted directly with HA and its HA2 subunits. Molecular docking analysis revealed that 4sc interacted with the cavity of HA2 stem region and HA1-HA2 interface which consist of 7 residues: L2₂, K26₂, G47₂ and F110₂ in HA2; M24₁, E25₁ and N27₁ in HA1. 4sc also potently and irreversibly neutralized PR8 (H1N1) virus, causing 10^{5.06 ± 0.26} fold decrease of virus titer after exposure for 10 min. 4sc blocked PR8 transmission to MDCK cells. Amazingly, virucidal effect of 4sc was not significantly reduced even at 4 °C. Furthermore, 4sc blocked viral transmission to mice.ConclusionOligothiophene compound 4sc is a novel selective virucide of influenza virus, which blocks entry by interfering viral hemagglutinin. Due to promising safety profile and stable virucidal effect at 4 °C, 4sc may be useful in disinfecting H5N1 and H1N1 influenza virus.     

Synthesis and activity of novel tetrazole compounds and their pyrazole-4-carbonitrile precursors against Leishmania spp

A new series of 5-(1-aryl-3-methyl-1H-pyrazol-4-yl)-1H-tetrazole derivatives (4a–m) and their precursor 1-aryl-3-methyl-1H-pyrazole-4-carbonitriles (3a–m) were synthesized and evaluated as antileishmanials against Leishmania braziliensis and Leishmania amazonensis promastigotes in vitro. In parallel, the cytotoxicity of these compounds was evaluated on the RAW 264.7 cell line. The results showed that among the assayed compounds the substituted 3-chlorophenyl (4a) (IC₅₀/24 h = 15 ± 0.14 μM) and 3,4-dichlorophenyl tetrazoles (4d) (IC₅₀/24 h = 26 ± 0.09 μM) were the most potent against L. braziliensis promastigotes, as compared the reference drug pentamidine, which presented IC₅₀ = 13 ± 0.04 μM. In addition, 4a and 4d derivatives were less cytotoxic than pentamidine. However, these tetrazole derivatives (4) and pyrazole-4-carbonitriles precursors (3) differ against each of the tested species and were more effective against L.braziliensis than on L. amazonensis.     

Elevated plasma vitamin B12 levels and cancer prognosis: A population-based cohort study

BackgroundElevated plasma vitamin B12 levels (cobalamin, Cbl) are associated with increased short-term cancer risk among patients referred for this laboratory measurement. We aimed to assess prognosis in cancer patients with elevated plasma Cbl.MethodsWe conducted a population-based cohort study using data from Danish medical registries during 1998–2014. The study included 25,017 patients with a cancer diagnosis and Cbl levels of 200–600 pmol/L (reference/normal range), 601–800 pmol/L and >800 pmol/L measured up to one year prior to diagnosis, and a comparison cohort of 61,988 cancer patients without a plasma Cbl measurement. Patients treated with Cbl were excluded. Survival probability was assessed using Kaplan–Meier curves. Mortality risk ratios (MRR) were computed using Cox proportional hazard regression, adjusted for age, sex, calendar year, cancer stage and comorbidity, scored using the Charlson comorbidity index.ResultsSurvival probabilities were lower among patients with elevated Cbl levels than among patients with normal levels and among members of the comparison cohort [(1-year survival,%) Cbl: 200–600 pmol/L: 69.3%; 601–800 pmol/L: 49.6%; >800 pmol/L: 35.8%; comparison cohort: 72.6%]. Thirty-day mortality was elevated for patients with Cbl levels of 601–800 pmol/L or >800 pmol/L, compared to patients with levels of 200–600 pmol/L [(MRR (95% confidence interval): 601–800 pmol/L vs. 200–600 pmol/L: 1.9 (1.6–2.2); >800 pmol/L vs. 200–600 pmol/L: 2.7 (2.4–3.1)]. This association remained robust for 31–90-day and 91–365-day mortality, showing similar dose-response patterns.ConclusionCancer patients with elevated Cbl levels had higher mortality than those with normal Cbl levels. These findings may have clinical significance for assessing the prognosis of cancer patients.