Diffuse lipomatosis of the thyroid with amyloid deposition.

BACKGROUND: The authors present a case of diffuse fatty infiltration of the thyroid gland with coexistent deposition of amyloid protein. METHOD: A case history and brief literature review concerning amyloid goitre and fatty infiltration of the thyroid are presented, and the relationship between these two phenomena is discussed. RESULTS: A patient with AA amyloidosis presented with a slowly enlarging goitre, which on histological examination was extensively infiltrated with adipose tissue. Amyloid protein was found on Congo red staining. CONCLUSION: To our best knowledge, this patient represents the first reported case of diffuse lipomatosis of the thyroid gland causing goitre in a patient with AA amyloidosis. The presence of amyloid protein within the thyroid was not sufficient to cause enlargement per se, and was therefore of unclear significance. Together with previous reports of the concurrent deposition of amyloid and fat, this case raises questions as to the relationship between these two phenomena.

Role of the VEGFR3/VEGFD receptor axis in TGFbeta1 activation of primary prostate cell lines.

BACKGROUND: Reports indicate that vascular endothelial growth factor receptor type 3 (VEGFR3) regulates cellular functions such as invasion, proliferation, and chemo-resistance. However, the exact function of the VEGFR3 signaling axis in prostate epithelial cells is poorly characterized. METHODS: The goal of this study was to evaluate whether TGFbeta1 in combination with VEGFD can promote pre-malignant invasive activities of intermediate basal cells (IBC-10a) isolated from human prostate cancer (Gleason score 6). RESULTS: hTERT immortalized IBC-10a cells normally grew as confluent "cobblestoned" monolayers, but treatment with TGFbeta1 (10 ng/ml for 2-6 hr) dissociated the cell-cell junctions and induced VEGFR3 translocation to the cell surface. This event was not inhibited by 10 microM cycloheximide or puromycin, indicating transcription and protein synthesis were not required. We further discovered that TGFbeta1 in combination with VEGFD induced a significant increase in the invasive activity of IBC-10a cells (>26% and 53% after 24 and 48 hr, respectively) in modified Boyden Chamber assays. TGFbetaRII receptor antibodies specifically blocked TGFbeta1 induction of VEGFR3 translocation to the cell surface and blocked VEGFD-induced invasion. Zymograms revealed that TGFbeta1 (and not VEGFR3) stimulated the secretion of MMP-2 and MMP-9, presumably to promote cell invasion. The cell invasion assays confirmed that antibodies specific for TGFbetaII receptor, MMP-2 and MMP-9 and VEGFR3, independently blocked TGFbeta1-induced invasion. CONCLUSIONS: For the first time, we have demonstrated the mechanism by which TGFbeta1 stimulates VEGFD/VEGFR3 receptor axis activation leading to increased cell migration and invasion by primary intermediate basal cell cultures.

Dysplasia of human prostate CD133(hi) sub-population in NOD-SCIDS is blocked by c-myc anti-sense.

BACKGROUND: The CD133(hi) sub-population of prostate epithelial cells has been demonstrated to possess tumor-initiating capacity consistent with that of the cancer stem cell theory. However, the involvement of oncogenes such as c-myc has not been fully elucidated in the CD133(hi) sub-population. METHODS: We have isolated primary prostate cell strains (IBC-10a) and immortalized them by transfection with hTERT. The in vitro and in vivo tumorigenic capacity of isolated CD133(hi) and CD133(lo) cells was evaluated with respect to c-myc expression using specific sense and anti-sense oligonucleotides. RESULTS: Freshly immortalized cells consisted of <3.3% CD133(hi)/CD24(hi) sub-population (SP). "Prostaspheres" generated from single CD133(hi) cells in the presence of EGF consisted of approximately 10% CD133(hi) SPs in 12-21 day cultures. A single Prostasphere generated from single CD133(hi) cells (6-10 cell stage at day 6 injected i.t.) produced dysplastic lesions in NOD-SCID mice (n = 4/5). Treatment of Prostaspheres from CD133(hi) SPs in vitro with c-myc or cyclin D1 anti-sense oligonucleotides totally blocked colony forming ability and growth. Furthermore, treatment of fully formed, 6-day Prostaspheres for 48 hr with c-myc anti-sense significantly reduced c-myc expression and their ability to generate lesions in NOD-SCIDs (n = 10 Prostaspheres injected i.t./mouse). CONCLUSIONS: These data demonstrate for the first time that a single CD133(hi) cell is competent to generate Prostaspheres in vitro and that CD133(hi) Prostaspheres require c-myc to grow and form dysplastic lesions in vivo.

Intra-operative parathyroid hormone monitoring using a laboratory based multichannel analyser.

Parathyroid hormone has a short half life in vivo. Intraoperative parathyroid hormone measurement can guide the surgeon by confirming successful removal of parathyroid adenomas. Point of care testing with a dedicated analyser and technician in theatre is expensive. This study shows that intraoperative parathyroid hormone is feasible using a central laboratory based analyser available in most hospitals. There are potential cost savings when compared with point of care testing.

Parapharyngeal abscess in a previously tonsillectomised child with periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome: first reported case.

OBJECTIVE: We present the first reported case of parapharyngeal abscess in a child with periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome, an uncommon syndrome of recurrent, self-limiting fever in children. METHOD: Case report and review of the literature to date concerning periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome. RESULTS: Periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome is an incompletely understood syndrome which requires careful and thorough investigation in order to distinguish it from other causes of recurrent fever. There has been much recent debate in the literature over the merits of various treatment strategies, including tonsillectomy. CONCLUSION: To the authors' knowledge, this is the first reported case of a parapharyngeal abscess in a child with periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome, made more significant by the fact that the child had undergone tonsillectomy one year prior. This case provides evidence that tonsillectomy does not protect against one of the more serious complications of oropharyngeal infection in children with this syndrome.

Primary hyperparathyroidism: do perioperative biochemical variables correlate with parathyroid adenoma weight or volume?

OBJECTIVES: To investigate the relationship between clinical variables and biochemical markers of calcium homeostasis and parathyroid adenoma size, in patients undergoing surgery for primary hyperparathyroidism. To determine the potential clinical utility of the findings in preoperative planning and prediction of postoperative hypocalcaemia. DESIGN: Retrospective data analysis. PARTICIPANTS: Ninety-two patients treated surgically for primary hyperparathyroidism caused by a solitary parathyroid adenoma between 1996 and 2006. MAIN OUTCOME MEASURES: Complete data was obtained for 77 participants including patient demographics, perioperative calcium, parathyroid hormone and phosphate levels, adenoma weight and histological dimensions. Multiple and binary logistic regression analyses were used to investigate the relationship between clinical and biochemical variables and adenoma weight and volume. Similar analysis was used to identify predictors of postoperative hypocalcaemia. SETTING: University Teaching Hospital Otolaryngology Department. RESULTS: The mean age at presentation was 59 years. The mean preoperative calcium and PTH levels were 2.86 +/- 0.2 mmol/L and 17.2 +/- 12.3 ng/L, respectively, falling to 2.3 +/- 0.01 and 4.1 +/- 2.7 postoperatively. The mean adenoma weight was 1.71 +/- 1.41 g. No correlation existed between clinical variables and preoperative biochemical markers of calcium homeostasis and adenoma weight or volume. There was a weak correlation between the preoperative to postoperative change in calcium and PTH levels {[deltaCa(2)+] vs. [deltaPTH]} (r = 0.24; P < 0.05) but no predictors of postoperative hypocalcaemia could be identified. CONCLUSIONS: Biochemical parameters will not accurately predict the size of a parathyroid adenoma. The size of a parathyroid adenoma does not correlate with postoperative calcium levels and is therefore not useful as a predictor of postoperative hypocalcaemia.

Methylene blue toxicity following infusion to localize parathyroid adenoma.

The parathyroid glands are small, inconspicuous, and variable in number, colour and position. Their identification is vital for excision of hyper-functioning glands and for preservation of normally functioning ones in patients undergoing thyroidectomy. Intravenous infusion of methylene blue at a dose of 7.5 mg/kg is commonly used to aid visualization of the parathyroid glands intra-operatively. Methylene blue is generally considered benign, and there are only two cases published in the literature reporting toxicity following intravenous infusion--such toxicity is a diagnosis of exclusion. We report a case of methylene blue toxicity resulting in expressive aphasia, confusion and disinhibition following infusion for parathyroid adenoma localization. The patient made a complete recovery over 48 hours. Methaemoglobinaemia was excluded as a cause. We suggest that the mechanism of toxicity was a direct effect of methylene blue, although an adverse interaction with serotonin re-uptake inhibitors could not be excluded. In keeping with the UK National Poisons Information Service recommendations, we have altered our practice and now use methylene blue at a dose not exceeding 4 mg/kg. This has not affected our success rate for identification of parathyroid glands. We report this case to highlight the rare occurrence of methylene blue toxicity when used at a dose of 7.5 mg/kg.

Preoperative localization of parathyroid adenomas: ultrasonography, sestamibi scintigraphy, or both?

Minimal access techniques are increasingly used to remove parathyroid adenomas. Such surgery depends on accurate preoperative localization but the selection of imaging modality remains controversial. We have reviewed the accuracy of ultrasonography, sestamibi scintigraphy and their combination in 48 cases of primary hyperparathyroidism. Ultrasound had a sensitivity of 64.3% (95% confidence interval 44.1-81.4) and positive predictive value (PPV) of 100% (81.5-100) for correct lateralization. Sestamibi had a sensitivity of 83.3% (69.8-92.5) and PPV of 87.1% (73.7-95.1). The simple combination of ultrasound with sestamibi had a sensitivity of 82.1% (63.1-93.9) and a PPV of 92.0% (74.0-99.0): little different from sestamibi alone. However, if the sestamibi result was disregarded in favour of ultrasonography in discordant cases, the sensitivity reached 96.4% (81.7-99.9) and the PPV was 100% (87.2-100). These results were not dependant on a learning curve or the size of adenoma.

A novel IL-10 signalling mechanism regulates TIMP-1 expression in human prostate tumour cells.

We have previously reported that interleukin 10 (IL-10) signalling stimulated activation of a specific enhancer element, termed HTE-1, to promote tissue inhibitor of matrix metalloproteinase1 (TIMP-1) expression in human bone metastatic PC-3 subclone (PC-3 ML) cells. Recently, we have identified an IL-10 responsive signal molecule, termed IL-10E1, which binds the HTE-1 element and cloned the gene encoding for the 22 kDa protein. In this paper, we have examined the mechanism of IL-10/IL-10 receptor signalling in two distinct human prostate cell lines, a 'normal' prostate epithelial cell line, termed NPTX-1532 and highly metastatic PC-3 ML tumour cells. Signalling cascade studies revealed that IL-10 stimulated tyrosine phosphorylation of JAK1 and TYK2 receptor kinases and tyrosine phosphorylation of IL-10E1. Phosphorylation, triggered IL-10E1's rapid translocation to the nucleus by 10-30 min. Deletion analysis combined with transient transfection experiments revealed that the n-terminal domain (approximately 74 a.a.) of the IL-10E1 protein, the nt-nls peptide, was stimulated by IL-10 to translocate to the nucleus and induce TIMP-1 expression. Site-directed mutagenesis further showed that phosphorylation of two tyrosine moieties (Y57 and Y62) of the nt-nls peptide was required for IL-10 activation of signalling and TIMP-1 expression. The data demonstrate, for the first time, that IL-10 receptor signalling of TIMP-1 expression is regulated by tyrosine phosphorylation of a novel gene, IL-10E1, in human prostate cells.

Significance of cysteine rich transcription factor (CRTF) in the synthesis of tissue inhibitor of metalloproteinases 1 (TIMP-1) in gastrointestinal cancers.

We previously reported that a novel promoter enhancer element "human tissue inhibitors of metalloproteinases 1 (TIMP-1) enhancer" (HTE) and a novel transacting protein "cysteine rich transcription factor" (CRTF) induced TIMP-1 synthesis in prostate cancer cells 2xN.I.PC-3. In the present study, to clarify the significance of CRTF in gastrointestinal cancers we measured the binding activity of CRTF to HTE using an electrophoretic mobility shift assay (EMSA), and the TIMP-1 concentration by ELISA after various stimulation of six cancer cell lines (KE-3, TE-9, MKN-28, MKN-45, KM12SM, SW620). In three cell lines (KE-3, MKN-45, SW620), both the binding activity of CRTF and TIMP-1 concentration significantly increased after IL-10 stimulation. Fetal bovine serum (FBS) did not affect the binding activity of CRTF, whereas FBS induced TIMP-1 synthesis in all cell lines. In KE-3 esophageal cancer cells and SW620 colon cancer cells, both the binding activity of CRTF and TIMP-1 concentration increased in the presence of a conditioned medium (CM) of fibroblasts which was isolated from human colon cancer tissues, but did not increase in MKN-45 cells. Moreover, in the fibroblasts, both the binding activity of CRTF and the TIMP-1 concentration increased in the presence of CM from KM12SM, SW620, and TE-9 cancer cell lines. These results suggested that IL-I0, and unknown factors in addition to IL-10, induced TIMP-1 synthesis via an increase in the binding activity of CRTF in gastrointestinal cancers, and that interaction between cancer cells and fibroblasts may play an important role in TIMP-1 synthesis through a signal transduction pathway consisting of CRTF phosphorylation and HTE activation.

Selective estrogen receptor modulators. An aid in unraveling the links between estrogen and breast cancer.

Breast cancer is a classic hormone-dependent malignant disease that is influenced by estrogen. However, the molecular links between estrogen and cell proliferation in healthy and malignant breast tissue are complex and as yet not well understood. The selective estrogen receptor modulators (SERMs), which are competitive inhibitors of estrogen binding at estrogen receptors alpha and beta, have become important weapons in the prevention and treatment of breast cancer. These agents also offer opportunities for the elucidation of the multiple molecular mechanisms by which estrogen affects cell proliferation. Each SERM-estrogen receptor complex has a unique structure that influences its activity in different body tissues. Unraveling the links between SERM structure and function not only may shed light on the signaling pathways that connect estrogen to cell proliferation but also may allow the design of new agents specifically targeted to affect certain events along these pathways.

SNOMED clinical terms: overview of the development process and project status.

Two large health care reference terminologies, SNOMED RT and Clinical Terms Version 3 , are in the process of being merged to form a comprehensive new work referred to as SNOMED Clinical Terms. The College of American Pathologists and the United Kingdom s National Health Service have entered into a collaborative agreement to develop this new work. Both organizations have extensive terminology development and maintenance experience. This paper discusses the process and status of SNOMED CT development and how the resources and expertise of both organizations are being used to develop this new terminological resource. The preliminary results of the merger process, including mapping, the merger of upper levels of each hierarchy, and attribute harmonization are also discussed.

Mapping between SNOMED RT and Clinical terms version 3: a key component of the SNOMED CT development process.

SNOMED RT and Clinical Terms Version 3 are two large, controlled medical terminologies that are being merged to form a new work titled SNOMED Clinical Terms (SNOMED CT). One of the first steps in this process was to create maps between semantically equivalent and proximate concepts in the two terminologies. Same-as and is-a relationships were used to map the descriptions from one terminology to concepts in the other terminology. The objectives were to identify semantically equivalent concepts in the two terminologies, to find the most semantically proximate is-a relationships for non-equivalent concepts, and to evaluate the synonymy in the source terminologies. The results suggest that the rate of semantic overlap between descriptions in SNOMED RT and CTV3 is approximately 28%. This article discusses the methodology, issues, and findings of the description mapping process.

Palliative tracheal stenting in invasive papillary thyroid carcinoma.

Malignant tracheal stenosis presents a considerable challenge to the head and neck surgeon. The use of intraluminal stents has been previously described, but current literature notes a paucity of supportive physiological data. We describe the use of a self-expanding metallic Wallstent in the palliation of a case of papillary thyroid carcinoma. This is accompanied by significant improvement in quantitative pulmonary function.

Graduate medical education for rural physicians: curriculum and retention.

The chronic shortage of rural physicians prompts further consideration of the educational interventions that have been developed to address this issue. Despite rural admission strategies and a variety of undergraduate, graduate and postgraduate curricular innovations, the recruitment and retention of family physicians into many rural areas has not kept pace with the retirement of older general practice physicians. This paper reviews the 1994 American Academy of Family Physicians' rural training recommendations in the light of several recent educational needs assessments. These studies affirm the need for rural residency rotations and the need to maintain and better implement the established rural clinical training guidelines. However, although preparation for rural medical practice has been addressed and is being adequately accomplished in the clinical knowledge and procedural skills areas, instruction and experiences relating to the "realities of rural living" need to be enhanced to increase the retention duration of rural physicians. This can be accomplished with more curricular emphasis on developing community health competencies, including community-oriented primary care (COPC). Physicians who know how to collaborate with community members on health improvement projects have skills that can also facilitate integration and, hence, retention.

Screening applicants for a rural medical education program.

The goal of the Rural Medical Education (RMED) Program of the University of Illinois College of Medicine at Rockford is to train rural family physicians. This article describes the screening instrument developed by RMED to identify appropriate candidates.

Increased cellularity of tumor-encased native vessels in prostate carcinoma is a marker for tumor progression.

Changes in the native vasculature of the prostate gland associated with prostate adenocarcinoma have not been well characterized. Eighty-nine whole mounts of entirely submitted radical prostatectomies were reviewed. Thirty prostates with a minimum of five native arteries surrounded by carcinoma with corresponding control arteries were found and included in this study. The number of nuclei in the media of native arteries was recorded per 0.138 mm2 using a 40x objective. The number of nuclei in vessels embedded in carcinoma (n = 204) was increased when compared with controls (26.37 versus 20.58 mean nuclei per 0.138 mm2; P < .001). Pathologic Stage T3 carcinomas contained vessels that were more cellular than stage T2 (P < .001). Vessels embedded in Gleason Grade 4 showed more cellularity than arteries embedded in Gleason Grade 3 (P < .002). Increased media cellularity of native prostate vessels encased in carcinoma is a histologic feature of higher grade/stage prostate carcinoma and provides positive indicator of advanced prostate cancer.