Thyroid cancer surgery guidelines in an era of de-escalation.

Well-differentiated thyroid carcinoma has seen a tremendous rise in global incidence over the past three decades, largely owing to widespread screening and identification of small, incidentally detected tumors. With this increased incidence has emerged a movement questioning whether all cases of thyroid cancer merit a treatment approach focused on oncologic completeness. Such trends towards thoughtful, evidence-based treatment de-escalation paradigms reflect better risk stratification of thyroid cancers, and recognition that not all detected disease poses a threat to health or survival. Thus, national and professional guidelines are evolving to incorporate higher thresholds for surgery, acceptance of less than total thyroidectomy in specific circumstances, higher thresholds for adjuvant therapy, and introduction of the role of active surveillance for selected cases of low risk disease. Despite these common themes, there are significant differences among guidelines. This lack of consensus in guidelines persists due to variation in clinical practice patterns, differences in consideration and interpretation of existing evidence, cultural and geographical considerations, and resources available for both diagnosis and treatment.

Designing fluoroquinolone breakpoints for Streptococcus pneumoniae by using genetics instead of pharmacokinetics-pharmacodynamics.

We determined fluoroquinolone microbiological resistance breakpoints for Streptococcus pneumoniae by using genetic instead of pharmacokinetic-pharmacodynamic parameters. The proposed microbiological breakpoints define resistance as the MIC at which >50% of the isolates carry quinolone resistance-determining region mutations and/or, if data are available, when Monte Carlo simulations demonstrate a <90% chance of bacteriological eradication. The proposed microbiological resistant breakpoints are as follows (in micrograms per milliliter): gatifloxacin, >0.25; gemifloxacin, >0.03; levofloxacin, >1; and moxifloxacin, >0.12. Monte Carlo simulations of the once daily 400-mg doses of gatifloxacin and 750-mg doses levofloxacin demonstrated a high level of target attainment (free-drug area under the concentration-time curve from 0 to 24 h/MIC ratio of 30) by using these new genetically derived breakpoints.

Neuregulin in neuron/glial interactions in the central nervous system. GGF2 diminishes autoimmune demyelination, promotes oligodendrocyte progenitor expansion, and enhances remyelination.

Glial growth factor 2 (GGF2) is a neuronal signal that promotes the proliferation and survival of the oligodendrocyte, the myelinating cell of the central nervous system (CNS). This study has focused on recombinant human GGF2 (rhGGF2) and it's potential to affect clinical recovery and repair to damaged myelin in chronic relapsing experimental autoimmune encephalomyelitis (EAE) in the mouse, a major animal model for the human demyelinating disease, multiple sclerosis (MS). Mice with EAE were treated with rhGGF2 during both the acute and relapsing phases, and GGF2 treatment led to delayed signs, decreased severity and resulted in statistically significant reductions in relapse rate. Further, rhGGF2-treated groups displayed CNS lesions with more remyelination than in controls. This correlated with increased expression of myelin basic protein exon 2, a marker for remyelination, and with an increase of the regulatory cytokine, IL-10. Thus, a beneficial effect of a neurotrophic growth factor has been demonstrated upon the clinical, pathologic and molecular manifestations of autoimmune demyelination, an effect that was associated with increased expression of a Th2 cytokine. rhGGF2 treatment may represent a novel approach to the treatment of MS (Cannella et al., 1998).

The neuregulin, glial growth factor 2, diminishes autoimmune demyelination and enhances remyelination in a chronic relapsing model for multiple sclerosis.

Glial growth factor 2 (GGF2) is a neuronal signal that promotes the proliferation and survival of the oligodendrocyte, the myelinating cell of the central nervous system (CNS). The present study examined whether recombinant human GGF2 (rhGGF2) could effect clinical recovery and repair to damaged myelin in chronic relapsing experimental autoimmune encephalomyelitis (EAE) in the mouse, a major animal model for the human demyelinating disease, multiple sclerosis. Mice with EAE were treated with rhGGF2 during both the acute and relapsing phases. Clinically, GGF2 treatment delayed signs, decreased severity, and resulted in statistically significant reductions in relapse rate. rhGGF2-treated groups displayed CNS lesions with more remyelination than in controls. This correlated with increased mRNA expression of myelin basic protein exon 2, a marker for remyelination, and with an increase in the CNS of the regulatory cytokine, interleukin 10, at both the RNA and protein levels. Thus, a beneficial effect of a neurotrophic growth factor has been demonstrated on the clinical, pathologic, and molecular manifestations of autoimmune demyelination, an effect that was associated with increased expression of a T helper 2 cytokine. rhGGF2 treatment may represent a novel approach to the treatment of multiple sclerosis.

Expression of Na-K-ATPase alpha- and beta-subunit mRNA and protein isoforms in the rat nephron.

Na-K-ATPase is a heterodimeric complex composed of an alpha-catalytic and a glycosylated beta-subunit. Previous studies using in situ hybridization and Northern blot analysis to determine alpha- and beta-subunit mRNA isoform expression in the rat kidney have given conflicting results. This heterogeneity may be due to detection of alpha 2- or alpha 3-isoforms arising from nonrenal epithelial sources such as peripheral nerves or vascular smooth muscle. To address this possibility, we investigated alpha-subunit mRNA isoform expression in different nephron segments using tubule microdissection and reverse transcription-polymerase chain reaction amplification. Southern blot analysis of polymerase chain reaction products using isoform-specific primers and probes detected the expression of alpha 1- and alpha 3-mRNA isoforms in whole kidney, cortical collecting ducts (CCD), and proximal tubule S2 subsegments (S2). No evidence for alpha 2 was found in kidney or microdissected CCD or S2. To determine whether alpha 1- or alpha 3-mRNA in the CCD or S2 is translated into protein, Western blot analysis of total protein from microdissected S2, CCD, medullary thick ascending limb (MTAL), or outer medullary collecting duct outer stripe (OMCDos) was performed. Total protein was separated according to size by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, then probed using polyclonal antibodies specific for the alpha 1-, alpha 2-, alpha 3-, beta 1-, and beta 2-protein isoforms. Rat brain was used as a positive control and demonstrated that the antibodies could detect a single 97- and 35-kDa band for the alpha- and beta-isoforms, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

The SIF binding element confers sis/PDGF inducibility onto the c-fos promoter.

The c-fos proto-oncogene is rapidly and transiently induced by a variety of extracellular stimuli. We have previously shown that conditioned media from v-sis transformed NRK cells rapidly induces a DNA binding protein which binds to a conserved sequence upstream of the human c-fos gene. We now show that purified recombinant c-sis/PDGF can induce this binding activity which we have termed SIF, for sis-inducible factor. Oligonucleotides which bind to the SIF protein will confer sis/PDGF inducibility onto a truncated, unresponsive c-fos promoter. However, sequences lying between -100 and -57 of the c-fos gene are required for this induction. The sis-responsive element functions independently of a region of dyad symmetry previously identified as the serum responsive element (SRE). The time course of c-fos expression driven by the sis-responsive element is similar to that mediated by the SRE. Unlike the SRE, which can respond to signals generated by sis/PDGF, serum or phorbol esters, the SIF binding element mediates c-fos induction only in response to sis/PDGF. The SRE and SIF elements function in an additive manner to stimulate the transcription of the c-fos gene in response to sis/PDGF.

Glucose tolerance testing in women with premenstrual syndrome.

Glucose tolerance tests (GTTs) were administered to 11 women with premenstrual syndrome (PMS) to ascertain whether the patients had abnormalities of glucose tolerance, to determine whether such abnormalities were related to menstrual cycle phase, and to compare the symptoms during the GTT with the PMS symptoms experienced in the luteal phase. Two GTTs were performed for each patient, one during the late follicular phase and one during the late luteal phase. Although many patients experienced symptoms of hypoglycemia during the GTT, the hypoglycemia symptoms were not specific to the luteal phase and did not resemble the patients' PMS symptoms.

Increased IgG secretion by unstimulated mononuclear cells in active multiple sclerosis and functional assessment of the T8 subset.

Unseparated mononuclear cells (10(5) cells/well) were cultured both in the presence and absence of pokeweed mitogen (PWM), and IgG secretion was measured by radioimmunoassay. In unstimulated cultures, levels of IgG secretion were found to be higher in a group of patients with multiple sclerosis (MS) than in control groups of healthy individuals or patients with other neurologic diseases (OND). By contrast, PWM-induced IgG secretion was similar in MS patients and in controls. In MS patients, levels of IgG secretion greater than 2500 ng/ml in unstimulated cultures were present in 29 (58%) of 50 patients with active disease and in only 3 (14%) of 21 patients with inactive MS (P less than 0.01; MS active vs inactive). Furthermore, levels of IgG secretion in unstimulated cultures were higher in patients who had abnormalities of circulating T-cell subsets consisting of reduced numbers of suppressor/cytotoxic (T8) cells and elevated helper:suppressor (T4:T8) ratios. In additional experiments using isolated populations of T-cell subsets, T8 cells from MS patients who had low percentages of circulating T8 cells were found to suppress PWM-induced IgG secretion by autologous cells to a similar extent as controls, suggesting that in vitro, T8 cells function normally in these patients. In vitro IgG secretion by unstimulated mononuclear cells in MS appears to be a further reflection of abnormal immune regulation in this disease.

Premenstrual syndromes: past and future research strategies.

Premenstrual Syndrome remains a poorly understood controversial disorder largely because of the errors in design found in research into this subject. The first task is to clearly define the entity to be studied. It is necessary to look at the nature, intensity and time of occurrence of symptoms in relation to menstruation. One must further differentiate the appearance of symptoms premenstrually from the premenstrual exacerbation of symptoms present throughout the menstrual cycle. Research has clearly shown the superiority of prospective versus retrospective data in establishing a linkage between symptoms and menstruation. Premenstrual Syndrome research offers a unique opportunity to study classical psychiatric disorders. A relationship appears to exist between this syndrome and major affective disorders. Studies of the appearance or exacerbation of mood disturbances in relation to the menstrual cycle may inform us about the development, course and vicissitudes of psychiatric illness.

Platelet-derived growth factor stimulates rapid polyphosphoinositide breakdown in fetal human fibroblasts.

The addition of human platelet-derived growth factor (PDGF) to confluent, quiescent cultures of human diploid fibroblasts induced the rapid breakdown of cellular polyphosphoinositides. The levels of 32P-labeled phosphatidylinositol 4,5-bisphosphate (PIP2), phosphatidylinositol 4-phosphate (PIP), and phosphatidylinositol (PI) decreased by 30 to 40% within 1 min after exposure of the cells to PDGF. The levels of PIP and PIP2 returned to their initial values within 3 and 10 min, respectively, after PDGF addition. The level of PI continued to increase after it had returned to control values and was up threefold within 30 min after PDGF addition. In cells prelabeled with myo-[3H]inositol PDGF caused an eightfold increase in the levels of inositol trisphosphate (IP3) within 2 min. Lesser increases, twofold and 1.3-fold, respectively, were seen in levels of inositol bisphosphate (IP2) and inositol monophosphate (IP). Within 10 min after PDGF addition the levels of all three inositol phosphates had decreased to control values. The levels of IP3 measured 2 min after PDGF addition depended on the PDGF concentration and were maximal at 5-10 ng/ml of PDGF. Similar concentrations of PDGF stimulate maximal cell growth and DNA synthesis in these cells.

Immunohistochemical staining of human brain with monoclonal antibodies that identify lymphocytes, monocytes, and the Ia antigen.

Using immunoperoxidase histochemistry, human brain sections obtained at biopsy were labeled with monoclonal antibodies which identify human lymphocyte subsets, monocytes, and the Ia antigen. Staining of a population of cells in white matter was present with the anti-Ia and the anti-M1 (monocyte-associated) antibodies but not with any of the 8 monoclonal antibodies which react with human T-cell subsets (anti-T1, 3, 4, 5, 6, 8, 10 and 12). The Ia antigen was present on 1-2% of cells in white matter, and approximately 5% of cells in white matter were M1-positive. Ia-positive cells demonstrated a pattern of diffuse surface membrane staining, whereas the M1 antigen appeared to cluster at proximal cell processes. Definitive identification of these cells as microglial cells, astrocytes or oligodendrocytes was not possible. These findings demonstrate that: (1) cells which bear the Ia and M1 determinants can be found in histologically normal human white matter, and (2) human oligodendrocytes do not react with monoclonal antibodies (anti-T5 and anti-T8) that identify human suppressor/cytotoxic cells.

Epinephrine-induced changes in the distribution of lymphocyte subsets in peripheral blood of humans.

We have previously demonstrated that mitogen responsiveness of mononuclear cells (MNC) from peripheral blood is reduced after a single injection of epinephrine to human subjects. The purpose of the present study was to characterize the relative distributions of MNC subsets after epinephrine administration using monoclonal antibodies and conventional cell markers. The absolute number of circulating MNC increased 64% within 30 min after injection of epinephrine, and returned to baseline by 2 hr. Analysis of MNC subsets revealed that there were no changes in the relative percentages of total T lymphocytes [T3+ cells, or neuraminidase-treated sheep red blood cell rosettes (EN-rosettes)], B lymphocytes (B1+, or cells with surface-bound immunoglobulin), or monocytes (by morphologic criteria) after epinephrine administration. The percentage of inducer T cells (T4+) declined at 30 and 60 min postinjection. Overall, the percentage of suppressor/cytotoxic T cells (T8+) did not change after injection of epinephrine; however, analysis of individual subjects revealed opposing responses of this subset. The T4:T8 ratio was 2.19 before injection, declined to 1.56 at 60 min, then increased to 3.10 2 hr postinjection. The percentage of natural killer/killer cells (HNK-1+) increased from a baseline of 15.5% before epinephrine injection to 29.6% at 30 min postinjection, then declined to 11.4% at 2 hr. Therefore, the administration of physiologic doses of epinephrine results in changes in the relative proportions of lymphocyte subsets in peripheral blood, in addition to reduced mitogen responsiveness as reported previously.

CSF cells in multiple sclerosis: monoclonal antibody analysis and relationship to peripheral blood T-cell subsets.

Mononuclear cells were analyzed in CSF and blood of 102 patients with MS. In CSF, the majority (78%) of cells were T lymphocytes (T3+), and the ratio of inducer (T4+) to suppressor/cytotoxic (T8+) cells was 2:1. No characteristic alterations in CSF phenotypes could be related to changes in circulating T8 cells or to disease activity. In a group of 75 patients, CSF cell count was higher in patients with low numbers of circulating T8 cells than in those with normal T8 cells. Thus, decreases in suppressor cells in the blood of MS patients are associated with CSF pleocytosis but not with fluctuations in the ratio of different subsets in CSF. Furthermore, large numbers of T8 cells are not sequestered in CSF when these cells are decreased in peripheral blood.

Immunoregulatory T-cells and lymphocytotoxic antibodies in active multiple sclerosis: weekly analysis over a six-month period.

Immunoregulatory T-cell subsets were measured at weekly intervals over a 4 to 6 month period using monoclonal antibodies (anti-T4 = inducer cell; anti-T8 = suppressor/cytotoxic cell) in a group of 6 patients with multiple sclerosis (MS) and in 4 age- and sex-matched controls. Decreases in the T8 subset and increases in the T4:T8 ratio were present in 4 of the patients with MS but not in controls. Two patients who were neurologically stable during the study period had no changes in the T4:T8 ratio; 2 patients with intermediate disease activity of the relapsing-remitting type had elevated ratios on 3 and 4 occasions respectively; the patient with the most clinically active MS had an abnormal ratio 12 of 27 times. One patient with chronic-progressive MS had an elevated ratio on each occasion tested. No abnormalities in T-cell subsets were present in any of the controls. On three occasions an elevated T4:T8 ratio appeared to precede an acute relapse by 1.5 to 7 days. Lymphocytotoxic antibodies (LCA) against whole lymphocytes or against isolated T-cell subsets were measured in these patients and in a larger group of MS patients, and were not found to correlate with changes in T-cell subsets. This report extends previous findings linking changes in T-cell subsets to disease activity in patients with MS.

Social activity and drinking patterns.

This paper reports data on the relationship between social activity and daily alcohol consumption in a random sample of adults in metropolitan Boston. The findings indicate that the frequency of going to bars and attending parties was significantly related to daily alcohol consumption.