Significant advances have been made in the development of targeted interventions for hematologic malignancies. Progress has been made in defining the molecular pathogenesis of human leukemias. Data indicate that nonrandom, somatically acquired translocations, inversions, and other abnormalities occur in many acute leukemias. In the treatment of acute promyelocytic leukemia (APL), targeted therapy with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy leads to dramatic improvements in disease-free survival. Imatinib mesylate, a signal transduction inhibitor that inhibits tyrosine kinase activity, the protein product of the ABL proto-oncogene, has remarkable activity in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL). Farnesyltransferase inhibitors (FTIs), a promising class of agents that target multiple pathways including Ras proteins, are potential anticancer therapy for a wide range of malignancies, including leukemias and myelodysplastic syndromes (MDS). There also is evidence that recombinant human erythropoietin therapy (r-HuEPO) can benefit patients with chronic lymphocytic leukemia (CLL), multiple myeloma, and lymphomas. This supplement will discuss advances in our understanding of human leukemias, including the use of unconjugated monoclonal antibodies such as Campath-1H (Wellcome, Beckenham, UK, and Ilex Oncology, San Antonio, TX) and rituximab and immunoconjugates such as gemtuzumab ozogamicin and BL-22. Although these novel therapies are beginning to fulfill their promise, continued research efforts are needed to determine the optimal role of targeted therapy in acute and chronic leukemias.

Total serum thyroxine (T4), free thyroxine index (FTI), thyroxine binding globulin (TBG) binding capacity, serum albumin, alpha-globulins and urinary protein excretion were measured in 50 patients with chronic renal failure, but without nephrotic syndrome. 25 patients were undergoing chronic hemodialysis. T4 was within the normal range in most patients. There was a tendency to lower T4 values as compared to an age and sex-matched control group, but this did not reach statistical significance. TBG was normal in most patients. 4 patients showed elevated TBG concomitant with elevation of other alpha-globulins. Serum albumin was significantly decreased. No correlation existed between daily protein excretion and TBG or alpha-globulins, but the correlation between serum albumin and proteinuria was highly significant. T4 and proteinuria correlated with borderline significance. A highly significant correlation between T4 and TBG-albumin values was found. No correlation existed between FTI and TBG-albumin levels. The data suggest that T4 and TBG are normal in most patients with renal failure, even in the presence of significant proteinuria. Low T4 values, when found in renal insufficiency, may be secondary to low serum albumin and possibly prealbumin.

BACKGROUND

Remote magnetic navigation (RMN) and contact force (CF) sensing catheters are available technologies for radiofrequency (RF) catheter ablation of atrial fibrillation (AF). Our purpose was to compare time to electrogram (EGM) modification suggesting transmural lesions between RMN and CF-guided AF ablation.

RESULTS

A total of 1,008 RF applications were analyzed in 21 patients undergoing RMN (n = 11) or CF-guided ablation (n = 10) for paroxysmal AF. All procedures were performed in sinus rhythm during general anesthesia. Time to EGM modification was measured until transmurality criteria were fulfilled: (1) complete disappearance of R if initial QR morphology; (2) diminution>> 75% of R if initial QRS morphology; (3) complete disappearance of R' of initial RSR' morphology. Impedance drop as well as force time integral (FTI) were also assessed for each application. Mean CF at the beginning of each RF application in the CF group was 11 ± 2 g and mean FTI per application was 488 ± 163 gs. Time to EGM modification was significantly shorter in the RMN group (4.52 ± 0.1 seconds vs. 5.6 ± 0.09 seconds; P < 0.00001). There was no significant difference between other procedural parameters.

CONCLUSIONS

Remote magnetic AF ablation is associated with faster EGM modification suggesting transmurality than optimized CF and FTI-guided catheter ablation.

OBJECTIVE

Protein intake is a key point to maintain an adequate nutritional status in hemodialysis (HD) patients. There are some studies that confirm the positive influence of intradialytic oral nutritional supplementation in several nutritional parameters in HD patients. The aim of this study was to evaluate the effect of an intradialytic protein rich meal in nutritional and body composition parameters on HD patients.

METHODS

This was a 6-months single center non-randomized study with 99 patients in HD from one Nephrocare dialysis unit in Portugal. Patients in the intervention group (IG) presented one albumin value ≤ 3.8 g/dL in the two measurements prior to the beginning of the study. The IG ate a protein rich meal during each treatment. The control group (CG) continued to eat their usual snack brought from home. Albumin, nPCR, potassium, phosphorus, C-reactive protein (CRP), dry weight and body composition were measured at baseline and at the end of the study.

RESULTS

Patient's mean age was 69.9 ± 12.9 years and HD vintage, 60.0 ± 50.5 months. Both groups were similar at the start of the study, except in albumin (p = 0.019). After the intervention, protein intake increased in the IG (p = 0.001). Albumin decreased in both groups but this difference was higher and only statistically significant in the CG (p = 0.039). Regarding body composition, in the CG, the fat tissue index (FTI) (p = 0.022) and the lean tissue index (LTI) (p = 0.003) diminished after the 6 months of the follow-up. However, in the IG the LTI value also reduced (p = 0.008) but FTI increased (p = <0.001) at the end of the study. There were no statistically significant differences on dry weight, potassium, phosphorus, and CRP.

CONCLUSIONS

Apart from the effect on protein intake, the importance of this study relies on the positive changes in regard to patient's body composition obtained after 6 months of an intradialytic intake of a protein rich meal during the HD treatment. This type of intervention can contribute to ameliorate patient's nutritional status without a negative effect on other parameters.

Using several variables known to be related to prostate cancer, a multivariate classification method is developed to predict the onset of clinical prostate cancer. A multivariate mixed-effects model is used to describe longitudinal changes in prostate specific antigen (PSA), a free testosterone index (FTI), and body mass index (BMI) before any clinical evidence of prostate cancer. The patterns of change in these three variables are allowed to vary depending on whether the subject develops prostate cancer or not and the severity of the prostate cancer at diagnosis. An application of Bayes' theorem provides posterior probabilities that we use to predict whether an individual will develop prostate cancer and, if so, whether it is a high-risk or a low-risk cancer. The classification rule is applied sequentially one multivariate observation at a time until the subject is classified as a cancer case or until the last observation has been used. We perform the analyses using each of the three variables individually, combined together in pairs, and all three variables together in one analysis. We compare the classification results among the various analyses and a simulation study demonstrates how the sensitivity of prediction changes with respect to the number and type of variables used in the prediction process.

Compared to conscious sedation (CS), the use of general anesthesia (GA) in pulmonary vein isolation (PVI) is associated with a lower recurrence rate of atrial fibrillation (AF). GA may improve catheter stability and mapping system accuracy compared to CS, but its influence on contact force (CF) parameters during ipsilateral PVI has not previously been investigated. The study population comprised 176 consecutive patients (107 in GA group and 69 in CS group) with AF who underwent their first PVI procedure. We retrospectively assessed CF parameters, force-time integral (FTI), FTI/wall thickness during anatomical ipsilateral PVI and long-term outcome after ablation. Complete PVI with single continuous circular lesions around the ipsilateral PVs was achieved in 54 patients (50.5%) in the GA group but only 24 patients (34.8%) in the CS group (P = 0.04). The distribution of gaps did not differ between the groups. All CF parameters were significantly higher in the GA group than in the CS group (average CF: 19.4 ± 8.7 vs. 16.7 ± 7.7 g, P < 0.0001; FTI: 399.0 ± 262.5 vs. 293.9 ± 193.4 gs, P < 0.0001; FTI/wall thickness: 155.5 ± 106.1 vs. 115.7 ± 85.5 gs, P < 0.0001). GA was associated with lower AF recurrence rate in patients with paroxysmal AF but not with persistent AF. Compared with CS, GA improves CF parameters, FTI and FTI/wall thickness, and reduced gap formation after ipsilateral PVI.

Thyroid function was measured in 24 patients before antidepressant treatment, and following failure of acute desipramine treatment but before triiodothyronine (T3) augmentation. While all measures of thyroid function were within the euthyroid range, eventual T3 augmentation responders were found to have, prior to any antidepressant treatment, lower levels of TSH and higher levels of thyroxine (T4) and free thyroxine index (FTI) than non-responders. This suggests that T3 augmentation may be of particular importance in subjects with comparatively elevated levels of serum FTI.

Protein-energy wasting, which involves loss of fat and muscle mass, is prevalent and is associated with mortality in hemodialysis (HD) patients. We investigated the associations of fat tissue and muscle mass indices with all-cause mortality in HD patients. The study included 162 patients undergoing HD. The fat tissue index (FTI) and skeletal muscle mass index (SMI), which represent respective tissue masses normalized to height squared, were measured by bioimpedance analysis after dialysis. Patients were divided into the following four groups according to the medians of FTI and SMI values: group 1 (G1), lower FTI and lower SMI; G2, higher FTI and lower SMI; G3, lower FTI and higher SMI; and G4, higher FTI and higher SMI. The associations of the FTI, SMI, and body mass index (BMI) with all-cause mortality were evaluated. During a median follow-up of 2.5 years, 29 patients died. The 5-year survival rates were 48.6%, 76.1%, 95.7%, and 87.4% in the G1, G2, G3, and G4 groups, respectively (P = 0.0002). The adjusted hazard ratio values were 0.34 (95% confidence interval [CI] 0.10-0.95, P = 0.040) for G2 vs. G1, 0.13 (95%CI 0.01-0.69, P = 0.013) for G3 vs. G1, and 0.25 (95%CI 0.07-0.72, P = 0.0092) for G4 vs. G1, respectively. With regard to model discrimination, on adding both FTI and SMI to a model with established risk factors, the C-index increased significantly when compared with the value for a model with BMI (0.763 vs. 0.740, P = 0.016). Higher FTI and/or higher SMI values were independently associated with reduced risks of all-cause mortality in HD patients. Moreover, the combination of the FTI and SMI may more accurately predict all-cause mortality when compared with BMI. Therefore, these body composition indicators should be evaluated simultaneously in this population.

Ras converting enzyme 1 (Rce1) is an endoprotease that catalyzes processing of the C-terminus of Ras protein by removing -aaX from the CaaX motif. The activity of Rce1 is crucial for proper localization of Ras to the plasma membrane where it functions. Ras is responsible for transmitting signals related to cell proliferation, cell cycle progression, and apoptosis. The disregulation of these pathways due to constitutively active oncogenic Ras can ultimately lead to cancer. Ras, its effectors and regulators, and the enzymes that are involved in its maturation process are all targets for anti-cancer therapeutics. Key enzymes required for Ras maturation and localization are the farnesyltransferase (FTase), Rce1, and isoprenylcysteine carboxyl methyltransferase (ICMT). Among these proteins, the physiological role of Rce1 in regulating Ras and other CaaX proteins has not been fully explored. Small-molecule inhibitors of Rce1 could be useful as chemical biology tools to understand further the downstream impact of Rce1 on Ras function and serve as potential leads for cancer therapeutics. Structure-activity relationship (SAR) analysis of a previously reported Rce1 inhibitor, NSC1011, has been performed to generate a new library of Rce1 inhibitors. The new inhibitors caused a reduction in Rce1 in vitro activity, exhibited low cell toxicity, and induced mislocalization of EGFP-Ras from the plasma membrane in human colon carcinoma cells giving rise to a phenotype similar to that observed with siRNA knockdowns of Rce1 expression. Several of the new inhibitors were more effective at mislocalizing K-Ras compared to a potent farnesyltransferase inhibitor (FTI), which is significant because of the preponderance of K-Ras mutations in cancer.

Muscle produces force by forming cross-bridges, using energy released from ATP. While the magnitude and duration of force production primarily determine the energy requirement, nearly a century ago Fenn observed that muscle shortening or lengthening influenced energetic cost of contraction. When work is done by the muscle, the energy cost is increased and when work is done on the muscle the energy cost is reduced. However, the magnitude of the 'Fenn effect' and its mirror ('negative Fenn effect') have not been quantitatively resolved. We describe a new technique coupling magnetic resonance spectroscopy with an in vivo force clamp that can directly quantify the Fenn effect [E=I+W, energy liberated (E) equals the energy cost of isometric force production (I) plus the work done (W)] and the negative Fenn effect (E=I-W) for one muscle, the first dorsal interosseous (FDI). ATP cost was measured during a series of contractions, each of which occurred at a constant force and for a constant duration, thus constant force-time integral (FTI). In all subjects, as the FTI increased with load, there was a proportional linear increase in energy cost. In addition, the cost of producing force greatly increased when the muscle shortened, and was slightly reduced during lengthening contraction. These results, though limited to a single muscle, contraction velocity and muscle length change, do quantitatively support the Fenn effect. We speculate that they also suggest that an elastic element within the FDI muscle functions to preserve the force generated within the cross-bridges.

OBJECTIVE

Despite promising preclinical findings regarding clinical utility of farnesyltransferase inhibitors (FTI), such as lonafarnib, success of clinical trials is limited. A multicentre AGO-OVAR-15 phase II trial reported an unfavourable effect of lonafarnib on the outcome of patients with advanced ovarian cancer. This study was performed as a genetic subgroup analysis of the AGO-OVAR-15 trial, and investigated the utility of the promoter polymorphism rs11623866 of the farnesyltransferase ß-subunit gene (FNTB) in predicting the clinical effectiveness of lonafarnib.

METHODS

The influence of rs11623866 (c.-609G>> C) on FNTB promoter activity was investigated by electrophoretic-mobility-shift assay, luciferase-reporter assay and RT-qPCR. A total of 57 out of 105 patients from the AGO-OVAR-15 trial, treated with carboplatin and paclitaxel ± lonafarnib, was genotyped for rs11623866 by restriction fragment length polymorphism analysis. Genotype-dependent survival analysis was performed by Kaplan-Meier analysis.

RESULTS

The presence of the G allele was associated with increased FNTB promoter activity compared with the C allele. An unfavourable effect of lonafarnib was limited to patients carrying a GG genotype (HRPFS 6.2, 95%CI = 2.01, 19.41, P = 0.002; HROS 9.6, 95%CI = 1.89, 48.54, P = 0.006). Median progression free survival (PFS) for patients with the GG genotype in the lonafarnib treated arm was 10 months, whereas median PFS without FTI-treatment was 40 months. Median overall survival (OS) in the lonafarnib-treated group was 19 months, whereas median OS was not reached in the untreated group.

CONCLUSIONS

Discrepancies between preclinical success and clinical failure may be due to the patients' genetic variability of FNTB. Therefore, our results may encourage retrospective evaluation of FNTB polymorphisms in previous FTI studies, especially those reporting positive FTI response.

Hyperactive Ras promotes proliferation and malignant phenotypic conversion of cells in cancer. Ras protein must be associated with cellular membranes for its oncogenic activities through post-translational modifications, including farnesylation. Farnesyltransferase (FTase) is essential for H-Ras membrane targeting, and H-Ras, but not N-Ras, has been demonstrated to cause an invasive phenotype in MCF10A breast epithelial cells. In the present study, it was observed that an FTase inhibitor (FTI), FTI-277, blocked epidermal growth factor (EGF)-induced H-Ras activation, but not N-Ras activation in MDA-MB-231 cells, which express wild-type H-Ras and N-Ras. FTI-277 exerted a more potent inhibitory effect on the proliferation of H-Ras-MCF10A cells and Hs578T breast cancer cells expressing an active mutant of H-Ras than that of MDA-MB-231 cells. The invasive/migratory phenotypes of the H-Ras-MCF10A and Hs578T cells were effectively inhibited by FTI-277 treatment. By contrast, FTI-277 did not affect the invasive/migratory phenotypes of MDA-MB-231 cells. However, the EGF-induced invasion of MDA-MB-231 cells was decreased by FTI-277, implicating that FTI-277 inhibits breast cell invasion and migration by blocking H-Ras activation. Taken together, the results of the present study suggest that FTase inhibition by FTI-277 may be an effective strategy for targeting H-Ras-mediated proliferation, migration and invasion of breast cells.

Farnesyltransferase inhibitors (FTIs) represent a new class of signal transduction inhibitors that block the processing of cellular polypeptides that have cysteine terminal residues and, by doing so, interdict multiple pathways involved in proliferation and survival of diverse malignant cell types. Tipifarnib is an orally bioavailable, nonpeptidomimetic methylquinolone FTI that is being tested clinically in diverse hematologic malignancies, in particular myeloid malignancies and myeloma. FTI therapy is accompanied by a relatively low toxicity profile, thereby providing an important alternative to traditional cytotoxic approaches for elderly patients who are not likely to tolerate or even benefit from aggressive chemotherapy. Current laboratory and clinical studies continue to define the determinants of FTI antitumor activity and resistance. The full development of FTIs for the therapy of hematologic malignancies will require the design and testing of rational combinations of cytotoxic, biologic and immunomodulatory agents in the laboratory and the clinic.

Human protein farnesyltransferase (FTase) catalyzes the addition of a C15-farnesyl lipid group to the cysteine residue located in the COOH-terminal tetrapeptide motif of a variety of important substrate proteins, including well-known Ras protein superfamily. The farnesylation of Ras protein is required both for its normal physiological function, and for the transforming capacity of its oncogenic mutants. Over the last several decades, FTase inhibitors (FTIs) were developed to disrupt the farnesylation of oncogenic Ras as anti-cancer agents, and some of them have entered cancer clinical investigation. On the other hand, some substrates of FTase were demonstrated to be related with other human diseases, including Hutchinson-Gilford progeria syndrome, chronic hepatitis D, and cardiovascular diseases. In this review, we summarize the roles of FTase in malignant transformation, proliferation, apoptosis, angiogenesis, and metastasis of tumor cells, and the recently anticancer clinical research advances of FTIs. The therapeutic prospect of FTIs on several other human diseases is also discussed.

Asymmetrically porous and aligned fibrous tubular conduit with selective permeability as a biomimetic neural scaffold was manufactured using polycaprolactone (PCL), silk, and quercetin by a modified electrospinning method. The outer surface of the randomly oriented fibrous scaffold had microscale pores that could prevent fibrous tissue invasion (FTI), but could permeate neurotrophic factors, nutrients, and oxygen. The inner surface of the aligned fibrous scaffold can be favorable for neurite outgrowth, because of their superior neural cell attachment, migration, and directional growth. In vitro and in vivo studies have demonstrated the therapeutic effect of Quercetin, a ubiquitous flavonoid widely distributed in plants, on neuropathy, by modulating the expression of NRF-2-dependent antioxidant responsive elements. In this study, the controlled inner and outer surface geometry of the 0.5, 1.0, and 2.0 wt% quercetin-containing electrospun PCL/silk fibrous tubular scaffold fabricated via a modified wound coil collector and L-shaped ground design (WCC-LG) was characterized by FE-SEM, TEM, FFT, FT-IR, and XRD. In addition, two types of neural cell lines, PC12 and S42, were used to evaluate the cell proliferation rate of the different amount of quercetin-loaded PCL/silk tubular scaffolds.

Progeria is a globally noticed rare genetic disorder manifested by premature aging with no effective treatment. Under these circumstances, farnesyltransferase inhibitors (FTIs) are marked as promising drug candidates. Correspondingly, a pharmacophore model was generated exploiting the features of lonafarnib. The selected pharmacophore model was allowed to screen the InterBioScreen natural compound database to retrieve the potential lead candidates. A series of filtering steps were applied to assess the drug-likeness of the compounds. The obtained compounds were advanced to molecular docking employing the CDOCKER module available with Discovery Studio (DS). Subsequently, three compounds (Hits) have displayed a higher dock score and demonstrated key residue interactions with stable molecular dynamics simulation results compared to the reference compound. Taken together, we therefore put forth three identified Hits as FTIs that may further serve as chemical spaces in designing new compounds.

BACKGROUND

Rasd1 is a member of the Ras family of monomeric G proteins that was first identified as a dexamethasone inducible gene in the pituitary corticotroph cell line AtT20. Using microarrays we previously identified increased Rasd1 mRNA expression in the rat supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus in response to increased plasma osmolality provoked by fluid deprivation and salt loading. RASD1 has been shown to inhibit adenylyl cyclase activity in vitro resulting in the inhibition of the cAMP-PKA-CREB signaling pathway. Therefore, we tested the hypothesis that RASD1 may inhibit cAMP stimulated gene expression in the brain.

RESULTS

We show that Rasd1 is expressed in vasopressin neurons of the PVN and SON, within which mRNA levels are induced by hyperosmotic cues. Dexamethasone treatment of AtT20 cells decreased forskolin stimulation of c-Fos, Nr4a1 and phosphorylated CREB expression, effects that were mimicked by overexpression of Rasd1, and inhibited by knockdown of Rasd1. These effects were dependent upon isoprenylation, as both farnesyltransferase inhibitor FTI-277 and CAAX box deletion prevented Rasd1 inhibition of cAMP-induced gene expression. Injection of lentiviral vector into rat SON expressing Rasd1 diminished, whereas CAAX mutant increased, cAMP inducible genes in response to osmotic stress.

CONCLUSIONS

We have identified two mechanisms of Rasd1 induction in the hypothalamus, one by elevated glucocorticoids in response to stress, and one in response to increased plasma osmolality resulting from osmotic stress. We propose that the abundance of RASD1 in vasopressin expressing neurons, based on its inhibitory actions on CREB phosphorylation, is an important mechanism for controlling the transcriptional responses to stressors in both the PVN and SON. These effects likely occur through modulation of cAMP-PKA-CREB signaling pathway in the brain.

BACKGROUND

Circumstances such as gender, age, diabetes mellitus (DM) and renal failure impact on the body composition of patients. However, we use nutritional parameters such as lean and fat tissue with reference values from healthy subjects to assess the nutritional status of haemodialysis (HD) patients.

OBJECTIVE

To analyse body composition by bioimpedance spectroscopy (BIS) of 6395 HD patients in order to obtain reference values of lean tissue index (LTI) and fat tissue index (FTI) from HD patients; and to confirm its validity by showing that those patients with LTI below the 10th percentile calculated for their group have greatest risk of death.

METHODS

We used the BIS to determine the LTI and FTI in our cohort of HD patients in Spain. We calculated the 10th percentile and 90th percentile of LTI and FTI in each age decile for patients grouped by gender and presence of DM. We collected clinical, laboratory and demographic parameters.

RESULTS

The LTI/FTI 10 and 90 percentile values varied by group (age, gender and presence of DM) and, after adjusting for other risk factors such as fluid overload, those patients with LTI lower than percentile 10 had a higher relative risk of death (OR 1.57) than those patients with higher values.

CONCLUSIONS

Monitoring the LTI and FTI of patients on HD using suitable reference values may help to identify risk in this patient population.

Biotechnological production of xylitol is an attractive route to add value to a sugarcane biorefinery, through utilization of the hemicellulosic fraction of sugarcane straw, whose availability is increasing in Brazil. Herein, supplementation of the sugarcane straw hemicellulosic hydrolyzate (xylose 57gL(-1)) with maltose, sucrose, cellobiose or glycerol was proposed, and their effect as co-substrates on xylitol production by Candida guilliermondii FTI 20037 was studied. Sucrose (10gL(-1)) and glycerol (0.7gL(-1)) supplementation led to significant increase of 8.88% and 6.86% on xylose uptake rate (1.11gL(-1)h(-1) and 1.09gL(-1)), respectively, but only with sucrose, significant increments of 12.88% and 8.69% on final xylitol concentration (36.11gL(-1)) and volumetric productivity (0.75gL(-1)h(-1)), respectively, were achieved. Based on these results, utilization of complex sources of sucrose, derived from agro-industries, as nutritional supplementation for xylitol production can be proposed as a strategy for improving the yeast performance and reducing the cost of this bioprocess by replacing more expensive nutrients.

In the quest for the development of pharmacological switches that control gene expression, no system has been reported that regulates at the translational level. To permit small-molecule control of transgene translation, we have constructed a farnesyl transferase inhibitor-responsive translation initiation factor. This artificial protein is a three-component chimaera consisting of the ribosome recruitment core of the eIF4G1 eukaryotic translation initiation factor, the RNA-binding domain of the R17 bacteriophage coat protein and the plasma membrane localization CAAX motif of farnesylated H-Ras. This membrane-delocalized translation factor is inactive unless liberated in the cytosol. Farnesyl transferase inhibitor FTI-277 prevents the membrane association of the CAAX motif and thus increases the cytoplasmic levels of the eIF4G fusion protein, which is then capable of inducing translation of the second cistron of a bicistronic messenger RNA containing an R17-binding site in its intercistronic space. Such direct translational control by farnesyl transferase inhibitors provides a system for fast, graded and reversible regulation of transgene expression.

To determine the incidence of unrecognized thyroid disease among admissions to a large acute care university teaching hospital, 364 samples taken on consecutive admissions were assayed for thyroid-stimulating hormone (TSH) and free thyroxine index (FTI). Patients with abnormal test results were further evaluated by determination of antimicrosomal and antithyroglobulin antibodies, and charts were reviewed for evidence of prior diagnosis of thyroid disease, especially severe illness, drug treatment that might affect thyroid function tests, and prior diagnosis of thyroid disease. Results of subsequent thyroid function tests performed during the patient's hospitalization were correlated with the admission serum assays, and data on subsequent testing during the following 6 months were also obtained. A total of 3.9% of patients had significantly depressed TSH, and 11.1% of values were significantly elevated. A total of 11.3% of patients had significantly low FTI values, and 1% had significantly elevated values. A total of 7.4% appeared to have the euthyroid sick syndrome, 5.8% appeared to have unrecognized or undertreated primary thyroid failure, 6% had apparent subclinical hypothyroidism, 2% were thyrotoxic, and 2.8% (all women) had suppressed TSH levels for inapparent reasons. Limiting testing to patients over 49 years of age, or to women, would have missed many individuals with abnormal test results. Considering widespread availability of tests, relative costs, and value of the information obtained, it is suggested that the FTI determination would provide an appropriate screening test for patients in a population such as this entering a large, acute care general hospital.

Psychiatric illness is a cause of "euthyroid sick syndrome" (ESS), defined as abnormal concentrations of circulating iodothyronines in euthyroid subjects with nonthyroidal illness (NTI). We describe a prospective study of 150 consecutive psychiatric admissions studied by endocrine and psychologic techniques. Based on 150 admission blood samples, we found a 7% incidence of ESS and with serial samples (74 patients) the incidence was 27%, demonstrating that ESS can develop after hospital admission. Of the 20 patients with ESS, 11 had elevation of both serum total T4 concentrations (T4) and free thyroxine index (FTI) while their serum total T3 concentrations (T3) remained normal; 5 had elevation of FTI without elevation of T4 or T3; and 4 had low T4 and low FTI and normal TSH. In 2 of the 4 patients in the last category, the T3 was also low. The free T3 index (FT3I) was normal in all but 1 patient who had low FT3I and FTI, low T4 and T3, and normal TSH. The serum thyroid hormone abnormalities were transient in the ESS patients during the 10 day period with 2 exceptions; 1 patient had persistently elevated T4 and FTI with normal T3 and FT3I values while another patient had persistently depressed T4 and FTI without abnormality of FT3I or TSH. Multivariate statistical analysis demonstrated a difference (P less than .06) in the psychologic attributes of somatic and autonomic symptoms in ESS patients compared to controls. We conclude that ESS is as common amongst psychiatric admissions as in general hospital patients previously studied and that blood thyroid function tests should be interpreted cautiously in all hospitalized patients.

Recently, the company that manufactures the levothyroxine product that we use most often in our practice switched to high-pressure liquid chromotography (HPLC) to monitor their product. As a result, the brand name product now contains 100% of expected potency as determined in our laboratory by radioimmunoassay. Previous studies in our laboratory demonstrated that this product had only 78% of expected potency. This year our patients have a higher mean serum free thyroxine index (FTI) than they have had in the past. In addition, there were more elevated serum FTI levels and fewer elevated serum thyroid-stimulating hormone levels this year. Physicians should be aware of possible product changes being made by manufacturers of levothyroxine products over the next year or so as more companies switch to the HPLC method. The thyroid function studies of patients receiving levothyroxine products should be rather carefully monitored during this transitional period. We suspect that the new products will be more consistent and have a more reliable shelf life.