Transcript-aware analysis of rare predicted loss-of-function variants in the UK Biobank elucidate new isoform-trait associations.

A single gene can produce multiple transcripts with distinct molecular functions. Rare-variant association tests often aggregate all coding variants across individual genes, without accounting for the variants' presence or consequence in resulting transcript isoforms. To evaluate the utility of transcript-aware variant sets, rare predicted loss-of-function (pLOF) variants were aggregated for 17,035 protein-coding genes using 55,558 distinct transcript-specific variant sets.

A20 Haploinsufficiency Aggravates Transplant Arteriosclerosis in Mouse Vascular Allografts: Implications for Clinical Transplantation.

Background: Inflammation is central to the pathogenesis of transplant arteriosclerosis (TA). We questioned whether physiologic levels of anti-inflammatory A20 influence TA severity.

Methods: We performed major histocompatibility complex mismatched aorta to carotid artery interposition grafts, using wild type (WT) or A20 heterozygote (HET) C57BL/6 (H-2) donors and BALB/c (H-2) recipients, and conversely BALB/c donors and WT/HET recipients.

Temporal network based analysis of cell specific vein graft transcriptome defines key pathways and hub genes in implantation injury.

Vein graft failure occurs between 1 and 6 months after implantation due to obstructive intimal hyperplasia, related in part to implantation injury. The cell-specific and temporal response of the transcriptome to vein graft implantation injury was determined by transcriptional profiling of laser capture microdissected endothelial cells (EC) and medial smooth muscle cells (SMC) from canine vein grafts, 2 hours (H) to 30 days (D) following surgery. Our results demonstrate a robust genomic response beginning at 2 H, peaking at 12-24 H, declining by 7 D, and resolving by 30 D.

Thyroidectomy using monitored local or conventional general anesthesia: an analysis of outpatient surgery, outcome and cost in 1,194 consecutive cases.

Background: Critical appraisal of safety, feasibility, and economic impact of thyroidectomy procedures using local (LA) or general anesthesia (GA) is performed.

Methods: Consecutive patients undergoing thyroidectomy procedures were selected from a prospective database from January 1996 to June 2003 of a single-surgeon practice at a tertiary center. Statistical analyses determined differences in patient characteristics, outcomes, operative data, and length of stay (LOS) between groups.

Clinical utility of an immunoradiometric assay for parathyroid hormone (1-84) in primary hyperparathyroidism.

The reliable diagnosis of primary hyperparathyroidism depends on the measurement of PTH. The PTH assays in widespread use measure not only the hormone but also hormone fragments, thus limiting the clinical utility of the assays. A new immunoradiometric assay (IRMA) using an antigenic determinant at the extreme amino-terminal of the PTH molecule detects only full-length PTH (1-84).

The impact of sestamibi scanning on the outcome of parathyroid surgery.

Although sestamibi scanning has been shown to have greater sensitivity and specificity than other preoperative localization techniques for parathyroid adenoma, it is unclear whether preoperative scanning improves outcomes for parathyroid surgery. Data from 528 consecutive patients who underwent neck exploration for primary hyperparathyroidism by one surgeon were collected prospectively over a 5-yr period. Patients were classified by preoperative scanning status (no scan, positive scan, and negative scan), and outcomes were compared in terms of operative time, length of hospital stay, and cure rate.

Thyroidectomy using local anesthesia in critically ill patients with amiodarone-induced thyrotoxicosis: a review and description of the technique.

Hyperthyroidism caused by amiodarone is a well-known and accepted side effect of therapy. This problem can frequently be treated by medical means if patients are stable. In some patients, particularly those who are critically ill with cardiac disease the addition of hyperthyroidism can be particularly detrimental.

Bilateral neck exploration for parathyroidectomy under local anesthesia: a viable technique for patients with coexisting thyroid disease with or without sestamibi scanning.

Background: Bilateral neck exploration (BNE) with the patient under general anesthesia has been the standard for parathyroidectomy. In efforts to minimize invasiveness and recovery from the procedure, unilateral neck exploration with the patient under local anesthesia in combination with sestamibi scanning is being done. Patients with a nonlocalized adenoma, concurrent thyroid disease, and/or multiple parathyroid adenomas have been excluded from this minimally invasive procedure.

Endothelial-monocyte activating polypeptide II, a novel antitumor cytokine that suppresses primary and metastatic tumor growth and induces apoptosis in growing endothelial cells.

Neovascularization is essential for growth and spread of primary and metastatic tumors. We have identified a novel cytokine, endothelial-monocyte activating polypeptide (EMAP) II, that potently inhibits tumor growth, and appears to have antiangiogenic activity. Mice implanted with Matrigel showed an intense local angiogenic response, which EMAP II blocked by 76% (P < 0.

Growth inhibition, enhancement of intercellular adhesion, and increased expression of carcinoembryonic antigen by overexpression of phosphoinositides-specific phospholipase C beta 1 in LS174T human colon adenocarcinoma cell line.

By using a retrovirus-derived system we generated derivatives of the human colon adenocarcinoma cell line LS174T (ATCC CL 188) that stably overexpress a full-length cDNA encoding the beta 1 isoform of bovine phosphoinositides-specific phospholipase C (PI-PLC). This was confirmed by the elevated levels of catalytic activity to release phosphoinositides from phosphatidylinositol (PI-PLC) or phosphatidylinositol-bis-phosphate (PIP2-PLC), and the enhanced expressions of messenger RNA and protein. PI-PLC beta 1 overexpresser clones grew to form cell clumps floating in liquid medium, whereas the pMV7-introduced control clones displayed morphologic characteristics that were very similar to those of the parent LS174T cell line.

Local/regional anesthesia for thyroidectomy: evaluation as an outpatient procedure.

Background: The purpose of this paper was to review my evolving experience with local/regional anesthesia in an outpatient setting.

Methods: Two hundred three consecutive patients during a 9-year period who chose to undergo thyroid operation under regional/local anesthesia were reviewed. Early discharge was offered to patients who were observed for 6 hours without neck swelling and who had no surgical reasons for delaying discharge.

Parathyroid surgery using monitored anesthesia care as an alternative to general anesthesia.

Background: Although there have been several reports in the literature describing a renewed interest in performing thyroid surgery under local anesthesia (LA), there has been little information regarding parathyroid surgery under local anesthesia.

Methods: We retrospectively reviewed our experience of 49 LA parathyroid patients over a 9-year period at a single institution. A bilateral cervical block (C2-C3) was administered by a single surgeon using lidocaine and bupivacaine.

Detection of circulating thyroid cells in peripheral blood.

Background: Detection of circulating malignant thyroid cells may provide a method to identify postoperative patients at risk for metastatic thyroid cancer.

Methods: On the basis of tissue specificity of thyroglobulin gene expression and the sensitivity of the reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, we performed RT-PCR using primers for thyroglobulin on blood samples from patients with thyroid disease to detect thyroglobulin RNA transcripts. Postoperative peripheral blood samples from 100 patients, including patients with known metastatic thyroid cancer (six papillary and three follicular), thyroid cancer and no evidence of current metastases (63 papillary, 10 follicular, and five patients with both papillary and follicular), benign thyroid disease (six nontoxic nodular goiters), and normal volunteers (seven).

A novel tumor-derived mediator that sensitizes cytokine-resistant tumors to tumor necrosis factor.

Therapeutic successes following treatment of murine tumors with tumor necrosis factor-alpha (TNF) have not been easily applied to clinical oncology because the concentrations of TNF required in humans induces systemic toxicity. This has led us to identify mediators which could sensitize tumors to the effects of TNF, permitting administration of lower doses and possible realization of the therapeutic potential of this cytokine. Our study reports the ability of a novel cytokine, endothelial-monocyte-activating polypeptide II (EMAP II), to sensitize initially resistant murine and human tumors to TNF-induced regression employing a murine model.

Expression of phospholipases gamma 1, beta 1, and delta 1 in primary human colon carcinomas and colon carcinoma cell lines.

The levels of expression of phosphoinositide-specific phospholipase Cs (PLCs) were examined in a series of primary human colon carcinomas and in eight colon carcinoma cell lines by using monoclonal antibodies and cDNA probes for PLC gamma 1, PLC beta 1, and PLC delta 1. Western and northern blot analyses of PLC gamma 1 revealed elevated expression of this isozyme at both the protein and mRNA levels in most tumors when compared with paired adjacent normal mucosa samples (in 11 of 13 pairs in the western blots and 8 of 9 pairs in the northern blots). On the other hand, decreased levels of the PLC delta 1 protein were seen in most colon carcinomas (12 of 13 paired samples).

The value of coarse needle biopsy in evaluating thyroid nodules.

At Columbia Presbyterian Medical Center, CPMC, the incidence of thyroid cancer found at surgery (CI) has recently changed. CI prior to 1950 was 3-4%. The CI gradually increased to 29% in 1975 without the use of needle biopsy.

The effects of bile acids on phospholipase C activity in extracts of normal human colon mucosa and primary colon tumors.

Phospholipase C (PLC) activity and its response to stimulation by bile acids was assayed in cellular extracts from 16 primary human colon tumors of various Duke's stages and paired adjacent normal mucosal samples. In the absence of bile acid, there was negligible degradation of phosphatidylinositol (PI) 1-stearoyl-2-[14C]-arachiodonoyl by tumor or normal tissue, but the addition of deoxycholic acid (DCA) or taurocholic acid (TCA) resulted in concentration-dependent and time-dependent stimulation of diacylglycerol (DAG) formation at optimal concentrations of 2 mM DCA and 4 mM TCA. Triton X-100 (0.

Thyroid surgery using monitored anesthesia care: an alternative to general anesthesia.

Forty consecutive patients undergoing thyroid surgery under local anesthesia (LA) by a single surgeon over a 5-year period were included in this retrospective review. In all cases, the indication for LA was patient request. The study included 29 females and 11 males with an average age of 44 years (range 22-66 years).

Decreased levels of protein kinase C enzyme activity and protein kinase C mRNA in primary colon tumors.

Purpose: We have previously reported decreased protein kinase C (PKC) enzyme activity in primary human colorectal carcinomas. The purpose of this study was to extend these findings to a larger number of cases and to also examine the levels of expression of mRNAs that encode specific isoforms of PKC in these tumors.

Methods: Colorectal carcinomas and paired grossly normal adjacent mucosal samples were collected from 39 patients.

Changes in type I collagen following laser welding.

Selection of ideal laser parameters for tissue welding is inhibited by poor understanding of the mechanism. We investigated structural changes in collagen molecules extracted from rat tail tendon (> 90% type I collagen) after tissue welding using an 808 nm diode laser and indocyanine green dye applied to the weld site. Mobility patterns on SDS-PAGE were identical in the lasered and untreated tendon extracts with urea or acetic acid.

Fecal excretion, uptake and metabolism by colon mucosa of diacylglycerol in rats.

In a previous paper we demonstrated that human fecal bacteria can convert phosphatidylcholine to diacylglycerol (DAG), an activator of protein kinase C. The present study demonstrates that several foods contain appreciable levels of DAG, especially certain vegetable oils. On the other hand, when rats were administered [14C]-labeled DAG by intragastric intubation less than 0.