Susceptibility locus for Alzheimer's disease on chromosome 10.

The apolipoprotein E (APOE) gene is the only genetic risk factor that has so far been linked to risk for late-onset Alzheimer's disease (LOAD). However, 50 percent of Alzheimer's disease cases do not carry an APOE4 allele, suggesting that other risk factors must exist. We performed a two-stage genome-wide screen in sibling pairs with LOAD to detect other susceptibility loci. Here we report evidence for an Alzheimer's disease locus on chromosome 10. Our stage one multipoint lod score (logarithm of the odds ratio for linkage/no linkage) of 2.48 (266 sibling pairs) increased to 3.83 in stage 2 (429 sibling pairs) close to D10S1225 (79 centimorgans). This locus modifies risk for Alzheimer's disease independent of APOE genotype.

Catecholamine transport and energy-linked function of chromafffin granules isolated from a human pheochromocytoma.

The structure and function of chromaffin granules of human pheochromocytoma was extensively investigated in a highly purified granule fraction obtained from a single specimen of human pheochromocytoma tissue. Pheochromocytoma chromaffin granules were analyzed for catecholamine, ATP, enkephalin, phospholipid, cytochrome and ion content. Using a variety of techniques it was found that the membrane of these granules is highly impermeable to Na+, K+, and H+, and that the intragranular pH was maintained at 5.1 irrespective of suspending media. The presence of MgATP induces a transmembrane potential (delta psi) across the membrane of these granules which is positive inside and which corresponds to 90 mV. Both delta pH and delta psi are coupled to biogenic amine accumulation into the granules in a process which is reserpine sensitive. These properties are compared with those of chromaffin granules isolated from normal human tissue or from other animal species and are discussed in terms of possible explanation at a biochemical or subcellular level of the clinical manifestation of the pheochromocytoma.

Parathyroid hyperplasia, thymic carcinoid and pituitary adenoma detected with technetium-99m-MIBI in MEN type I.

We report a case of a 57-yr-old woman with history of multiple endocrine neoplasia type I (MEN I). A 99mTc-sestamibi scan demonstrated a hyperplastic parathyroid gland, a large anterior mediastinal mass and a pituitary adenoma during a study done to evaluate recurrent hyperparathyroidism. The importance of this case is that much of the nonparathyroid pathology in patients with MEN I syndrome may be detected with this one study.

Mechanisms of accumulation of tyramine, metaraminol, and isoproterenol in isolated chromaffin granules and ghosts.

The effects of the transmembrane pH gradient (delta pH) and the transmembrane potential gradient (delta psi) on the uptake of several sympathomimetic amines were investigated, using bovine adrenal chromaffin granules isolated in isotonic sucrose. As previously described [R. Johnson and A. Scarpa, J. Biol. Chem. 254 3750 (1979)], freshly isolated chromaffin granules maintain an intragranular pH of 5.5 as measured by [14C] methylamine distribution and, in the presence of ATP, generate a delta psi of 80 mV, positive inside, as measured by [14C] methylamine distribution. When tyramine, metaraminol, and isoproterenol (1-50 mM) were added to well-buffered suspensions of granules at pH 7.0, a dose-related alkalinization of the granule interior was observed. Study of the time-resolved influx of the same amines labeled radiochemically (5-21 microM) revealed that all the amines were accumulated against an apparent concentration gradient. However, while accumulation of [14C] serotonin and [3H] isoproterenol was totally inhibited by reserpine, [14C] tryramine accumulation was inhibited by only 60% and [14C[ metaraminol uptake was unaffected. The ATP-dependent generation of a delta psi produced a stimulation of amine uptake in the order: serotonin greater than isoproterenol greater than tyramine; metaraminol accumulation was not enhanced by ATP addition. The relationship between the electrochemical proton gradient (delta micro H+) and the electrochemical gradient for each of the sympathomimetic amines (delta micro A) was investigated utilizing chromaffin ghosts devoid of endogenous matrix gradients or components. All amines were accumulated in the presence of delta pH alone. In the presence of delta psi alone, [14C] serotonin, (14C] tyramine, and [3H] isoproterenol were accumulated, but no [3H] metaraminol uptake was demonstrable. The results indicate that serotonin and isoproterenol accumulated in isolated chromaffin granules and ghosts via a reserpine-sensitive mechanism, driven by the magnitude of the electrochemical proton gradient. Conversely, metaraminol permeated the membrane of the chromaffin granule through the apolar lipid phase and distributed according to the delta pH alone. Tyramine uptake proceeded by both mechanisms. The implications of the mechanism of accumulation of these potent physiologic and pharmacologic agents for their in vivo action are discussed.

Prognostic markers in pheochromocytoma.

Clinical and histopathological features do not reliably distinguish between benign and malignant pheochromocytomas. Additional markers that might be useful prognostic indicators in the pathological assessment of these tumors are sought. Immunohistochemical expression of MIB-1, Bcl-2, cathepsin B, cathepsin D, basic fibroblast growth factor (bFGF), c-met, and type IV collagenase were studied on formalin-fixed tissue from 33 nonconsecutive cases of pheochromocytoma, selected on the basis of reliable long-term follow-up, to determine associations with malignancy. The study group included 33 patients, 19 men and 14 women, with a mean age of 45 years, including five cases of neurofibromatosis (NF), three familial, and one MEN IIb. Mean follow-up was 63.2 months. Ten patients were determined to have malignant pheochromocytomas by the presence of metastatic disease. Features found to be associated with malignancy included MIB-1 labeling index (5% vs 1%) (P = .0009), male gender (90% vs 43%) (P = .008), extra-adrenal location (40% vs 9%) (P = .03), tumor weight (481 g vs 124 g) (P = .05), and young age (38 years vs 49 years) (P = .05). None of the five cases with NF were malignant (P = .04). S-100 positivity showed a significant (P = .02) but nonlinear association with benign tumors. Absent S-100 correlated with greater tumor weight. Malignancy was not associated with right versus left side or bilaterality, although bilateral tumors were smaller. C-met, bFGF, cathepsin B, cathepsin D, and collagenase were strongly expressed in most tumors and were not predictive of outcome, nor was bcl-2, which was variably expressed. Using multiple logistic regression with malignancy as the dependent variable, MIB-1 continued to show a significant association with malignancy (P = .005) independent of any association with sex, age, or extra-adrenal location. Using a cutoff value of MIB-1 labeling of greater than 3% yielded a specificity of 100% and a sensitivity of 50% in predicting malignancy.

Retroperitoneal bronchogenic cyst masquerading clinically and radiologically as a phaeochromocytoma.

Bronchogenic cysts are relatively rare congenital anomalies that represent malformations of the embryonic foregut and are morphologically expressed as maldevelopments of the respiratory system. Anatomically, they can be positioned at any location along the central axis of the respiratory system, but are more commonly discovered in the thorax. Infradiaphragmatic bronchogenic cysts are rare and retroperitoneal ones distinctly unusual. We report a retroperitoneal bronchogenic cyst clinically masquerading as a phaeochromocytoma.

Success of unilateral neck exploration for sporadic primary hyperparathyroidism.

BACKGROUND: Unilateral neck exploration for primary hyperparathyroidism (PHPTH) is controversial because of concern about missed multiglandular disease. METHODS: In patients with sporadic PHPTH our approach has been arbitrarily to surgically explore the right neck first unless preoperative or intraoperative evidence suggests left-sided parathyroid pathologic condition. When an adenoma is identified and a normal ipsilateral gland is confirmed on histologic examination, the contralateral side is not explored. A 15-year series of 371 patients with sporadic PHPTH was reviewed retrospectively to determine the efficacy of this strategy. RESULTS: At operation unilateral exploration was possible in 125 patients (34%). Of these 122 had a single adenoma and two patients had parathyroid carcinoma. One patient with unrecognized hyperplasia required subsequent subtotal parathyroidectomy. There were no major complications. Bilateral surgical exploration was required in 246 patients including 18 with hyperplasia, 4 with double adenomas, and 4 with parathyroid cancer. Bilateral surgical exploration failed in 18 patients (14 persistent and 4 recurrent PHPTH) and was complicated by one recurrent nerve palsy and two cases of permanent hypocalcemia. Operative time was significantly shorter in the unilaterally explored group. CONCLUSIONS: When possible, unilateral exploration for PHPTH is safe and effective, avoids obliterative scarring of the contralateral neck, and may reduce morbidity and operative time.

Prospective study of aggressive resection of metastatic pancreatic endocrine tumors.

BACKGROUND: Because metastatic pancreatic endocrine tumors (MPET) have a poor prognosis, 17 patients with potentially resectable MPET were prospectively studied to define the efficacy of aggressive resection. METHODS: Patients underwent resection when the full extent of MPET was deemed operable after imaging studies were obtained. Two patients underwent three reoperations for recurrent tumor. RESULTS: MPET were completely excised in 16 of 20 cases by major resections of liver, viscera, and nodes, with no operative mortality. Survival was 87% at 2 years and 79% at 5 years with mean follow-up of 3.2 years. Median imaging disease-free interval was 1.8 years, and four of 17 patients remain biochemically cured. After aggressive resection patients with MPET limited in extent had higher survival than patients with extensive MPET (p < 0.019). In a nonrandomized cohort of 25 patients with inoperable tumor, survival was 60% at 2 years and 28% at 5 years. CONCLUSIONS: In select patients MPET can be resected safely with a favorable outcome; most patients will experience recurrence, but some may be cured. Resection of extensive MPET does not appear to improve survival. Resection of limited MPET should be considered as life-extending and potentially curative therapy.

Concise parathyroidectomy: the impact of preoperative SPECT 99mTc sestamibi scanning and intraoperative quick parathormone assay.

BACKGROUND: Results of initial operation for sporadic primary hyperparathyroidism are generally excellent, yet today there is pressure to improve outcome and resource utilization. METHODS: We designed a prospective longitudinal cohort study comparing two approaches to concise parathyroidectomy. Strategy A was defined as the palpation method for selective unilateral exploration. Strategy B was defined as the routine use of both preoperative 99mTc sestamibi single photon emission computed tomography (SPECT) imaging and intraoperative quick parathormone assay. With either strategy the study period was 19 months and patients explored unilaterally were candidates for same-day discharge. We compared surgical outcome for 128 consecutive consenting patients each with 6 months or more of follow-up (mean 12 +/- 7.6 months). RESULTS: Demographic, biochemical and pathologic findings did not differ between groups. SPECT imaging precisely localized hyperfunctioning parathyroid tissue. Compared with Strategy A (n = 61), the 67 patients treated by use of Strategy B experienced a higher rate of unilateral exploration (41.0% versus 62.7%, p < 0.00001) and a shorter length of stay (1.07 versus 1.90 days, p < 0.00001) and tended to have shorter operative times, fewer operative failures, and less morbidity. Total perioperative costs did not differ between groups. CONCLUSIONS: Routine use of intraoperative quick parathormone measurement and preoperative 99mTc sestamibi SPECT is as safe, effective, and cost-effective as conventional approaches to parathyroidectomy. Use of this strategy is associated with significant reductions in extent of surgery and length of hospital stay.

Human telomerase reverse transcriptase (hTERT) gene expression in FNA samples from thyroid neoplasms.

BACKGROUND: Although fine-needle aspiration (FNA) is the most sensitive method for the detection of thyroid carcinoma, it cannot provide a definitive diagnosis of malignancy in 60% of the patients operated on for suspicious lesions. Recently, human telomerase reverse transcriptase (hTERT) has been found to be a diagnostic marker of malignancy. We therefore sought to determine whether hTERT gene expression could serve as an adjunct to FNA in the differential diagnosis of thyroid nodules. METHODS: Twenty-four FNA samples from thyroid nodules that were suspected of malignancy were collected. RNA was extracted, and hTERT gene expression was examined by RT-PCR. Cytologic and histologic examinations were also performed. RESULTS: Two of three follicular, three of three Hürthle cell, and eight of eight papillary thyroid carcinomas had corresponding FNA samples that were positive for hTERT. One of two Hürthle cell adenomas was hTERT positive. FNA samples from three follicular adenomas and five hyperplastic nodules were negative for hTERT. Positive and negative predictive values were 93% and 90%, respectively. CONCLUSIONS: The detection of hTERT gene expression in thyroid FNA samples holds promise as a diagnostic marker in the distinction of benign from malignant thyroid lesions. Its application could alter the surgical management of these patients.

The variable penetrance and spectrum of manifestations of multiple endocrine neoplasia type 1.

BACKGROUND: Some experts maintain that (1) > 90% of patients with multiple endocrine neoplasia type 1 (MEN1) are first seen with hyperparathyroidism (HPTH) so that routine screening for other features is unnecessary and (2) MEN1 has > or = 94% penetrance by age 50 years. METHODS: We constructed a regional registry of patients with or at risk for MEN1 and examined phenotypic profiles in 34 patients. MEN1 was defined as (1) endocrinopathy of 2 of the 3 principal related tissues (parathyroid, gastrointestinal endocrine, pituitary) or (2) 1 such feature plus a first-degree relative with MEN1. RESULTS: The initial feature of MEN1 was HPTH in 50%, pituitary tumor in 18%, and gastrointestinal endocrine tumor in 32% of patients, with overall incidences of 82%, 65%, and 74%, respectively. HPTH developed by age 50 years in 73% of patients and by age 70 years in 83%. Penetrance of MEN1 at age 50 years was 82%. Associated features included renal (1) and rectal (1) cancer, malignant thymic carcinoid (1), and malignant pheochromocytoma (1). CONCLUSIONS: Expression of MEN1 can vary considerably from established patterns. In our geographic region HPTH does not routinely precede other features of MEN1 and cannot be used to distinguish affected patients among those at risk. MEN1 can be inapparent until late in life and may be significantly underdiagnosed.

Identification of the rpmF-plsX-fabH genes of Rhodobacter capsulatus.

The rpmF-plsX-fabH gene cluster of Rhodobacter capsulatus homologous to that of Escherichia coli was identified. rpmF encodes ribosomal protein L32, plsX plays an undefined role in membrane lipid synthesis, and fabH encodes beta-ketoacyl-acyl carrier protein synthase III. The R. capsulatus plsX gene complemented a defect in an E. coli strain with the plsX50 mutation. Overproduction of the fabH gene product of R. capsulatus in E. coli resulted in dramatically increased beta-ketoacyl-acyl carrier protein synthase III activity. These results indicate that plsX and fabH apparently function the same in R. capsulatus as in E. coli.

No association between the alpha-2 macroglobulin I1000V polymorphism and Alzheimer's disease.

Recent reports have suggested that variability in the alpha2-macroglobulin gene is a genetic risk factor for Alzheimer's disease. Here we have both tested a common polymorphism in the gene (I1000V) for association with the disease in a four-site case control study design, and tested the locus for linkage in a large series of sibpairs afflicted with late onset disease. Our results fail to show an association between this polymorphism and disease.

Respiratory rate measurement in adults--how reliable is it?

Measurement of respiratory rate (RR) is essential in the evaluation of respiratory disorders. However, the variability in RR measurement in adults has never been adequately assessed. Respiratory rate was measured twice in 245 patients; the two measurements were performed by the same observer in 137 patients, by different observers in 58 patients and simultaneously by different observers in 50 patients. The mean (SD) difference between the first and second measurements was 0.03 (3); 95% limits of agreement-4.86-4.94 breaths min(-1), -5.7-5.7 breaths min(-1), and -4.2 to 4.4 breaths min(-1) for the same observer, different observer and simultaneous observer groups, respectively. The difference in RR measurements did not vary with RR. In conclusions on average, there is very good agreement between observers in RR measurement. Inter-observer variability may account for a difference of up to 6 breaths min(-1). This is relevant when applying clinical prediction rules based on threshold RR values.

Parathyromatosis: a cause for recurrent hyperparathyroidism.

OBJECTIVE: To report a case of parathyromatosis as a cause for recurrent hyperparathyroidism. METHODS: We present the case history, laboratory results, operative interventions, and pathologic findings in a 36-year-old woman. Relevant reports from the literature are reviewed. RESULTS: Our patient, who had been undergoing long-term hemodialysis because of renal failure, presented with secondary hyperparathyroidism and progressive bone pain. After an uneventful subtotal parathyroidectomy (removal of 3-1/2 glands), her symptoms resolved in conjunction with normalization of parathyroid hormone levels. Subsequently, however, recurrent hyperparathyroidism and severe bone pain necessitated second and third neck explorations, during which parathyromatosis was discovered. A total thyroidectomy was performed because of the bilateral nature of the disease. Postoperatively, the patient's bone pain resolved substantially, although her parathyroid hormone levels remained high. CONCLUSION: Parathyromatosis is a rare cause of recurrent hyperparathyroidism after parathyroidectomy. It consists of hyperfunctioning parathyroid tissues scattered throughout the neck, due either to intraoperative tissue spillage and subsequent implantation or to hyperplasia of parathyroid rests from embryologic development. This is one of the few case reports of parathyromatosis and the first case report of a mixed form of the disease, consisting of features of both subcapsular parathyroid rests and extracapsular implantation.

Local anaesthetic wound infiltration following paediatric appendicectomy: a randomised controlled trial: Time to stop using local anaesthetic wound infiltration following paediatric appendicectomy?

OBJECTIVE: This study sought to determine the efficacy of post-operative wound infiltration with local anaesthetic following paediatric appendicectomy. METHOD: In a randomised, controlled, prospective, clinical trial children aged between five and sixteen years were assigned to one of three treatment arms; infiltration of the surgical wound with bupivicaine, saline, or no infiltration. Anaesthetic and analgesic protocols were employed. Patients and observers were blinded to the treatment group. The primary end-points were post-operative pain, scored at intervals during the first twenty post-operative hours, and additional post-operative analgesic requirements beyond that which was provided by a standard protocol. In addition, adverse wound outcomes were recorded. RESULTS: Eighty-eight children were recruited. There were no differences in age, sex or other confounding variables between groups. There was no significant difference in mean pain scores or analgesic requirements between groups through-out the post-operative period. CONCLUSION: Wound infiltration with local anaesthetic following appendicectomy in children provides no additional benefit over regular simple analgesia. Its routine use represents dogmatic practise which ought to be challenged for this patient group.