Expression patterns of the immune checkpoint ligand CD276 in urothelial carcinoma.

BACKGROUND: CD276 is an immune checkpoint molecule. Elevated CD276 expression by urothelial carcinoma is associated with poor prognosis, but little is known about its expression across different tumor stages. We therefore investigated CD276 expression in bladder cancer (BC) cells and in tissue samples of BC stages from pT2 to pT4. METHODS: CD276 expression was explored in 4 urothelial cancer cell lines and 4 primary normal urothelial cell populations by quantitative RT-PCR, Western blot and flow cytometry. CD276 was investigated in bladder tumors from 98 patients by immunohistochemistry using a score (0-300) incorporating both, staining intensity and area of CD276 staining. Normal appearing urothelium in the bladder of the same patients served as controls. RESULTS: The urothelial carcinoma cell lines expressed significantly higher levels of CD276 on transcript (p < 0.006), total protein levels (p < 0.005), and on the cell surface (p < 0.02) when compared to normal urothelial cells. In pT2-T4 tumor tissue samples, CD276 was overexpressed (median score 185) when compared to corresponding healthy tissues from the same patients (median score 50; p < 0.001). No significant differences in CD276 expression were recorded in late, locally advanced ≥ pT3a tumors (median score 185) versus organ-confined < pT3a tumors (median score 190), but it was significantly lower in the normal urothelial tissue associated with ≥ pT3a tumors (median score 40) versus < pT3a tumors (median score 80; p < 0.05). CONCLUSION: CD276 expression is significantly elevated in urothelial carcinoma cells in all stages but varies between individuals considerably. Reduced CD276 expression in normal urothelial cells may imply that these cells would be protected from CD276-mediated immuno therapies.

Enzymatic Reactions in a Lab-on-Valve System: Cholesterol Evaluations.

The micro sequential injection analysis / lab-on-valve (µSIA-LOV) system is a miniaturized SIA system resulting from the implementation of a lab-on-valve (LOV) atop of the selection valve. It integrates the detection cell and the sample processing channels into the same device, promoting the reduction of reagent consumption and waste generation, the improvement of the versatility, and the reduction of the time of analysis. All of these characteristics are really relevant to the implementation of enzymatic reactions. Additionally, the evaluation of cholesterol in serum samples is widely relevant in clinical diagnosis, since higher values of cholesterol in human blood are actually an important risk factor for cardiovascular problems. An automatic methodology was developed based on the µSIA-LOV system in order to evaluate its advantages in the implementation of enzymatic reactions performed by cholesterol esterase, cholesterol oxidase and peroxidase. Considering these reactions, the developed methodology was also used for the evaluation of cholesterol in human serum samples, showing reliable and accurate results. The developed methodology presented detection and quantification limits of 1.36 and 4.53 mg dL-1 and a linear range up to 40 mg dL-1. This work confirmed that this µSIA-LOV system is a simple, rapid, versatile, and robust analytical tool for the automatic implementation of enzymatic reactions performed by cholesterol esterase, cholesterol oxidase, and peroxidase. It is also a useful alternative methodology for the routine determinations of cholesterol in real samples, even when compared with other automatic methodologies.

Assessment of essential elements and chemical contaminants in thirteen fish species from the Bay Aratu, Bahia, Brasil.

Concentrations of ten elements (Cd, Cr, Cu, Fe, Ni, Pb, Se, Sr, V and Zn) were determinate in muscle tissues of 13 fish species from Aratu Bay, Bahia, Brazil by inductively coupled plasma optical emission spectrometry. The accuracy and precision of our results were checked by using two certified reference materials: BCR-422 cod muscle and SRM 1566b oyster tissue. The average trace element concentrations in the fish species varied in the following ranges, in µg g-1: 0.03-0.8 for Cr; 2.0-33.7 for Cu, 2.4-135.1 for Fe, 1.6-25.6 for Se; 1.6-35.1 for Sr; and 2.8-40.5 for Zn. The Diaptereus rhombeus (carapeba) specie presented the highest concentrations of Se, Cu and Fe. Chromium and Se were present at levels above the limit of tolerance allowed by the National Agency of Sanitary Vigilance (ANVISA). The results were also evaluated using the multivariate analysis techniques: principal component analysis (PCA) and hierarchical cluster analysis (HCA).

Distribution of trace elements in tissues of shrimp species Litopenaeus vannamei (Boone, 1931) from Bahia, Brazil.

In this study, concentrations of trace elements in tissues of shrimp species (Litopenaeus vannamei) from farming and zone natural coastal located in the northeastern Brazil were investigated. The elements determination was performed by optical emission spectrometry with inductively coupled plasma (ICP OES). The following ranges of concentrations in the tissues were obtained in µg g-1 dry weight: Al: 13.4-886.5, Cd: 0.93-1.80; Cu: 24.8-152; Fe: 3.2-410.9; Mn: 0.36-24.4; Se: 0.094-9.81 and Zn: 20.3-109.4. The shrimp muscle can be a good iron source (about 88.9 mg-1g dry weight). The distribution of Se concentration in tissues showed much variation between locations, and the concentration levels found in shrimp muscles of wild samples were high, where its levels in 67% of muscle and 50% of others tissues samples exceeded the ANVISA limit, indicating evidence of selenium bioaccumulation. Significant correlation was observed between the following pairs of elements: Fe-Zn (r= -0.70), Mn-Cu (r= -0.74), Se-Cu (r= -0.68), Se-Mn (r= 0.82) in the muscles; Fe-Al (r= 0.99), Mn-Al (r= 0.62), Mn-Fe (r= 0.62), Se-Al (r = 0.88), Se-Fe (r= 0.87), Se-Mn (r= 0.58) in the exoskeleton and Cu-Zn (r = 0.68), Al-Cu (r= 0.88), Fe-Cu (r= 0.95) and Fe-Al (r= 0.97) in the viscera.

Transcriptional activation of TRADD mediates p53-independent radiation-induced apoptosis of glioma cells.

Survival of patients with Glioblastoma Multiforme (GM), a highly malignant brain tumor, remains poor despite concerted efforts to improve therapy. The median survival of patients with GM has remained approximately 1 year regardless of the therapeutic approach. Since radiation therapy is the most effective adjuvant therapy for GM and nearly half of GM tumors harbor p53 mutations, we sought to identify genes that mediate p53-independent apoptosis of GM cells in response to ionizing radiation. Using broad-scale gene expression analysis we found that following radiation treatment, TRADD expression was induced in a uniquely radiosensitive GM cell line but not in radioresistant GM cell lines. TRADD over-expression killed GM cells and activated NF-kappa B. We found that blocking the TRADD-mediated pathway using a dominant-negative mutant of FADD (FADD-DN) enhanced radiation resistance of GM cells, as reflected in both susceptibility to apoptosis and clonogenic survival following irradiation. Conversely, stable expression of exogenous TRADD enhanced radiation-induced apoptosis of GM cell lines, reflecting the biological significance of TRADD regulation in p53-independent apoptosis. These findings generate interest in utilizing TRADD in gene therapy for GM tumors, particularly in light of its dual function of directly inducing rapid apoptosis and sensitizing GM cells to standard anti-neoplastic therapy.

GTP-binding proteins in adrenocortical mitochondria.

We have identified two GTP-binding proteins in mitochondria from bovine adrenal cortex (fasciculata). Sub-mitochondrial particles were fractionated into inner membrane, contact point and outer membrane vesicles on sucrose density gradients. These sub-mitochondrial fractions were identified by the presence of enzyme markers and electron microscopy. Photoaffinity labelling with [gamma-32P]GTP identified a 45 kDa GTP-binding protein in outer mitochondrial membranes and a 19 kDa protein in the contact points. The molecular weight of 45 kDa and requirement for Mg2+ ions raise the possibility that this protein is an alpha subunit of a heterotrimeric GTP-binding protein or a novel GTP-binding protein. The specificity of nucleotide binding, the requirement for low concentrations of Mg2+ (0.1 mM) and molecular weight of 19 kDa suggest that this protein is a typical member of the so-called small GTP-binding protein family. The location of 45 kDa in the outer membrane and that of 19 kDa in the contact points suggest roles for these proteins in the interaction with the extramitochondrial environment and in the regulation of mitochondrial membranes, respectively.

Newly generated dentate granule cells from epileptic rats exhibit elongated hilar basal dendrites that align along GFAP-immunolabeled processes.

Previous studies showed that neurogenesis occurs in the dentate gyrus of the adult rodent. Recent evidence suggests that the resulting newly born neurons integrate into pre-existing hippocampal circuitry. Newly born neurons in the developing and adult dentate gyrus exhibit a transient basal dendrite. In adult pilocarpine-induced epileptic rats, basal dendrites persist and are ectopically located in the hilus where they receive synaptic input from mossy fiber axons. We hypothesize that these hilar basal dendrites are derived from newly born neurons that are born after the pilocarpine-induced seizures. To test this hypothesis, the length of basal dendrites from epileptic rats was compared with that from control rats using doublecortin immunocytochemistry, which labels newly born neurons and their processes for up to 3 weeks after their genesis. The data on hilar basal dendrites in pilocarpine animals indicate that those from newly born neurons are significantly longer than those found in the control rats. We also demonstrate that 20% of newly born neurons in the epileptic rat have a basal dendrite that enters the hilus at an angle greater than 30 degrees from its cell body as compared with <2% in the control rats. Lastly, we provide evidence that the hilar basal dendrites in the epileptic rats are adjacent to glial fibrillary acidic protein-labeled astrocytic processes in the hilus and suggest that an ectopic glial scaffold in the hilus is involved with the formation of hilar basal dendrites. In conclusion, the data show that newly born neurons from epileptic rats have longer hilar basal dendrites and their formation might relate to gliosis which occurs as a result of hilar neuronal cell loss after status epilepticus.

The composition of the intracellular domains of the B cell antigen receptor complex studied from the cytoplasmic side of the membrane.

Immunoglobulins of the classes M and D function as antigen receptors on B lymphocytes. They are linked to other proteins to form B cell antigen receptor (BCR) complexes which transduce the signal triggered by the binding of antigen. In order to study the components that interact with BCR complexes in the cell it is essential that they are accessible to biochemical studies. Therefore, we have developed a simple and rapid method that allows the purification and labelling of B lymphocyte plasma membranes. For this, B cells are attached to polyacrylamide beads. Upon disruption of the cells, bead-bound membranes are obtained which expose the cytoplasmic side into the medium. The membrane proteins can then be radioiodinated and eluted with detergents. The combination of the improved methods for the preparation of bead-attached membrane patches and radiolabelling of the proteins has allowed for the first time an investigation into the cytoplasmic side of the BCR complex. All the subunits that had been previously described could be detected in 2D autoradiographs. Furthermore, it could be shown that the protein Ig-beta, which is part of an Ig-associated heterodimer, is predominantly labelled at the extracellular domain. The second component, Ig-alpha, is labelled to a higher degree at its intracellular domain. In addition, further proteins could be detected exclusively at the cytoplasmic side of the membrane. Results from 2D autoradiographs show that they may form heterodimers. These proteins are candidates for the interaction of BCR complexes with further members of the signalling cascade, such as protein tyrosine kinases and/or G proteins.

Calcium/calmodulin induces phosphorylation of vimentin and myosin light chain and cell rounding in cultured adrenal cells.

In previous reports on adrenal cells we have shown that calcium/calmodulin regulates cholesterol transport to mitochondria and induces phosphorylation of cytoskeleton homogenates. In this study, we have used bovine fasciculata cells permeabilized in situ to identify the phosphorylated proteins and to investigate the manner in which the cytoskeleton components may act together in any subsequent reorganization of the cell. The main cytoskeletal proteins namely vimentin, tubulin, actin, and the associated protein myosin light chain were identified on polyacrylamide gel electrophoresis by their molecular weights and by Western blotting using affinity-purified monoclonal antibodies. In permeabilized cells, calcium/calmodulin promoted phosphorylation of vimentin and myosin light chain within the first 10 min. When incubation time was extended in the presence of 1 mM non-radiolabeled ATP, cell contraction was seen after 15 min. Immunofluorescent microscopy showed that actin microfilaments and myosin light chain displayed a similar pattern of distribution which indicates the actomyosin. Electron microscopy revealed the actomyosin as a dense ring around the cell beneath the plasma membrane. Intermediate filaments (10 nm) were seen within this ring which gave rise to a mixed network in which microfilaments appeared to interconnect intermediate filaments. Immunogold electron microscopy revealed that the 10-nm filaments, found within the actomyosin ring, are vimentin intermediate filaments. It is proposed that calcium/calmodulin causes phosphorylation of the myosin light chain which triggers contraction, and this process involves the intermediate filament protein vimentin. The redistribution of the cytoskeleton and hence the cell rounding is due, in part to the interconnection between vimentin intermediate filaments and actin microfilaments.(ABSTRACT TRUNCATED AT 250 WORDS)

Suicide and violence associated with panic attacks.

Several studies have indicated that patients with panic attacks have a higher rate of suicide attempts as well as deaths from suicide. Additionally, several investigators have presented case reports of individuals manifesting suicidal and violent behaviors directly and temporally associated with panic attacks. We report on four additional cases and suggest that these findings may explain, in part, the increased rate of suicidal behavior among patients with panic attacks found by some investigators. Furthermore, these case reports offer preliminary evidence that the relationship between violent behavior and the panic state may be clinically significant and deserving of further elucidation.

Defense mechanisms in risk of suicide and risk of violence.

This paper reports on an empirical study of defense mechanisms in 60 psychiatric inpatients. Eight defenses--compensation, denial, displacement, intellectualization, projection, reaction formation, regression, and repression--were studied in the context of a two-stage model of suicidal and violent behavior. The results showed that use of regression as a defense differentiated suicidal from nonsuicidal patients, and use of displacement differentiated violent from nonviolent patients. Repression tended to turn aggression inward, and projection and denial turned aggression outward.

Correlates of risk of suicide in violent and nonviolent psychiatric patients.

OBJECTIVE: This study was designed to identify variables that correlate with the risk of suicide in two patient groups that differ mainly in their level of expressed aggression. METHOD: Twenty-eight psychiatric patients with a history of violent behavior who were in a forensic psychiatric facility were tested and compared to 28 psychiatric inpatients without a history of violence who were admitted to a large municipal hospital. Measures used included a battery of self-report questionnaires, with acceptable reliability and validity, that provided indices of risk of suicide, risk of violence, impulsivity, anger, anxiety, and various mood states. RESULTS: The two groups, matched on demographic variables and overall risk of suicide, differed significantly on the measured risk of violence. The two groups showed similar patterns of correlations between risk of suicide and such variables as risk of violence, anger, fear, state and trait anxiety, lack of impulse control, suspiciousness, and rebelliousness. They differed in the correlation between suicide risk and depression. In the nonviolent patients there was a high correlation between risk of suicide and sadness; in the violent patients there was no correlation between these variables. CONCLUSIONS: The low correlation between sadness and risk of suicide in the violent patients, and the low prevalence of affective disorder diagnoses in these patients compared to other patients, suggests that suicidal risk should be managed differently in highly violent patients than in others.

Phase I study with a weekly 1 h infusion of paclitaxel in heavily pretreated patients with metastatic breast and ovarian cancer.

Paclitaxel has proven to be an active agent in the treatment of breast and ovarian cancer [Seidman AD, Ann Oncol 1994, 5 (Suppl. 6), 17-22], but the optimal dose and schedule remain undefined. We performed a phase I study with a weekly 1 h infusion of paclitaxel. After premedication, patients received a 1 h infusion of paclitaxel on days 1, 8, 15, 22, 29 and 36 (every 50 days) using the following dose levels: dose level 1 70 mg/m2, dose level 2 80 mg/m2, dose level 90 mg/m2, dose level 4 100 mg/m2, 20 patients (17 breast, 3 ovarian cancer) with anthracycline- or platinum-refractory disease entered this trial. No dose limiting toxicities occurred at dose levels 1-3. 2 of the 4 patients at dose level 4 had neutropenia WHO grade 4. At all dose levels responses could be observed. Maximal tolerable dose (MTD) was reached using dose level 4. Paclitaxel, given in a weekly 1 h infusion, is safe and shows mild toxicity in heavily pretreated breast and ovarian cancer patients. We recommend dose level 3 for phase II studies.

Differential hepatic gene expression in a polygenic mouse model with insulin resistance and hyperglycemia: evidence for a combined transcriptional dysregulation of gluconeogenesis and fatty acid synthesis.

New Zealand obese (NZO) mice exhibit severe insulin resistance of hepatic glucose metabolism. In order to define its biochemical basis, we studied the differential expression of genes involved in hepatic glucose and lipid metabolism by microarray analysis. NZOxF1 (SJLxNZO) backcross mice were generated in order to obtain populations with heterogeneous metabolism but comparable genetic background. In these backcross mice, groups of controls (normoglycemic/normoinsulinemic), insulin-resistant (normoglycemic/hyperinsulinemic) and diabetic (hyperglycemic/hypoinsulinemic) mice were identified. At 22 weeks, mRNA was isolated from liver, converted to cDNA, and used for screening of two types of cDNA arrays (high-density filter arrays and Affymetrix oligonucleotide microarrays). Differential gene expression was ascertained and assessed by Northern blotting. The data indicate that hyperinsulinemia in the NZO mouse is associated with: (i) increased mRNA levels of enzymes involved in lipid synthesis (fatty acid synthase, malic enzyme, stearoyl-CoA desaturase) or fatty acid oxidation (cytochrome P450 4A14, ketoacyl-CoA thiolase, acyl-CoA oxidase), (ii) induction of the key glycolytic enzyme pyruvate kinase, and (iii) increased mRNA levels of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase. These effects were enhanced by a high-fat diet. In conclusion, the pattern of gene expression in insulin-resistant NZO mice appears to reflect a dissociation of the effects of insulin on genes involved in glucose and lipid metabolism. The data are consistent with a hypothetical scenario in which an insulin-resistant hepatic glucose production produces hyperinsulinemia, and an enhanced insulin- and substrate-driven lipogenesis further aggravates the deleterious insulin resistance of glucose metabolism.

Tardive dystonia: four case histories.

Tardive dystonia is an uncommon, disabling side effect of antipsychotic medication that is generally believed to be resistant to treatment. On the basis of a literature review and their experience, the authors propose treatment strategies and report the results of treatment in four patients.

Nosological tunnel vision in biological psychiatry. A plea for a functional psychopathology.

Classical nosology has been the major cornerstone of biological psychiatric research; finding biological markers and eventually causes of disease entities has been the major goal. Another approach, one we have designated as "functional," seems possible, attempting to correlate biological variables with psychological dysfunctions, the latter being considered to be the basic units of classification in psychopathology. We have pursued this route for many years, and based on the resulting findings we formulated the following hypothesis. Signs of diminished dopamine, serotonine, and noradrenaline metabolism, as have been found in psychiatric disorders, are not disorder-specific, but rather are related to psychopathological dimensions; i.e., hypoactivity/inertia; increased aggression/anxiety and anhedonia, independent of the nosological framework in which these dysfunctions occur (van Praag et al. 1990). In this paper only the 5-HT data have been discussed. Implications of the functional approach for psychiatry are discussed, including a shift from nosological to functional application of psychotropic drugs. Functional psychopharmacology will be dysfunction-oriented and therefore inevitably geared towards utilizing drug combinations. This prospect is hailed as progress, both practically and scientifically.

Panic-associated suicidal and aggressive ideation and behavior.

Some investigators have noted an increased incidence of suicidal ideation and attempts in individuals with panic attacks. The direct temporal relationship between the panic state and suicidal thoughts and behaviors has not been well elucidated however. Furthermore, although aggressive behavior is often manifested in individuals with suicidal behavior, the relationship between aggression and panic has received little attention. The aim of this study was to assess the frequency and type of reported suicidal and aggressive ideation and behaviors that occur during the panic state in patients with panic disorder. In order to evaluate the contribution of depression, individuals with pure (i.e. uncomplicated) panic disorder were compared with individuals who had comorbid panic and major depression. Nineteen patients with a diagnosis of pure panic disorder and 28 patients with comorbid panic plus major depression were included in the study. All patients were given the Panic, Suicide and Aggression Scale (PSAS), a questionnaire specifically designed to assess reported suicidal and aggressive thoughts and behaviors that occur during panic attacks. Other scales given to all patients included overall measures of impulsivity, suicide risk and violence risk. Patients with pure panic disorder reported high rates of suicidal and aggressive ideation and behavior during panic. The presence of comorbid depression resulted in a doubling of the rate of reported panic-associated suicidal ideation, property destruction and assaults, and a five-fold increase in the rate of homicidal ideation. The rate of reported suicide attempts was equal in the pure panic and comorbid group. There were also high correlations in all panic patients between measures of panic-associated suicide and aggression with the psychometric measures of impulsivity, suicide risk and violence risk.

Denosologization of biological psychiatry or the specificity of 5-HT disturbances in psychiatric disorders.

5-Hydroxytryptamine (5-HT) disorders have been reported to occur in a variety of psychiatric disorders. The situation has been called chaotic, the disturbances non-specific. We reject this viewpoint. 5-HT disturbances are non-specific only from a nosological/categorical viewpoint; they seem rather specific from a functional/dimensional point of view, correlating as they do with particular psychopathological dimensions, i.e. aggression-, anxiety- and possibly mood-disregulation, across diagnosis. The evolution of 5-HT research in psychiatry illustrates the importance of what we have called the functional approach, implying dissection of a given psychopathological syndrome in its component parts, i.e., the psychological dysfunctions, and searching for correlations between biological and psychological dysfunctions. The rigid preoccupation of biological psychiatry with the search for markers of disease entities has hampered progress. The functional approach should be incorporated in biological psychiatry, not as an alternative for the nosological approach but as its complement.

Infusional 5-FU, folinic acid, paclitaxel, and cisplatin for metastatic breast cancer.

Our phase II study results demonstrating high efficacy and low toxicity for a weekly schedule of high-dose, 24-hour infusional 5-fluorouracil(5-FU)/folinic acid (HD5-FU/FA) in intensively pretreated patients with metastatic breast cancer prompted addition of paclitaxel (Taxol) to the regimen, for a phase I/II study of outpatient second-line treatment of metastatic breast cancer. That study further prompted the addition of cisplatin (Platinol) to the regimen for first-line treatment. So far, 28 patients with metastatic breast cancer have been evaluated. Pretreatment comprised adjuvant chemotherapy in 24 of 28 patients, but no prior chemotherapy for metastatic disease. Patients were treated with HD5-FU 2 g/m2 (24-hour infusion) plus FA 500 mg/m2 (2-hour infusion prior to FU) weekly for 6 weeks (days 1, 8, 15, 22, 29, and 36); in addition, paclitaxel 175 mg/m2 (3-hour infusion) was administered on days 0 and 21 and cisplatin 50 mg/m2 (1-hour infusion) on days 1 and 22 prior to HD5-FU/FA, repeated every 50 days. Patients were treated as outpatients using Port-a-Cath systems and portable pumps. Neutropenia was common (67% World Health Organization grade 3) but mild to moderate in most patients and was of short duration. No hospitalizations were required because of febrile neutropenia, and no granulocyte colony-stimulating factor support was used. Aside from common total alopecia, nonhematologic toxicities consisted mainly of moderate myalgia, diarrhea, mucositis, and nausea and vomiting. Hand-foot syndrome and peripheral neuropathy were cumulative and occurred most commonly during the third treatment cycle, with mild-to-moderate expression. In 28 patients with bidimensionally measurable disease, 25% (7/28) attained a complete response, 57% (16/28) achieved partial response, 11% (3/28) had stable disease, and 7% (2/28) had disease progression. Overall response was 82% (95% confidence interval, 66% to 100%). Eight of 28 patients are still receiving treatment. It is concluded that the combination of paclitaxel/cisplatin with weekly HD5-FU/FA appears to be effective in the first-line treatment of metastatic breast cancer. Preliminary results must be confirmed by the final analysis of response duration, time to progression, and survival.

Food chloride distribution in nature and its relation to sodium content.

Because of growing interest in the biological and clinical effects of dietary chloride as the anion accompanying the dietary cation sodium and because the standard food composition tables used in the United States to estimate sodium content do not contain data on chloride content, we analyzed the nutrient data base of the English workers Paul and Southgate, which contains an extensive listing of both chloride and sodium contents in foods. To examine food chloride distribution in nature, we focused on the uncooked, unadulterated, discrete, primitive foods in the data base (no. = 216 food items). The findings indicate the existence of both a large variability of chloride content among foods and a high degree of coupling of chloride with sodium. The contents of chloride and sodium varied over a similarly large range (coefficients of variation, 229% vs. 263%), differed very little from each other on the average (less than 20%), and correlated (r = 0.84, p less than 0.001) to the extent that greater than two-thirds of the overall variation of chloride content was linked to that of sodium content. Those findings accord with the often posited but untested assertion that the chloride content of foods approximates and parallels that of sodium.(ABSTRACT TRUNCATED AT 250 WORDS)