ACTH Antagonists

Structural modifications within the active site of the ACTH molecule have produced analogs that inhibit the hormone sensitive adenylate cyclase system of bovine adrenal cortical plasma membranes. It is demonstrated that the tryptophan residue of the ACTH molecule is essential for stimulation of the enzyme. Substitution of tryptophan by phenylalanine or by N(alpha)-methyltryptophan as in [Gln(5), Phe(9)]corticotropin(1-20) amide or [N(alpha)-Metrp(9)]corticotropin(1-24) provides ACTH analogs that exhibit high affinity for the ACTH receptor(s) but fail to activate the adenylate cyclase system. It is concluded that affinity for the receptors alone is not sufficient for expression of hormonal activity. The observation that adrenal cortical adenylate cyclase activated by fluoride ion is not inhibited by the antagonists indicates that hormonal and fluoride activation proceed via different mechanisms.     

Computed Tomography–Guided Percutaneous Needle Biopsy of Pulmonary Nodules: Impact of Nodule Size on Diagnostic Accuracy

PurposeThis study was undertaken to compare the diagnostic accuracy and complication rate of computed tomography (CT)—guided percutaneous lung biopsies of lung nodules ≤ 1.5 cm versus > 1.5 cm in diameter.Patients and MethodsA total of 139 patients (age range, 18-89 years; mean, 62.5 years) underwent CT-guided percutaneous fine-needle aspiration biopsy or 20-gauge core biopsy using an automated biopsy gun. In 37 patients, the lung nodule measured ≤ 1.5 cm (mean, 1.1 cm), and in 102 patients, the lung nodule was > 1.5 cm (mean, 2.8 cm). Diagnostic accuracy was determined by cytopathology results. Major and minor complications were documented.ResultsOverall diagnostic accuracy, pneumothorax rate, and thoracostomy tube insertion rates were 67.6%, 34.5%, and 5%, respectively. Of the 98 patients with malignancy, 77 patients (78.6%) had a definite diagnostic biopsy. Overall, nodules > 1.5 cm were statistically more likely to result in a diagnostic specimen (73.5%) than nodules ≤ 1.5 cm (51.4%; P = .012). Similarly, diagnostic accuracy for malignancy was higher in nodules > 1.5 cm than in those ≤ 1.5 cm (81.3% vs. 69.6%); however, this was not statistically significant. There was no correlation between nodule size and the incidence of complications.ConclusionOverall, diagnostic accuracy of CT-guided percutaneous lung biopsy of lung nodules ≤ 1.5 cm is slightly lower than that of nodules > 1.5 cm. However, the diagnostic accuracy for malignancy is high in both groups, with a low risk of complications     

Carcinoma of the external auditory canal and middle ear: therapeutic strategy and follow up

BACKGROUND: Carcinomas of the external auditory canal (EAC) and the middle ear are rare and considered to have a poor prognosis. The recommended therapeutic strategy consists of surgical excision and postoperative radiotherapy. However, there are different opinions about the extend of the primary operation. PATIENTS AND METHODS: A series of 21 patients with carcinoma of the EAC and middle ear were treated at the ENT-Department of the Hospital Fulda from 1985 to 2003. Their records and radiologic findings were reviewed retrospectively with particular reference to tumor type and size, its relation to surrounding tissues, surgical procedures and radiation techniques. The tumors were staged according to the modified Pittburgh staging system for temporal bone carcinomas. The average follow-up time was 6.2 years (range 0.2 - 18.75). RESULTS: 17 patients suffered from carcinoma of the EAC, 4 carcinomas were primarily located in the middle ear. There were 15 squamous cell carcinomas, 3 adenoidcystic carcinomas, 2 adenocarcinomas and one mucoepidermoid carcinoma. 12 patients came primarily to our institution and were staged as follows: pT1 (n = 2), pT3 (n = 2), pT4 (n = 8). 8 patients showed up with recurrent or residual tumors (all of T3 or T4 stage). One patient could not be classified. In 5 cases the tumor was inoperable. These patients underwent combined chemoradiation therapy. All other 16 patients were operated and most of them received adjuvant radiation therapy. In the group of patients who were primarily operated overall 5-year survival rate was 100 %. In contrast, patients who's recurrent or residual tumors were resected had a 5-year survival rate of only 33 %. Patients who received combined chemoradiation therapy showed a 2-year survival rate of 75 %. CONCLUSION: Carcinoma of the EAC and middle ear should be treated primarily by a lateral or subtotal temporal bone resection stage dependent combined with a parotidectomy as well as a neck dissection. Local resection of the EAC is not sufficient, not even in T1 tumors. As from stage T2, in cases of recurrent tumor removal and questionable free margins as well as in cases with lymph node metastases an adjuvant radiation therapy should be added. The most important survival factor is removal of the primary tumor with histologically clear margins.     

The G1057D polymorphism of IRS-2 gene is not associated with type 2 diabetes and obese patients among ethnic groups in Tunisian population

BackgroundType 2 of diabetes is the most common metabolic disorder and results from the interaction between genetic and environmental factors. Insulin receptor substrate-2 (IRS-2), one of the major substrates of the insulin receptor, has a crucial role in insulin signalling and in beta cell development and survival. While several polymorphisms have been identified in the IRS-2 gene, the association of the Gly1057Asp polymorphism with type 2 diabetes has been studied in European and Chinese populations, but the results have been inconsistent.ObjectivesThe aim of this study was to investigate the association of Gly1057Asp polymorphism in insulin receptor substrate-2 (IRS-2) gene among patients with type 2 diabetes in well defined ethnic groups from Djerba Island in Southeastern Tunisia.MethodsThe studied population (172 Arabs and 100 Berbers) includes 162 patients with type 2 diabetes and 110 healthy controls. BMI was calculated for each subject. The subjects were unrelated and randomly selected Arabs and Berbers were equally distributed between controls and diabetics. The G1057D polymorphism of the IRS-2 gene was genotyped using PCR-RFLP assay.ResultsThis case/control study indicated that frequency of the IRS-2 Gly1057Asp polymorphism was not significantly different between the healthy controls and type 2 diabetic groups, neither between healthy nor obese subjects, in both ethnic groups. Moreover, this polymorphism is present at a lower frequency in Djerbian than in neighbouring European populations.ConclusionThese results strongly argue against a major role of the Gly1057Asp IRS-2 polymorphism in the pathogenesis of type 2 diabetes in Djerbian subjects.     

Identification of a single peridinin sensing Chl-a excitation in reconstituted PCP by crystallography and spectroscopy

The peridinin-chlorophyll a-protein (PCP) of dinoflagellates is unique among the large variety of natural photosynthetic light-harvesting systems. In contrast to other chlorophyll protein complexes, the soluble PCP is located in the thylakoid lumen, and the carotenoid pigments outnumber the chlorophylls. The structure of the PCP complex consists of two symmetric domains, each with a central chlorophyll a (Chl-a) surrounded by four peridinin molecules. The protein provides distinctive surroundings for the pigment molecules, and in PCP, the specific environment around each peridinin results in overlapping spectral line shapes, suggestive of different functions within the protein. One particular Per, Per-614, is hypothesized to show the strongest electronic interaction with the central Chl-a. We have performed an in vitro reconstitution of pigments into recombinant PCP apo-protein (RFPCP) and into a mutated protein with an altered environment near Per-614. Steady-state and transient optical spectroscopic experiments comparing the RFPCP complex with the reconstituted mutant protein identify specific amino acid-induced spectral shifts. The spectroscopic assignments are reinforced by a determination of the structures of both RFPCP and the mutant by x-ray crystallography to a resolution better than 1.5 Å. RFPCP and mutated RFPCP are unique in representing crystal structures of in vitro reconstituted light-harvesting pigment-protein complexes.     

Fulminant legionellosis in two patients treated with infliximab for Crohn’s disease: Case series and literature review

Two cases of fulminant pulmonary legionellosis, complicated by prolonged intensive care unit stays and acute respiratory distress syndrome, and who were recently treated with infliximab for Crohn’s disease, are described. A review of the literature revealed three additional cases in patients with inflammatory bowel disease, and a total of 22 cases of Legionella pneumophila pneumonia in the context of treatment with antitumour necrosis (TNF)-alpha medications. The median age of the patients was 49 years, and men and women were affected equally. The case fatality rate was 14% (three of 22). Early recognition and treatment of this anti-TNF-alpha-related complication would likely result in reduced mortality and morbidity. Physicians prescribing anti-TNF-alpha drugs should be aware of this association.     

Functional impairment in social anxiety disorder

The present study examined functional impairment among treatment seekers with social anxiety disorder (SAD). We investigated the effects of diagnostic subtypes of SAD and comorbidity with mood and anxiety disorders on impairment. In addition, we used cluster analysis procedures to empirically identify subgroups of individuals with distinct patterns of impairment. Participants were 216 treatment-seeking individuals with SAD. Clinical interviews were undertaken to determine diagnoses of anxiety disorders and major depressive disorder, and a battery of self-report measures was administered to index symptoms of social anxiety, depression and extent of impairment. Results indicated that individuals with the generalized subtype of SAD had greater impairment in all three life domains compared to individuals with the nongeneralized subtype. Comorbidity with mood disorders was associated with greater impairment than SAD alone, but comorbidity with anxiety disorders was not. Four distinct impairment profiles emerged from the cluster analysis: primary work/studies impairment, primary social life impairment, both work/studies and social impairment, and impairment in all domains. Findings from this study suggest that SAD is associated with substantial impairment across multiple domains, and that individuals with SAD present diverse impairment profiles. These profiles may inform subtyping of the disorder as well as therapeutic interventions.     

Cerebral activation patterns in patients with writer's cramp: a functional magnetic resonance imaging study

Functional MRI (fMRI), visualizing changes in cerebral blood oxygenation, has to date not been performed either in patients with writer's cramp or in healthy subjects during writing. We compared the cerebral and cerebellar activation pattern of 12 patients with writer's cramp during writing with a group of 10 healthy subjects performing the same tasks over 30-s periods of rest or writing. Sixty echo planar imaging multi-slice datasets were analysed using SPM96 software. Data were analysed for each subject individually and groupwise for patients vs. controls. Healthy subjects showed a significant activation of the ipsilateral dentate nucleus, contralateral cerebellar hemisphere, contralateral primary sensorimotor cortex, and contralateral precentral gyrus during writing. Patients with writer's cramp showed significantly greater activation of the ipsilateral cerebellar hemisphere than controls. Also the activation in the primary sensorimotor cortex extended further caudally and anteriorly towards the premotor association area. Activation was observed in the thalamus during writing only among the patients. Our results indicate an increased basal ganglia output via the thalamus to the motor and premotor cortical areas in dystonia patients and support the notion of disinhibition of the motor cortex leading to coconcentrations and dystonic postures. Received: 10 November 1999 / Received in revised form: 4 April 2000 / Accepted: 26 April 2000