Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10

Multiple endocrine neoplasia type 2 is characterized by germline mutations in RET. For exon 10, comprehensive molecular and corresponding phenotypic data are scarce. The International RET Exon 10 Consortium, comprising 27 centers from 15 countries, analyzed patients with RET exon 10 mutations for clinical-risk profiles. Presentation, age-dependent penetrance, and stage at presentation of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism were studied. A total of 340 subjects from 103 families, age 4-86, were registered. There were 21 distinct single nucleotide germline mutations located in codons 609 (45 subjects), 611 (50), 618 (94), and 620 (151). MTC was present in 263 registrants, pheochromocytoma in 54, and hyperparathyroidism in 8 subjects. Of the patients with MTC, 53% were detected when asymptomatic, and among those with pheochromocytoma, 54%. Penetrance for MTC was 4% by age 10, 25% by 25, and 80% by 50. Codon-associated penetrance by age 50 ranged from 60% (codon 611) to 86% (620). More advanced stage and increasing risk of metastases correlated with mutation in codon position (609?620) near the juxtamembrane domain. Our data provide rigorous bases for timing of premorbid diagnosis and personalized treatment/prophylactic procedure decisions depending on specific RET exon 10 codons affected.

5a-Butyl-1,3,8,10-tetra-chloro-7,13-bis-(4-nitro-benzo-yl)-5a,6a,12a,12b-tetra-hydro-7H,13H-thieno[2,3-b:4,5-b']bis-(1,4-benzoxazine)

The title compound, C(34)H(24)Cl(4)N(4)O(8)S, is a linear penta-cyclic system formed of two substituted benzoxazinyl groups fused to 2-n-butyl-tetra-hydro-thio-phene. The oxazine ring, which is fused to the n-butyl-substituted side of the thio-phene ring, is in a boat conformation. The other fused oxazine ring and the tetra-hydro-thiene ring are each in an envelope conformation. The bridgehead C atom alpha to both the S and N atoms forms the flap of each envelope. This results in a twist of the penta-cyclic system such that the dihedral angle between the terminal dichloro-benzene rings is 82.92 (8)°. In the crystal, inversion-related mol-ecules form a weakly hydrogen-bonded dimer, with two C-H⋯O inter-actions between an H atom on the oxazine ring and an amide O atom. Additionally, C-H⋯O inter-actions occur between an H atom on a screw-related nitro-benzene ring and an O atom on the nitro-benzene ring of one mol-ecule. One of the Cl atoms and the butyl group are disordered over two sets of sites with occupancy ratios of 0.94 (2):0.06 (2) and 0.624 (4):0.376 (4), respectively.

14-3-3- and II/3-10-gene expression as molecular markers to address viability and growth activity of Echinococcus multilocularis metacestodes

The present study aimed to search for and characterize parasite molecules, whose expression levels correlate with the viability and growth activity of Echinococcus multilocularis metacestodes. We focused on the expression profiles of 2 parasite-derived genes, 14-3-3 and II/3-10, as putative molecular markers for viability and growth activity of the larval parasite. In experiments in vivo, gene expression levels of 14-3-3 and II/3-10 were relatively quantified by real-time reverse transcription-PCR using a housekeeping gene, beta-actin, as a reference reaction. All three reactions were compared with growth activity of the parasite developing in permissive nu/nu and in non-permissive wild type BALB/c mice. At 2 months p.i., the transcription level of 14-3-3 was significantly higher in parasites actively proliferating in nu/nu mice compared to parasites moderately growing in wild type mice. Immunoblotting experiments confirmed at the protein level that 14-3-3 was over-expressed in parasites derived from nu/nu mice at 2 months p.i. In vitro treatment of E. multilocularis with an anti-echinococcal drug nitazoxanide resulted in a significant decrease of both 14-3-3 and II/3-10 transcription levels found after 8 days of treatment, which correlated with the kinetics of a housekeeping gene, beta-actin. The conclusion is that 14-3-3, combined with II/3-10, exhibits good potential as a molecular marker to assess viability and growth activity of the parasite.

Treatment outcomes and mortality of 94 patients with acromegaly

Due to new therapeutic modalities and modified therapeutic goals outcome of patients with acromegaly may change over time and differ by centre. We analysed treatment outcomes and mortality of our patients with acromegaly seen between 1971 and 2003.

Acetabular reinforcement ring in primary total hip arthroplasty: a minimum 10-year follow-up

INTRODUCTION: We report the results of a titanium acetabular reinforcement ring with a hook (ARRH) in primary total hip arthroplasty (THA), which was introduced in 1987 and continues to be used routinely in our center. The favorable results of this device in arthroplasty for developmental dysplasia and difficult revisions motivated its use in primary THA. With this implant only minimal acetabular reaming is necessary, anatomic positioning is achieved by placing the hook around the teardrop and a homogenous base for cementing the polyethylene cup is provided. MATERIALS AND METHODS: Between April 1987 and December 1991, 241 THAs with insertion of an ARRH were performed in 178 unselected, consecutive patients (average age 58 years; range 30-84 years) with a secondary osteoarthrosis in 41% of the cases. RESULTS: At the time of the latest follow-up, 33 patients (39 hips) had died and 17 cases had been lost to follow-up. The median follow-up was 122 months with a minimum of 10 years. Eight hips had been revised, leaving 177 hips in 120 living patients without revision. Six cups were revised because of aseptic loosening. Two hips were revised for sepsis. The mean Merle d'Aubigné score for the remaining hips was 16 (range 7-18) at the latest follow-up. For aseptic loosening, the probability of survival of the cup was 0.97 (95% confidence interval, 0.94-0.99). However, analysis of radiographs implied loosening in seven other cups without clinical symptoms. CONCLUSIONS: The results of primary THA using an acetabular reinforcement ring parallel the excellent results of these implants often observed in difficult primary and revision arthroplasty at a minimum of 10 years. Survivorship is comparable to modern cementless implants. Medial migration that occurs with loosening of the acetabular component seems to be prevented with this implant. Radiographic loosening signs can exist without clinical symptoms.

Incident malignancies among older long-term breast cancer survivors and an age-matched and site-matched nonbreast cancer comparison group over 10 years of follow-up

BACKGROUND Of the approximately 2.4 million American women with a history of breast cancer, 43% are aged ≥ 65 years and are at risk for developing subsequent malignancies. METHODS Women from 6 geographically diverse sites included 5-year breast cancer survivors (N = 1361) who were diagnosed between 1990 and 1994 at age ≥ 65 years with stage I or II disease and a comparison group of women without breast cancer (N = 1361). Women in the comparison group were age-matched and site-matched to breast cancer survivors on the date of breast cancer diagnosis. Follow-up began 5 years after the index date (survivor diagnosis date or comparison enrollment date) until death, disenrollment, or through 15 years after the index date. Data were collected from medical records and electronic sources (cancer registry, administrative, clinical, National Death Index). Analyses included descriptive statistics, crude incidence rates, and Cox proportional hazards regression models for estimating the risk of incident malignancy and were adjusted for death as a competing risk. RESULTS Survivors and women in the comparison group were similar: >82% were white, 55% had a Charlson Comorbidity Index of 0, and ≥ 73% had a body mass index ≤ 30 kg/m(2) . Of all 306 women (N = 160 in the survivor group, N = 146 in the comparison group) who developed a first incident malignancy during follow-up, the mean time to malignancy was similar (4.37 ± 2.81 years vs 4.03 ± 2.76 years, respectively; P = .28), whereas unadjusted incidence rates were slightly higher in survivors (1882 vs 1620 per 100,000 person years). The adjusted hazard of developing a first incident malignancy was slightly elevated in survivors in relation to women in the comparison group, but it was not statistically significant (hazard ratio, 1.17; 95% confidence interval, 0.94-1.47). CONCLUSIONS Older women who survived 5 years after an early stage breast cancer diagnosis were not at an elevated risk for developing subsequent incident malignancies up to 15 years after their breast cancer diagnosis.

The role of postoperative prophylactic antibiotics in the treatment of facial fractures: a randomised, double-blind, placebo-controlled pilot clinical study. Part 3: Le Fort and zygomatic fractures in 94 patients

The aim of this study was to evaluate the difference between the effect of a 5-day and a 1-day postoperative course of antibiotics on the incidence of infection after midfacial fractures. A total of 98 patients with displaced Le Fort or zygomatic fractures that required operation were randomly assigned into 2 groups, both of which were given amoxicillin/clavulanic acid 1.2g intravenously every 8h from the time of admission until 24h postoperatively. The 5-day group was then given amoxicillin/clavulanic acid 625mg orally 8-hourly for another 4 days. The 1-day group was given placebo orally at the same time points. Patients were followed up 1, 2, 4, 6, and 12 weeks, and 6 months, postoperatively. The development of an infection of the wound was the primary end point. Ninety-four of the 98 patients completed the study. Two of the 45 patients in the 5-day group (4%) and 2/49 in the 1-day group (4%) developed postoperative wound infections. One in each group had a purulent infection, while the others had only wound breakdown. Two patients of the 5-day group and one in the 1-day group developed rashes on the trunk. There were no significant differences in the incidence of infection or side effects between the groups. In midfacial fractures a 1-day course of antibiotics postoperatively is as effective in preventing infective complications as a 5-day regimen.

Stable isotope analysis and temperature reconstruction data from DSDP Hole 94-609B and ODP Hole 162-984B

The Greenland ice sheet is accepted as a key factor controlling the Quaternary glacial scenario. However, the origin and mechanisms of major Arctic glaciation starting at 3.15 Ma and culminating at 2.74 Ma are still controversial. For this phase of intense cooling Ravelo et al. proposed a complex gradual forcing mechanism. In contrast, our new submillennial-scale paleoceanographic records from the Pliocene North Atlantic suggest a far more precise timing and forcing for the initiation of northern hemisphere glaciation (NHG), since it was linked to a 2-3 °C surface water warming during warm stages from 2.95 to 2.82 Ma. These records support previous models, claiming that the final closure of the Panama Isthmus (3.0- ~2.5 Ma induced an increased poleward salt and heat transport. Associated strengthening of North Atlantic Thermohaline Circulation and in turn, an intensified moisture supply to northern high latitudes resulted in the build-up of NHG, finally culminating in the great, irreversible climate crash at marine isotope stage G6 (2.74 Ma). In summary, there was a two-step threshold mechanism that marked the onset of NHG with glacial-to-interglacial cycles quasi-persistent until today.

(Table 1) Potassium, radiogenic Argon 40 and dated age for DSDP Hole 94-608 sediments

K-Ar dates were obtained for three pillow basalt samples recovered from Site 608 (Samples 608-58-1, 103-109 cm; 608-59-1, 3-7 cm; 608-59-1, 48-53 cm). Reliable K-Ar dates cannot be routinely obtained for deep-sea igneous rocks, because they may be subject to inaccuracies related to seawater alteration (Seidemann, 1977, doi:10.1130/0016-7606(1977)88<1660:EOSAOK>2.0.CO;2) and/or the presence of excess radiogenic 40Ar (Dalrymple and Moore, 1968, doi:10.1126/science.161.3846.1132; Dymond, 1970, doi:10.1130/0016-7606(1970)81[1229:EAISBP]2.0.CO;2). Thus, the possibility that the samples dated in this study were subject to these sources of inaccuracy must be evaluated.