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Objective: To determine the effect of daily consumption of 100 g of dried plum (Prunus domestica L.) on the bowel habits of postmenopausal women.Method: Fifty-eight postmenopausal women not on hormone replacement therapy and free of any gastrointestinal problems or eating disorders were randomly assigned to receive either 100 g of dried plum or 75 g of dried apples daily for 3 months. During the first week of treatment and each month thereafter, the participants were asked to fill out a validated questionnaire regarding their weekly bowel habits. The parameters used to assess bowel habits included stool frequency, estimated fecal bulk, consistency of stool, strain and pain during bowel movement, and feeling of constipation.Results: In both treatment regimens, there were no significant differences between the 4 different time points for any of the parameters used to assess bowel function. Conclusion: Many postmenopausal women can take advantage of all the health benefits that accompany prune consumption, such as improving blood lipid profile and reducing bone loss, without negative gastrointestinal side effects. [ABSTRACT FROM AUTHOR]

Normal urine residual volume (URV) in dogs has not previously been established by direct measurement. Twenty-two client-owned normal healthy dogs (8 female spayed, 12 male castrated, 2 male intact) without history of urinary abnormalities were included. Dogs were walked outside for 5 min to allow for natural voiding, immediately followed by urinary bladder ultrasound and urinary catheterization. The URV was recorded, and the ultrasound images were used to estimate URV for each dog. There was no significant difference between male and female URV; therefore, all data were pooled. With a 90% confidence interval, URV was 0-0.47 mL/kg with a mean URV of 0.21 mL/kg and a median value of 0.175 mL/kg. There was no significant difference between the measured URV and the ultrasound-determined URV. This case series supports previously established normal URV in the dog; however, a reference interval based on a larger population of dogs with further evaluation of body size/weight, sex, and neuter status is recommended to be established for use in clinical setting to differentiate normal urination from urinary retention in patients., (© 2023 by American Animal Hospital Association.)

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non-clear cell renal cell carcinoma, and are intended to assist with clinical decision-making. These NCCN Guidelines Insights summarize the NCCN Kidney Cancer Panel discussions for the 2020 update to the guidelines regarding initial management and first-line systemic therapy options for patients with advanced clear cell renal cell carcinoma.

In recent years, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Adult Cancer Pain have undergone substantial revisions focusing on the appropriate and safe prescription of opioid analgesics, optimization of nonopioid analgesics and adjuvant medications, and integration of nonpharmacologic methods of cancer pain management. This selection highlights some of these changes, covering topics on management of adult cancer pain including pharmacologic interventions, nonpharmacologic interventions, and treatment of specific cancer pain syndromes. The complete version of the NCCN Guidelines for Adult Cancer Pain addresses additional aspects of this topic, including pathophysiologic classification of cancer pain syndromes, comprehensive pain assessment, management of pain crisis, ongoing care for cancer pain, pain in cancer survivors, and specialty consultations.

The NCCN Guidelines for Hepatobiliary Cancers provide treatment recommendations for cancers of the liver, gallbladder, and bile ducts. The NCCN Hepatobiliary Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's discussion and updated recommendations regarding systemic therapy for first-line and subsequent-line treatment of patients with hepatocellular carcinoma.

Background: Renal denervation (RDN) can reduce blood pressure (BP) in patients with resistant hypertension, but less so in patients with isolated systolic hypertension. A possible explanation is that patients with stiffer arteries may have lesser neural contribution to their hypertension., Method: We hypothesized that arterial stiffness predicts the response to RDN. From ambulatory BP monitoring (ABPM), ambulatory arterial stiffness index (AASI) was calculated as 1 - the regression slope of DBP versus SBP., Results: In 111 patients with resistant hypertension, RDN reduced office and 24-h SBP after 3, 6, and 12 months (by -11 ± 22, -11 ± 25, -14 ± 21 mmHg for office, and -4 ± 11, -5 ± 12, -5 ± 15 mmHg for 24-h SBP, respectively, P < 0.01). Patients with baseline AASI above the median (>0.51) showed no change in 24-h SBP at 6 months after RDN (-0.4 ± 12.3 mmHg, P > 0.05), whereas an AASI below 0.51was associated with a marked reduction (-9.3 ± 11.0 mmHg, P < 0.01). Across AASI quartiles, patients in the highest quartile (AASI ≥ 0.60) had lower muscle sympathetic nerve activity than the other three quartiles (39 ± 13 versus 49 ± 13 bursts/min, P = 0.035). The responder rate, defined as a 24-h SBP reduction of at least 5% was 58% in the lowest AASI quartile (<0.45) and 16% in the highest quartile (≥0.60). After adjustment for age, sex, BMI, office and 24-h SBP, an AASI less than 0.51predicted those who respond to RDN (odds ratio 3.46, P = 0.04)., Conclusion: We conclude that in patients with resistant hypertension, a lower AASI is an independent predictor of the BP response to RDN, possibly explained by a more pronounced neurogenic rather than biomechanical contribution to their BP elevation.

Background: We previously demonstrated the effectiveness of renal denervation (RDN) to lower blood pressure (BP) at least partially via the reduction of sympathetic stimulation to the kidney. A number of adipocyte-derived factors are implicated in BP control in obesity. Aim: The aim of this study was to examine whether RDN may have salutary effects on the adipokine profile in patients with resistant hypertension (RH). Methods: Fifty seven patients with RH undergoing RDN program have been included in this study (65% males, age 60.8 ± 1.5 years, BMI 32.6 ± 0.7 kg/m 2 , mean ± SEM). Throughout the study, the patients were on an average of 4.5 ± 2.7 antihypertensive drugs. Automated seated office BP measurements and plasma concentrations of leptin, insulin, non-esterified fatty acids (NEFA), adiponectin and resistin were assessed at baseline and the 3 months after RDN. Results: There was a significant reduction in mean office systolic (168.75 ± 2.57 vs. 155.23 ± 3.17 mmHg, p < 0.001) and diastolic (90.68 ± 2.31 vs. 83.74 ± 2.36 mmHg, p < 0.001) BP 3 months after RDN. Body weight, plasma leptin and resistin levels and heart rate remained unchanged. Fasting insulin concentration significantly increased 3 months after the procedure (20.05 ± 1.46 vs. 29.70 ± 2.51 uU/ml, p = 0.002). There was a significant drop in circulating NEFA at follow up (1.01 ± 0.07 vs. 0.47 ± 0.04 mEq/l, p < 0.001). Adiponectin concentration was significantly higher after RDN (5,654 ± 800 vs. 6,644 ± 967 ng/ml, p = 0.024). Conclusions: This is the first study to demonstrate that RDN is associated with potentially beneficial effects on aspects of the adipokine profile. Increased adiponectin and reduced NEFA production may contribute to BP reduction via an effect on metabolic pathways. Clinical Trial Registration Number: NCT00483808, NCT00888433.

The T2*-weighted gradient recalled echo sequence is a sensitive means to detect blood degradation products. While not a routine sequence in magnetic resonance imaging of the spine in small animals, it can provide additional valuable information in select cases. The goal of this retrospective, cross-sectional study was to describe findings when acquiring this sequence during magnetic resonance imaging examination of the spine in small animals. The University of Tennessee's veterinary radiology database was searched for dogs and cats that underwent magnetic resonance imaging for suspect spinal disease in which a T2*-weighted gradient recalled echo sequence was acquired and susceptibility artifact was identified. The following information was recorded: signalment, clinical signs, location and appearance of susceptibility artifact, and final diagnosis. Thirty-nine cases were included in the study. Extradural susceptibility artifacts were observed in cases of intervertebral disc herniation with or without associated hemorrhage (n = 28), extradural hemorrhage associated with spinal trauma (n = 2), hemophilia (n = 1), and in a cystic extradural mass (n = 1). Remaining lesions displaying susceptibility artifact were intramedullary and included presumptive acute noncompressive nucleus pulposus extrusion (n = 2), hematoma (n = 1), hemangiosarcoma metastasis (n = 1), intramedullary disc extrusion (n = 1), presumptive meningomyelitis (n = 1), and a mass of undetermined etiology (n = 1). Inclusion of a T2*-weighted gradient recalled echo sequence may be helpful in spinal magnetic resonance imaging when standard imaging sequences are ambiguous or intramedullary lesions are observed., (© 2015 American College of Veterinary Radiology.)

Diabetes mellitus is a major health concern, affecting more than 5% of the population. Here we describe a potential novel therapeutic agent for this disease, FGF-21, which was discovered to be a potent regulator of glucose uptake in mouse 3T3-L1 and primary human adipocytes. FGF-21-transgenic mice were viable and resistant to diet-induced obesity. Therapeutic administration of FGF-21 reduced plasma glucose and triglycerides to near normal levels in both ob/ob and db/db mice. These effects persisted for at least 24 hours following the cessation of FGF-21 administration. Importantly, FGF-21 did not induce mitogenicity, hypoglycemia, or weight gain at any dose tested in diabetic or healthy animals or when overexpressed in transgenic mice. Thus, we conclude that FGF-21, which we have identified as a novel metabolic factor, exhibits the therapeutic characteristics necessary for an effective treatment of diabetes.

Background: Dietary modification contributes significantly in reducing cardiovascular disease (CVD) risk factors including lowering cholesterol and atherosclerosis. The purpose of this study was to investigate the effects of flaxseed, a rich source of lignans, alpha-linolenic acid and soluble fiber mucilage, on the prevention of ovariectomy-induced rise in total cholesterol and atherosclerotic lesions., Methods: Seventy-two 6-month-old female Golden Syrian hamsters were either ovariectomized (ovx) or sham-operated (sham) and randomly assigned to six groups (n = 12): sham, ovx, or ovx plus either 17beta-estradiol (E(2), 10 microg/kg body weight) or semi-purified diet adjusted for macronutrients and fiber to contain one of the three doses of flaxseed (7.5, 15, or 22.5%) for 120 days., Results: Ovariectomy significantly elevated plasma total-, HDL-, and free-cholesterol concentrations. Similar to estrogen, all doses of flaxseed were effective in preventing the ovx-induced rise in plasma total cholesterol. Triglyceride concentrations were significantly higher in the flax-fed hamsters. There were no significant differences in plasma non-HDL- and esterified-cholesterol among the treatment groups. Ovariectomy also increased the number of hamsters with lesions and the aortic fatty streak area. All three doses of flaxseed reduced the fatty streak area and the incidence of lesions to levels similar to the sham group., Conclusion: The findings of this study show that flaxseed is beneficial in reducing plasma cholesterol and plaque formation induced by ovarian hormone deficiency.

Recent reports indicate that ovariectomy (ovx) increases lymphopoiesis. Ipriflavone, a synthetic isoflavone, has been reported to reduce lymphocytes in postmenopausal women. The aim of this study was to investigate whether naturally occurring isoflavones also affect lymphopoiesis in ovarian hormone deficiency. The present study was carried out using an ovariectomized (ovx) rat model. To mimic early menopause, forty-eight 12-month-old Sprague-Dawley rats were either sham-operated (sham; 1 group) or ovx (3 groups) and were fed a standard semi-purified diet for 120 days. Thereafter, the ovx groups received one of the three doses of isoflavones: 0 (ovx), 500 (ISO500), or 1000 (ISO1000) mg/kg diet for 100 days. Ovariectomy increased total leukocyte counts significantly (p < 0.05) as a result of increased (p < 0.05) lymphocyte, monocyte, eosinophil, and basophil differential counts. Isoflavones at 500 and 1000 mg/kg diet returned the total leukocyte counts, as well as leukocyte subpopulations, to levels comparable to that of sham-operated rats. No other hematological parameters, e.g., red blood cell counts or red cell indices, were affected by ovariectomy or isoflavones. We conclude that soy isoflavones restore normal leukocyte counts elevated in ovarian hormone deficiency.

Hereditary periodic fever syndromes comprise a group of distinct disease entities linked by the defining feature of recurrent febrile episodes. Hyper IgD with periodic fever syndrome (HIDS) is caused by mutations in the mevalonate kinase (MVK) gene. The mechanisms by which defects in the MVK gene cause febrile episodes are unclear and there is no uniformly effective treatment. Mutations of the TNFRSF1A gene may also cause periodic fever syndrome (TRAPS). Treatment with the TNFR-Fc fusion protein, etanercept, is effective in some patients with TRAPS, but its clinical usefulness in HIDS has not been reported. We describe a 3-year-old boy in whom genetic screening revealed a rare combination of two MVK mutations producing clinical HIDS as well as a TNFRSF1A P46L variant present in about 1% of the population. In vitro functional assays demonstrated reduced receptor shedding in proband's monocytes. The proband therefore appears to have a novel clinical entity combining Hyper IgD syndrome with defective TNFRSF1A homeostasis, which is partially responsive to etanercept.

Over the last few years, the importance of apoptosis in determining the fate of thyrocytes in autoimmune thyroid disease has been the topic of intense investigation. It is now clear that thyrocytes from patients with Hashimoto's thyroiditis are destroyed as a result of an apoptotic process. However, there is no general consensus on whether the intrathyroidal lymphocytes or the thyrocytes themselves are responsible for their death. The use of a wide range of techniques has contributed to the assessment of this process both in situ on thyroid sections and in vitro on thyroid cell preparations. The apoptosis field of research is rapidly evolving and as the pathways to cell death become unravelled, novel methods will emerge. As each technique offers some advantage, it is critical to know the most suitable method for a specific study. Equally, each method also has intrinsic limitations. Thus, to achieve reliable results, it is necessary to use more than one technique per study. In addition, techniques related to the measurement of the expression of pro-apoptotic and anti-apoptotic genes have been contributing to the study of the susceptibility of the cells to apoptosis and/or to their ability to kill themselves or neighbouring cells. In this review we will focus on the most relevant techniques.

The risk of cardiovascular disease and osteoporosis drastically increases at the onset of menopause. Phytoestrogens have been suggested to inhibit bone loss and protect the cardiovascular system, in part by improving lipid profiles. The purpose of the present study was to examine the effects of flaxseed, a rich source of the phytoestrogens called lignans, on lipid metabolism and biomarkers of bone turnover in postmenopausal women. Postmenopausal women who were not on hormone replacement therapy were assigned to one of two treatment groups in a double-blind randomized study. Women were asked to consume 40 g of either ground flaxseed or wheat-based comparative control regimen daily for 3 months. In addition, all subjects received 1,000 mg calcium and 400 IU vitamin D daily. Flaxseed supplementation lowered (P < 0.05) both serum total cholesterol and non-high-density lipoprotein cholesterol by 6%, whereas the comparative control regimen had no such effect. Flaxseed regimen reduced serum levels of both low-density- and high-density-lipoprotein cholesterol by 4.7% and triglyceride by 12.8%, albeit not statistically significant. Serum apolipoprotein A-1 and apolipoprotein B concentrations were significantly (P < 0.005) reduced by 6 and 7.5%, respectively, by the flaxseed regimen. Markers of bone formation and resorption were not affected by either of the treatments. The findings of this study indicate that flaxseed supplementation improves lipid profiles but has no effect on biomarkers of bone metabolism in postmenopausal women.

In Hashimoto's thyroiditis, thyrocytes die by apoptosis. Whether this is the result of impaired antiapoptotic gene expression or hyperexpression of proapoptotic signals or other mechanisms is not fully established. Following the suggestion that thyrocytes from Hashimoto's glands die by a fratricidal killing mediated by Fas/Fas ligand, we have investigated whether thyroid cells from different clinical conditions are able to kill Fas-expressing target cells. We have studied whether this effector ability was mediated by Fas/Fas ligand, perforin or other death receptors/ligands, i.e., tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R). We have confirmed that thyroid preparations can kill Fas-expressing HUT78 targets through apoptosis. Cell death was only partially dependent on Fas/Fas ligand but it was trypsin-sensitive. Blocking perforin did not affect Fas-expressing target killing while caspase inhibitors had a consistent although limited effect. Thyroid cells were not sensitive to TRAIL/TRAIL-R. We have also found that both thyrocytes and lymphocytes from Graves' disease thyroids were effective at killing autologous and heterologous Fas-expressing targets. Conversely, killing of these targets could be shown only with lymphocytes (but not with thyrocytes) from Hashimoto's glands. In Hashimoto's thyroiditis, thyrocytes were poorly functional while lymphocytes were able to operate as effectors. It is envisaged that thyrocyte death in Hashimoto's would result from autologous thyrocyte killing perpetrated by lymphocytes. Death receptors/ligands would appear to play a role. However, a caspase-independent mechanism may also coexist and contribute to cell death in Hashimoto's thyroiditis.

Programmed cell death or apoptosis is central both in physiology during development and in disease. The mechanism of apoptosis is under the control of antiapoptotic survival genes of the Bcl-2 family and proapoptotic death receptors of the TNF superfamily (Fas, TNFR, TRAILR). Following death signal, the death receptor binds to its own receptor and initiates, through binding of adaptors, a cascade of events mediated by the autoproteolytic activation of specific enzymes called caspases. This enzyme activation is ultimately responsible for the dissembly of basic nuclear and cytoplasmic cell structures leading to cell death. In certain cell systems, antiapoptotic genes of the Bcl-2 family prevent the proapoptotic pathway. One of their roles is to maintain mitochondrial function integrity. In autoimmune destructive thyroiditis high levels of apoptosis have been demonstrated particularly within the destructed follicles near the infiltrated areas in comparison to Graves' disease and non autoimmune glands. In Hashimoto's thyroiditis Fas expression has been found increased on thyrocytes and in vitro can be modulated by proinflammatory cytokines. FasL expression on thyrocytes remains controversial. Thyroid cells from Graves' disease and multinodular glands are known to kill Fas expressing target cells although Hashimoto's thyrocytes are not efficient effector cells. Intrathyroidal lymphocytes from Hashimoto's thyroids maintain functional killer activity. These findings would suggest that intrathyroidal lymphocytes could be responsible for thyrocyte death in vivo. Whether this mechanism is Fas/FasL, TRAIL/TRAILR dependent can not be confirmed as specific blocking reagents were not able to inhibit cell induced death. In Hashimoto's thyroiditis an impairment of Bcl-2 and Bcl-X anitapoptotic genes on thyrocytes has also been detected. Bcl-X expression can be down-regulated in vitro by incubation with cytokines. These findings suggest that thyrocyte death may not exclusively be the result of specific interactions between death receptor and their ligands but it may involve simultaneous impairment of protective genes of the Bcl-2 family. Whether the impairment of the Bcl-2 family is a direct consequence of environmental stimuli or is the result of an intrinsic thyrocyte (mitochondrial?) alteration is as yet not known.

The effects of ethanol on conditioned freezing, a species-specific defensive behavior used as an assay of fear, was examined in mice. In Experiment 1, ethanol, 1.2 g/kg, significantly increased freezing compared to a saline control when the mice were reexposed to a context in which they were previously shocked. Experiment 2, which administered ethanol or saline to no-shock control animals, demonstrated that the potentiated freezing produced by ethanol in Experiment 1 was specific to the interaction of ethanol and the stress response. These results suggest that both the qualitative and quantitative dimensions of the environmental stressor, as well as the dose of ethanol used, may be critical for determining ethanol's effect on a stress response.

The level of apoptosis has been investigated in thyroid tissue from eight patients with Graves's disease, one with Hashitoxicosis, three with Hashimoto's thyroiditis, and five patients with multinodular goitre, using flow cytometry and an in situ immunofluorescence technique. Cryostat sections have also been studied for Bcl-2 and APO-1/Fas expression in the thyrocytes and infiltrating lymphocytes, to determine their susceptibility to apoptosis. An increased level of apoptosis was detected in Hashimoto's glands. This was associated with decreased Bcl-2 staining and a patchy APO-1/Fas reactivity on thyrocytes. In addition, APO-1/Fas expression was noted within the germinal centres of lymphoid follicles. It is suggested that the dysregulation of apoptosis-related genes could be an important factor in the progression of destructive thyroid autoimmune disease.

A major pre-beta-amyloid protein695 (APP695) processing activity from Alzheimer's disease brain extracts was identified and found to be indistinguishable from the activity of cathepsin D.APP695 processing activity cleaved APP695 into a series of fragments that reacted on immunoblots to a monoclonal antibody (C286.8a) against beta-amyloid-(1-7)-peptide and cleaved N-dansyl-APP-(591-601)-amide at the Glu-Val and Met-Asp bonds. Fragments of 5.5 kDa and 10-12 kDa were formed from the cleavage of APP695 by cathepsin D at the Glu593-Val594 bond, and had the same N-terminus as a minor form of beta-amyloid released by cells. The Lys595-->Asn and Met596-->Leu substitutions found in a pedigree of familial Alzheimer's disease, increased the cathepsin D-catalyzed rate of accumulation of 5.5 kDa and 10-12 kDa C286.8a-reactive fragments 5-10fold. This substitution also increased the rate of N-dansyl-APP-(591-601)-amide cleavage at the Xaa-Asp bond by up to 41-fold. These observations suggest a role of cathepsin D in beta-amyloid formation under certain circumstances.

Certain precursor proteins (APP751 and APP770) of the amyloid beta-protein (AP) present in Alzheimer's disease contain a Kunitz-type serine protease inhibitor domain (APPI). In this study, the domain is obtained as a functional inhibitor through both recombinant (APPIr) and synthetic (APPIs) methodologies, and the solution structure of APPI is determined by 1H 2D NMR techniques. Complete sequence-specific resonance assignments (except for P13 and G37 NH) for both APPIr and APPIs are achieved using standard procedures. Ambiguities arising from degeneracies in the NMR resonances are resolved by varying sample conditions. Qualitative interpretation of short- and long-range NOEs reveals secondary structural features similar to those extensively documented by NMR for bovine pancreatic trypsin inhibitor (BPTI). A more rigorous interpretation of the NOESY spectra yields NOE-derived interresidue distance restraints which are used in conjunction with dynamic simulated annealing to generate a family of APPI structures. Within this family, the beta-sheet and helical regions are in good agreement with the crystal structure of BPTI, whereas portions of the protease-binding loops deviate from those in BPTI. These deviations are consistent with those recently described in the crystal structure of APPI (Hynes et al., 1990). Also supported in the NMR study is the hydrophobic patch in the protease-binding domain created by side chain-side chain NOE contacts between M17 and F34. In addition, the NMR spectra indicate that the rotation of the W21 ring in APPI is hindered, unlike Y21 in BPTI, showing a greater than 90% preference for one orientation in the hydrophobic groove.

The survival rate of patients with cystic fibrosis has improved considerably in the last 20 years. Although not all of the factors accounting for this change are understood, aggressive nutritional management and treatment of pulmonary exacerbations certainly play a role. Home intravenous (IV) antibiotic delivery for pulmonary exacerbation has proved to be as effective as hospital treatment and offers significant advantages to the patient and family. This article examines the microbiology of pulmonary infections in patients with cystic fibrosis, as well as antimicrobial therapy, methods of IV administration, home IV therapy, and the nurse practitioner's role in this home program in the future.

Venous access in acute and chronically ill patients can become problematic when attempting to maintain a reliable system. The need for safe and dependable intravascular systems has become quite evident. This article examines the Port-A-Cath (Pharmacia, Inc., St. Paul, MN) and the Per-Q-Cath (Gesco International, Inc., San Antonio, TX). These systems are preferred by several patient populations who require frequent or prolonged intravenous therapy.

Inappropriate expression of HLA class II molecules by human thyroid epithelial cells (thyrocytes) is commonly associated with autoimmune thyroid disease. HLA class II expression can be modulated in thyrocytes in vitro by a variety of substances: in particular, it is readily induced by interferon-gamma (IFN-gamma). Here we show that recombinant IFN-alpha 1 (rIFN-alpha 1) does not induce HLA class II expression by thyrocytes, but rather it suppresses the induction of such expression by rIFN-gamma. Similar effects were observed with IFN-alpha derived from a lymphoblastoid cell line. The effect of rIFN-alpha 1 on thyrocytes differs from its effect on human monocytes, reported by others, in which it was found to enhance the expression of HLA class II. Thus, rIFN-alpha 1 appears to have a differential effect on HLA class II expression, depending on the cell type involved.

Inappropriate expression of HLA class II by human thyroid epithelial cells (thyrocytes) occurs in autoimmune thyroid diseases where it may contribute to the pathogenesis. Several substances have been found to induce or up-regulate thyrocyte HLA class II expression in vitro. The present investigations show that the induction of HLA class II in human thyrocytes cultured with interferon (IFN)-gamma can be partially suppressed by exposure of the thyrocytes to epidermal growth factor (EGF): this occurs when the thyrocytes are treated with the two reagents simultaneously and also when the exposure to EGF is before or after that with IFN-gamma. Concentrations of EGF at least as low as 0.1 ng/ml show this inhibitory effect, which can be over-ridden by very high concentrations of IFN-gamma. Thyrocyte HLA class II expression stimulated by thyroid-stimulating hormone (TSH) (in the presence or absence of IFN-gamma) is also suppressed by EGF. Transforming growth factor-alpha (TGF alpha), which is structurally related to EGF and interacts with the same cell surface receptor, has a similar inhibitory activity on the induction of thyrocyte HLA class II expression. The existence of substances which can down-regulate, as well as those which can up-regulate, thyrocyte HLA class II expression raises the possibility that the occurrence of such expression in vivo may be determined by the balance between factors with opposing modulatory effects.

Reducing equivalents derived from the tissue re-oxidation of NADPH (NADPH-diaphorase) have been implicated in the peroxidation that is involved in the organification of iodine in the production of thyroid hormones. Immunoglobulin (Ig) fractions from patients with thyroid diseases and from normal controls, in a standard dose of 125 micrograms/ml and 0.3 microunits/ml thyrotrophin (TSH) were incubated with segments of guinea-pig thyroid gland maintained in vitro. A quantitative cytochemical study was made on how these fractions influenced the enzyme activity. A good correlation was found between the ability of such Ig fractions to stimulate the NADPH-diaphorase activity and (1) the degree of hyperthyroidism in the patients and (2) the amount of T3 secreted by the thyroid segments in vitro.

The problem of maintaining independence between response rates and reinforcement probabilities when determining the effect of varying the response-reinforcement contingency upon free-operant behavior was solved by programming local reinforcement probabilities for response and no response on a second-by-second basis. Fifty-seven rats were trained to lever-press on schedules of water reinforcement involving different values of contingency. All rats were first trained on a high positive contingency and then shifted to less positive, zero, or negative contingencies. Under these conditions, rate of lever-pressing declined appropriately when the contingency between response and reinforcement decreased or was made negative. The decline in rate produced by a zero contingency cannot be attributed to extinction, since the probability of reinforcement given the occurrence of a response was the same as for the positive contingency from which the shift to zero was made. That is, there was no change in the opportunity for response-reinforcement contiguity. It was concluded that the technique of programming local reinforcement probabilities offers promise for more critical examinations of the effects of contingency upon free-operant behavior.

A new bioassay is described for detecting the growth stimulating immunoglobulins (TGI) that contribute to goitre formation in human thyroid autoimmune diseases. It measures the incorporation of tritiated thymidine into intact rat thyroid follicles grown in tissue culture. This radiometric assay demands much less technical skill than the cytochemical bioassays (CBA) previously employed. It has good reproducibility and the techniques and apparatus are available in many clinical laboratories. Immunoglobulins (Igs) from 68% of patients with goitrous Graves' disease were positive, in proportion with goitre size, and this showed no correlation with T3 levels, or three accepted methods for conventional thyroid stimulating antibodies. Non-toxic nodular goitre cases gave positive results in 3/9 who had recurrences after one or more thyroidectomies and in 1/10 cases of familial simple goitre. All normal subjects and all endemic goitre cases were negative as well as 21 cases of sporadic non-toxic nodular goitre. Although it is less sensitive than the 'growth CBA' it clearly emphasizes the essential difference between the intensity of growth stimulus which leads to the regular hyperplasia of thyroid epithelium seen in Graves' thyrotoxicosis and the disorganized and metabolically uncoordinated hyperplasia typical of non-toxic nodular goitre.

We recently showed that human thyroid epithelial cells, which are normally negative for HLA-DR molecules, express HLA-DR in thyroid autoimmunity. Furthermore, induction of HLA-DR on normal thyroid cells can be achieved by culture with plant lectins. We have now found that recombinant human interferon-gamma (IFN-gamma) induces expression of HLA-DR molecules on cultured human thyroid cells, whereas Namalva IFN-alpha, recombinant IFN-beta or recombinant interleukin-2 (IL-2) do not. All three IFN, but not IL-2, enhanced thyroid cell HLA-A,B,C expression. The results strongly implicate T cells (which are the source of IFN-gamma) in the aberrant induction of DR on thyroid epithelial cells which is proposed to be a central feature of the immunopathological processes leading to autoimmunity.

Human thyroid epithelial cells (thyrocytes) express HLA Class II molecules in autoimmune thyroid diseases (ATD). Normal thyrocytes do not express Class II, but can be induced to do so by culture with interferon-gamma (gamma-IFN). We have examined HLA-D subregion expression in sections and monolayers of thyroid by indirect immunofluorescence using appropriate monoclonal antibodies. The results indicate that, in ATD, the incidence and intensity of Class II subregion expression by thyrocytes varies between patients, and follows the pattern DR greater than DP greater than DQ. The same hierarchy is observed in cultured normal thyrocytes treated with gamma-IFN: strong induction of Class II, and of DP and DQ in particular, requires relatively high concentrations of gamma-IFN or additional factors such as thyroid stimulating hormone. These findings suggest that HLA-D subregion expression by thyrocytes in on-going ATD is determined by the levels of disease related factors in the affected tissue.

It has been shown previously that both thyrotrophin (TSH), and also immunoglobulins (Ig) derived from patients with goitrous Graves' disease, stimulate DNA-synthesis in guinea-pig thyroid tissue maintained in vitro. Here we describe the use of the same in vitro system and methods of quantitative cytochemistry to test the effect of these substances on the generation of NADPH, which is another indicator of the potential for growth. As could be predicted by its trophic action, TSH stimulated the generation of NADPH by glucose 6-phosphate dehydrogenase. The Ig-fraction from normal subjects depressed this activity. The Ig-fraction from Graves' disease patients with goitres stimulated the generation of NADPH, whereas the Ig from patients with Graves' disease but with minimal enlargement of the thyroid gland behaved like normal Ig. A similar lack of stimulation was found with Ig from patients with Pendred's syndrome, other dyshormonogenetic goitres, and autonomous single adenomas. In all specimens tested, there was good correlation between the amount of DNA-synthesis, measured by Feulgen cytophotometry, and the activity of glucose 6-phosphate dehydrogenase activity that generated NADPH. These results support the concept that there is a distinct type of autoantibody that influences thyroid growth.

HLA Class II molecules are expressed by human thyroid epithelial cells (thyrocytes) in thyroid autoimmunity, although these cells are normally Class II-. gamma-Interferon (gamma-IFN) is probably involved in this expression, as suggested by its ability to induce Class II in cultured normal thyrocytes. We have now found that thyroid stimulating hormone (TSH) enhances Class II expression induced in cultured thyrocytes by gamma-IFN, and effects similar to those of TSH were obtained with dibutyryl cyclic AMP. A proportion of thyrocytes also expressed Class II following treatment with TSH or dibutyryl cyclic AMP in the absence of gamma-IFN, but the optimal activity of these mediators then appeared to be dependent upon the occurrence of some pre-existing Class II expression. These findings give insights into how a variety of mediators may influence Class II expression in thyroid autoimmunity.

Several experiments have found complete retention of conditioned suppression when overall suppression to the signal for shock was measured. The present experiment examined retention of conditioned suppression but did so with a paradigm that produced temporal discrimination of shock occurrence. Nine rats were exposed to a flashing light signal of 5-min duration that always terminated with a shock. After several months, a temporal discrimination was well established, as shown by maximum suppression toward the end of the signal period. After remaining in the home cage for 25 days, the rats were again subjected to the conditioning procedure. The overall level of suppression remained the same but the temporal discrimination was not observed.