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Dredged sediments with initial water contents between 200% and 400% were treated with single and composite binders. Samples were subjected to open and semi-closed freeze–thaw (f–t) cycles to investigate the impact of f–t cycling on hydraulic conductivity (HC) and unconfined compressive strength (UCS). A grace period (GP) for thaw consolidation is included to assess healing potential of the affected stabilized mass. Findings of this study show that the impact of f–t cycles depends on initially achieved UCS and HC values prior to the f–t cycling and time of testing after f–t cycles. The HC of specimens with an initial UCS value of 87 kPa increased with number of f–t cycles. The UCS values decreased in the range of 50%–80% when specimens were tested directly after the thaw period and values decreased in the range of 14%–60% when specimens were tested at the end of the GP. The HC of specimens with an initial UCS value of 299 kPa remained almost the same. These samples experienced permanent loss in the UCS values, irrespective of time of testing. Detrimental effects of the freezing action on the UCS were greater under semi-closed than open freezing conditions.

Acupuncture has been demonstrated to improve menstrual frequency and to decrease circulating testosterone in women with polycystic ovary syndrome (PCOS). Our aim was to investigate whether acupuncture affects ovulation frequency and to understand the underlying mechanisms of any such effect by analyzing LH and sex steroid secretion in women with PCOS. This prospective, randomized, controlled clinical trial was conducted between June 2009 and September 2010. Thirty-two women with PCOS were randomized to receive either acupuncture with manual and low-frequency electrical stimulation or to meetings with a physical therapist twice a week for 10–13 wk. Main outcome measures were changes in LH secretion patterns from baseline to after 10–13 wk of treatment and ovulation frequency during the treatment period. Secondary outcomes were changes in the secretion of sex steroids, anti-Müllerian hormone, inhibin B, and serum cortisol. Ovulation frequency during treatment was higher in the acupuncture group than in the control group. After 10–13 wk of intervention, circulating levels of estrone, estrone sulfate, estradiol, dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, testosterone, free testosterone, dihydrotestosterone, androsterone glucuronide, androstane-3α,17β-diol-3-glucuronide, and androstane-3α,17β-diol-17-glucuronide decreased within the acupuncture group and were significantly lower than in the control group for all of these except androstenedione. We conclude that repeated acupuncture treatments resulted in higher ovulation frequency in lean/overweight women with PCOS and were more effective than just meeting with the therapist. Ovarian and adrenal sex steroid serum levels were reduced with no effect on LH secretion.

OBJECTIVES: Numerous studies have shown associations between an on-going depression and elevated serum levels of the acute-phase reactant C-reactive protein (CRP). Also, in suicidal behaviour, a proinflammatory state has been suggested to be of importance for the pathophysiology. There is a genetic susceptibility to suicidal behaviour, but studies with respect to genes related to inflammation are sparse. We have previously reported an association between a polymorphism located in the CRP gene, +1444C>T (rs1130864), and the personality trait impulsiveness in women assessed using the Karolinska Scales of Personality. The present study aims to replicate these results in suicide attempters and examine whether the polymorphism is associated with suicidal behaviour. MATERIALS AND METHODS: The +1444C>T polymorphism was genotyped in suicide attempters from two cohorts (a total of 106 patients) and healthy controls (n=517). RESULTS: We could replicate our previous finding, as the +1444T allele was associated with higher scores in the Karolinska Scales of Personality factor extraversion and its subscale impulsiveness in one of the patient cohorts. Furthermore, the +1444T allele was significantly more common among suicide attempters compared with the +1444C allele. CONCLUSION: The present results lend further support to the relevance of inflammation for suicidal behaviour. The association between the polymorphism and personality trait impulsiveness reinforces our hypothesis of the importance of immune-related genes also for normal mental functions such as personality traits. Given the fact that impulsiveness is a well-known risk factor for suicidal behaviour, we further hypothesize that the polymorphism studied may in part explain this relationship.

Summary Elevated serum levels of S100B have proven useful as an indicator of brain-injury but have also been shown in patients diagnosed with psychiatric disorders. Recently, associations were found between variations in the S100B gene and schizophrenia as well as bipolar affective disorder. The aim of the present study was to investigate whether some of these genetic variations influence general aspects of human behaviour as portrayed by normal dimensions of personality. Two single nucleotide polymorphisms within the S100B gene, 2757C>G and 5748C>T, were genotyped in two population based cohorts consisting of 42-year-old women (n = 270) and 51-year-old men (n = 247), respectively. The two polymorphisms were analysed with respect to personality traits assessed using the Temperament and Character Inventory (TCI). In men, the 2757C>G polymorphism was found to significantly influence the TCI dimension self-directedness with higher scores in 2757G homozygotes. A similar tendency towards association was seen in the female cohort; however, this correlation did not remain significant after correction for multiple comparisons. Furthermore, the 5748C>T polymorphism was highly associated with self-directedness in men. Self-directedness is an overall estimate of adaptive strategies to adjust behaviour to conceptual goals as well as coping strategies and is strongly correlated to general mental health and absence of personality disorder. These preliminary findings suggest that the S100B gene may be implicated not only in certain pathological brain conditions but also in processes involved in normal behaviour.

Context: Studies of fibrinolysis/coagulation status in women with polycystic ovary syndrome (PCOS) are contradictory. Objectives: The aim of the study was to investigate whether women with PCOS have disturbed circulating levels of fibrinolysis/coagulation markers and, if so, whether the disturbances are related to hemodynamics, metabolic variables, sex steroids, SHBG, lipids, and inflammatory variables in women with PCOS. Design/Main Outcome Measures: Anthropometric variables, hemodynamics, circulating hemostatic and inflammatory markers, and serum lipid profile were measured in women with untreated PCOS (n = 74) and controls (n = 31). Results: After adjustments for age and body mass index (BMI), circulating plasminogen activator inhibitor 1 (PAI-1) activity and fibrinogen levels were higher in women with PCOS than controls; lipid profile, blood pressure, and levels of D-dimer, von Willebrand factor, factor VIII, tissue plasminogen activator, and inflammatory markers were comparable in the two groups. In multiple linear regression analyses including women with PCOS, low SHBG and high insulin predicted high PAI-1 activity (R2 = 0.526; P < 0.001); elevated high-sensitivity C-reactive protein and soluble E-selectin in combination with heart rate predicted high fibrinogen (R2 = 0.333; P < 0.001). Differences in PAI-1 activity were not significant after adjustments for age, BMI, SHBG, and insulin. Conclusions: PCOS is characterized by a prothrombotic state, as reflected by increased PAI-1 activity and fibrinogen, without signs of dyslipidemia or a proinflammatory state. Low SHBG and high insulin may partly explain the BMI-independent difference in PAI-1 activity between women with PCOS and controls. High-sensitivity C-reactive protein and E-selectin may be involved in regulating fibrinogen in PCOS.

Receptors of the 5-HT2C subtype are of importance for the influence of serotonin on food intake, and 2 single nucleotide polymorphisms in this gene (HTR2C)--Cys23Ser (rs6318) and -759CT (rs3813929)--have been reported to be associated with weight and/or antipsychotic-induced weight gain. The present study aimed to replicate these associations; in addition, the 5-HTTLPR polymorphism in the promoter region of the serotonin transporter gene (SLC6A4) was assessed. The polymorphisms were genotyped in subjects recruited from the normal population (n = 510), and possible associations between genotype and body mass index (BMI) were assessed. The Ser23 allele was more common in underweight subjects (BMI20) than in normal- and overweight (BMIor =20) subjects (P = .006). The T allele of the -759C/T polymorphism was less common in the overweight group (BMIor =25) (P = .007). Homozygosity for the short allele of 5-HTTLPR was more frequent in underweight subjects (P = .015). Our results are in agreement with previous studies, suggesting polymorphisms in HTR2C to be associated with body weight, particularly in women; and they also suggest that 5-HTTLPR may influence this phenotype. Further studies on the importance of the investigated genes for eating disorders and drug-induced weight gain are warranted.

A case of pure red cell aplasia appearing 6 months following thymectomy is reported in a 43-year-old man. Immunofluorescence studies of the patient's bone marrow have demonstrated the presence of membrane-bound IgG on the majority of erythroblasts and some mature erythrocytes. It is suggested that the IgG represents anti-erythroid autoantibodies. The number of Ig-bearing lymphocytes in peripheral blood was decreased as was the level of immunoglobulins indicating a B-lymphocyte deficiency. T-lymphocyte functions were without remarks. The patient was initially treated with corticosteroids and oxymetholone. He responded well to this therapy but relapsed 9 month later. Cyclophosphamide treatment was started and followed by a complete haematologic remission.

Ninety-one previously untreated patients with chronic myeloid leukemia admitted to three Stockholm hospitals 1973-1978 were studied. There were 49 men and 42 women with a mean age of 56 years (range 15-93). Sixty-five patients were Philadelphia chromosome (Ph1) positive and 17 were Ph1 negative (mean age 51 and 70 years, respectively). After a mean observation time of 5.2 years, 64 patients had deceased, 45 of them in blast transformation. A low hemoglobin value and a high total blast cell count at diagnosis were associated with a poor prognosis in the Ph1 positive group. Other routine clinical and laboratory variables were of subordinate prognostic importance. Early splenectomy in 15 Ph1 positive patients did not improve survival. Median survival from diagnosis was 38 months for Ph1 positive patients as compared to 12 months for the Ph1 negative group.

Blood T-lymphocyte functions were studied in 167 healthy adults (age range 19-91 years). Lymphocyte DNA synthesis induced by concanavalin A, pokeweed mitogen and PPD antigen declined with age while the spontaneous DNA synthesis remained essentially unchanged. Relative and total T-cell counts but not total lymphocyte counts were moderately decreased in elderly persons. The lymphocyte response to mitogens correlated with the PPD-induced activation in vitro. Lymphocyte and T-cell counts did not show any association with the response to mitogens and antigen. A few subjects were tested on several occasions during 2-7 years confirming a good reproducibility of the techniques employed. Thus ageing is associated with diminished number of T-cells and impairment of lymphocyte activation by T-cell mitogens and PPD antigen. The clinical importance of this general age-related T-cell deficiency remains largely unresolved.

We studied the immunocompentence of 6 healthy twins, whose monozygotic or dizygotic same-sexed twin partner had died from Hodgkin's disease. Lymphocyte DNA synthesis induced by concanavalin A was markedly reduced at 3 different concentrations in all twins compared to an age-matched group of healthy controls. The lymphocyte response to pokeweed mitogen and to phytohaemagglutinin was also impaired. PPD induced lymphocyte DNA synthesis was low in 3 twins and correlated well with their delayed skin hypersensitivity to the antigen. One twin was completely anergic to 3 different skin antigens. The mean total blood lymphocyte count did not differ from that of controls. There was no change in T- or B-lymphocyte subpopula-tions. The presence of a functional lymphocyte deficiency in all twins strongly suggests that the immunodeficiency in Hodgkin's disease is partly caused by genetic and/or environmental factors.

The presence of T cells binding F(ab')2 fragments of the idiotypic immunoglobulin was examined by immunofluorescence in peripheral blood of patients with monoclonal gammopathy. In 3 out of 11 tested patients, 1-15% idiotype-binding T cells of either CD4 or CD8 phenotype were found. In 1 patient both a CD4+ and a CD8+ idiotype-binding T-cell fraction were present. In 1 patient the idiotype-binding T cells also reacted with a mAb directed against the variable parts of the TCR alpha or beta chains, further indicating a clonal origin at the alpha/beta level. 3 patients had an expanded predominant T-cell receptor V gene usage based on the reactivity with the limited panel of TCR mAb, but these "clonal" T cells did not bind the idiotype. The study supports the existence of idiotype-specific T cells in peripheral blood of patients with monoclonal gammopathy. Such cells might have a regulatory role on the monoclonal B-cell clone and may be an important target for immunotherapy.

The immunological side-effects under treatment with antihypertensive drugs are mainly limited to autoimmunity and autoimmune disease caused by alpha-methyldopa and hydralazine. Autoimmune hemolytic anemia is more common during treatment with alpha-methyldopa. Hydralazine may induce antinuclear antibodies. Some patients develop a SLE-like syndrome. Its clinical picture is less severe and its prognosis is more favourable than that of spontaneous SLE. During treatment with low doses the disease develops exclusively in patients who are slow acetylators. It may appear also in rapid acetylators during the high dose treatment. The symptoms are usually reversible after withdrawal of the drug.

The blood lymphocytosis in CLL is caused mainly by a rise of immunoglobulin (Ig)-bearing leukemic lymphocytes. Most cells carry Fc-receptors, while the percentage with receptors for human complement is very low with the present technique. The leukemic lymphocytes carry only one of the light chain types, which suggests a monoclonal origin. CLL patients with lymphocytes expressing kappa light chains may have a more benign disease than lambda-CLL. T-lymphocyte levels are high during the early course of the disease but decrease with its progression and are low in patients with "active" disease.

Immunological functions of 9 non-splenectomized and 8 splenectomized patients with Hodgkin's disease were studied before and after treatment. The two groups compared well with regard to age, clinical and immunological findings at diagnosis and observation time. When retested, all patients had enjoyed an unmaintained complete remission for 2 to 5 years following total nodal radiotherapy. After therapy, total lymphocyte and T-lymphocyte counts decreased in non-splenectomized patients but remained unchanged in splenectomized patients. The blood lymphocyte DNA synthesis after activation by concanavalin A or pokeweed mitogen persisted at the same low level after treatment. The delayed skin hypersensitivity and the lymphocyte activation by PPD antigen were restored in several patients in both groups. The IgM concentration decreased after therapy independent of splenectomy. The IgA level was low in non-splenectomized patients. Splenectomy seems to protect from the therapy-induced lymphocytopenia. No alterations of immunoglobulins and blood lymphocyte functions could be ascribed to splenectomy.

10 patients thymectomized about 20 years earlier were tested for delayed skin reactivity against mumps, streptokinase-streptodornase and PPD antigens. The T and B lymphocytes in peripheral blood were determined. 6 patients were surgically thymectomized and 2 of the received postoperative irradiation. 4 patients were treated with only high dose irradiation to the mediastinal compartment. None of the patients responded to all skin antigens, 1 was positive to two antigens and 3 to one antigen. The remaining patients were non-responders. The number of peripheral blood lymphocytes was slightly decreased in the patients. A significant decrease in the number of T-lymphocytes (p less than 0.005) was found in the whole patient group, and the depression was more pronounced in the surgically thymectomized patients (p less than 0.001). The number of B-lymphocytes was unaltered. It is concluded that the abnormalities in this patient group reflect a T-lymphocyte deficiency. The immunologic status of the patients before treatment is not known. However, in 3 patients with recently discovered untreated thymomas no abnormalities were found. Thus, adult thymectomy in man seem to lead to deficiency of cell mediated immunity, indicating an influence of the thymus in immunological functions during adult life.

4 children with idiopathic thrombocytopenic purpura were treated with high dose i.v. IgG. Platelet associated immunoproteins were determined with an Elisa technique. Platelet counts increased in all patients, while simultaneously platelet associated IgG, IgA, IgM, C3 and C4 decreased. Serum antiplatelet antibody increased during treatment suggesting that administration of high doses of IgG interferes with the binding of antiplatelet antibody.

Purified blood lymphocytes from 81 consecutive and previously untreated patients with Hodgkin's disease were studied in vitro. The patients were evaluated 23 to 52 months after institution of therapy and were divided into two prognostic groups: 1. Complete remission with or without previous relapse/relapses. 2. Uncontrolled relapse or decreased from Hodgkin's disease. Lymphocyte activation by concanavalin A, pokeweed mitogen or phytohaemagglutinin was impaired and spontaneous DNA synthesis was high in patients with poor prognosis as compared to the good prognosis group. The prognostic information increased if the four lymphocyte tests were combined in a score (range 0-8). All 8 patients with pronounced lymphocyte defects (score 7-8), died, while all patients with score 0 and 1 were in complete remission. In contrast, total lymphocyte and T-lymphocyte counts and lymphocyte stimulation by PPD were of no prognostic value. The ability of certain lymphocyte functions to predict prognosis was equal or better than that of age and better than clinical staging, histopathology and symptoms.

Three elderly patients admitted to hospital because of suspected malignancy have been diagnosed as disseminated tuberculosis during life. Classical features of disseminated tuberculosis such as miliary mottlings on the chest roentgenogram and choroidal tuberculosis were absent in two of the patients. The difficulties hindering the establishment of the diagnosis of “cryptic” disseminated tuberculosis are emphasized by the patient records. Response to treatment with isoniazide and para-amino-salicylic acid is in some cases the only evidence of tuberculosis. Moreover, the early institution of such therapy when other evidence of tuberculosis is lacking may cure the disease before it enters an irreversible state, and is strongly recommended.

Natural killer (NK) activity and NK-related cell surface markers (CD16, CD56, CD57) of peripheral blood lymphocytes were studied in patients with multiple myeloma and MGUS (monoclonal gammopathy of undetermined significance). A strong correlation (p less than 0.0001) was found between the numbers of cells positive for the different NK cell surface markers. The proportion of CD16+ cells correlated highly to the lytic capability (lytic units/10(6) cells) of K562 cells (p less than 0.0001). High NK activity and high numbers of cells with NK-related cell surface markers were found in patients with a low tumor burden compared to controls, whereas low values were seen in patients with an advanced disease. The results indicate that NK cells might be involved in the disease process in monoclonal gammopathies, perhaps by exerting a regulatory function on the proliferating B-cell clone.

Spontaneously DNA synthesizing blood and spleen lymphocytes in 9 patients with Hodgkin's disease have been studied by surface markers and by autoradiography after in vitro labelling with 3H-thymidine of cell specimens separated according to size. The findings have been related to functional characteristics of blood lymphocytes. The distribution of E and EAC rosetting cells in blood and spleen was similar also after separation according to cell size. The number of mainly large activated blood and spleen cells was increased in patients as compared to controls. Both E and EAC rosetting cells participated in this unexplained cell challenge.

Spontaneous and mitogen induced blood lymphocyte DNA synthesis was studied in relation to weight and tumor involvement of the spleen in 33 untreated patients with Hodgkin's Disease. Splenic tumor involvement was found in 14 patients. In this group there was a strong inverse correlation between spleen weight and lymphocyte DNA synthesis induced by PWM, ConA and PPD. In patients with uninvolved spleens the spontaneous blood lymphocyte DNA synthesis increased with spleen weight. No correlation with the mitogen response was observed in this group.

Blood and lymph node T-lymphocyte subpopulations have been studied in untreated non-Hodgkin lymphoma (NHL) patients and healthy controls. T-lymphocytes were determined by the E-rosette technique and by OKT3/LEU4 monoclonal antibodies; OKT4/LEU3 and OKT8/LEU2 monoclonal antibodies were used to identify T-cell subsets with helper/inducer and suppressor/cytotoxic activity, respectively. OKT4+ T-cells were low in patients, while OKT8+ T-cell numbers were normal. The OKT4+/OKT8+ blood lymphocyte ratio was below the normal range in about 50% of the patients. The ratio was higher in lymph nodes than in blood of patients and controls. The results may suggest that untreated NHL patients have a reduced pool of T-cells with phenotypic markers of OKT4/LEU3. Monoclonal blood B-lymphocytes were found in 45% of the cases. The presence of such cells in blood was frequently associated with a low OKT4+/OKT8+ ratio.

In a prospective study, sixty-five histologically verified Swedish cases of Hodgkin's disease were HL-A typed. The antigen frequencies in the patient group did not deviate from a group of normal controls. The frequency of HL-A8 was slightly increased in patients over 40 years (P less than 0.05). HL-A12 was markedly increased in patients below 40 years with a favourable histopathology (P less than 0.001). No association between sex or clinical stage and distribution of HL-A phenotypes was observed. The number of T-lymphocytes in blood and the spontaneous DNA synthesis and DNA synthesis induced by concanavalin A, pokeweed mitogen, phytohemagglutinin and PPD antigen in blood lymphocytes in vitro were determined in 60 patients. A significant increase of HL-A28 was noted in patients with advanced disease (P less than 0.01) and in patients responding poorly to PPD (P less than 0.001) and PWM (P less than 0.01). No correlation between HL-A antigen distribution and T-lymphocyte counts was observed.

Increased lipolysis in abdominal adipocytes has been suggested to be of importance for the insulin resistance typical for abdominal obesity. In order to differentiate between fat distribution, measured as waist/hip ratio (WHR), and amount of body fat, glucose disposal during a euglycaemic clamp as well as lipolysis in isolated cells from abdominal and gluteo-femoral regions were studied in 20 obese and 20 lean postmenopausal women with a high (n = 10) and low (n = 10) WHR, respectively. The lipolytic response was increased in cells from obese women irrespective of region. Furthermore, lipolysis was enhanced in abdominal compared with the gluteo-femoral cells in obese women with a high WHR. Fasting blood glucose and insulin were increased in both groups of obese women while the degree of insulin resistance was most pronounced in the obese women with a high WHR. It is concluded that increased body fat is associated with both insulin resistance and increased lipolysis, and that this relationship is stronger in the presence of a high WHR. A high WHR may increase the expression of obesity as a risk for insulin resistance and this may be mediated through an increased lipolytic rate.

Glucocorticoid receptors (GRs) are cytoplasmaticreceptors regulating the expression of cortisol and bind to specific sites on chromatin. The glucocorticoid receptor gene (GRL) is located on chromosome 5q31 and encodes for either a 777-amino acid (GRalpha) or a 742-amino acid (GRbeta) polypeptide. The objective of the current study was to examine the prospective association of 3 polymorphisms-a Tth111I restriction fragment in the promoter region, a BclI polymorphism in intron 2, and an A/G polymorphism in exon 2-of the GRL gene on estimates of obesity, hypertension, and diabetes in 163 unrelated Swedish men born in 1944. These data showed a significant increase in body weight, body mass index, abdominal obesity, fasting glucose, insulin, and homeostasis model assessment over the 5-year follow-up among homozygotes for the rare BclI allele. In contrast, no significant associations with the Tth111I or A/G polymorphism were detected. It is concluded that the genetic information about GRL would be useful for further genetic study of obesity, diabetes, and related metabolic diseases.

OBJECTIVE: Oestrogen and progesterone are known to influence the release of human prolactin. The present study was undertaken in order to investigate the possible influence of polymorphisms of the genes encoding the oestrogen receptor (ER)alpha, ERbeta and the progesterone receptor (PGR), on prolactin levels in premenopausal women. DESIGN AND MEASUREMENTS: Serum levels of prolactin were measured in the follicular phase of the menstrual cycle. Subjects were genotyped with respect to a TA repeat polymorphism of the ERalpha gene, a CA repeat polymorphism of the ERbeta gene, and two polymorphisms of the PGR gene: one insertion polymorphism (PROGINS) and one single nucleotide polymorphism (G331A). SUBJECTS: A population-based cohort of 270 42-year-old women. RESULTS: The CA repeat polymorphism of the ERbeta gene and the G331A polymorphism of the PGR gene appeared to be associated with prolactin levels. In contrast, we found no evidence for an influence of the PROGINS polymorphism of the PGR gene or the TA repeat polymorphism of the ERalpha gene on the levels of this hormone. CONCLUSIONS: These data suggest that genetic variants of both the ERbeta and the PGR may influence prolactin release.

The associations were examined in women between personality traits and steroid hormones, particularly androgens, as well as polymorphisms in genes regulating androgen concentration and effects. Women, all 42 years of age and premenopausal (n = 270), were recruited randomly. Conventional “masculine” and “feminine” personality traits were examined by questionnaire and set in relation to psychosocial and socioeconomic conditions, behavior in childhood, hormones, risk factors for disease, and polymorphisms in microsatellites in the CYP aromatase and the androgen receptor gene. The proportions of personality traits considered as being dominated by “masculinity” (M) or “femininity” (F) were 44.9%, respectively 15.0%, the rest consisting of a combination of M and F (33.2%) or “undifferentiated” (6.9%). M characteristics were positively associated with education, sporting, self-confidence, and good adaptation to work situation. M scores correlated with reports of “tomboyism” as girls. There was essentially no difference in hormones or disease risk factors between M and F women. The number of (CAG) repeats in the microsatellite of the transactivating domain of the androgen receptor was 19 (2.3; M and SD). M characteristics were more pronounced in the presence of longer repeat stretches (n > 20). No associations were found with F scores. There were no significant associations to the number of tetranucleotide repeats (TTTA) in the fourth introne of the aromatase gene. It was concluded that a majority of women showed M type of personality traits, associated with normal hormones, somatic health, and a long microsatellite in the transactivating domain of the AR gene.

An abnormal regulation of the hypothalamic-pituitary-adrenal (HPA) axis is associated with risk factors for cardiovascular disease and Type 2 diabetes mellitus. The objective of this study was to examine if morning saliva cortisols show similar associations. Twenty-eight men, all 53 yr of age, delivered during an ordinary working day saliva cortisol samples immediately upon awakening and 15 min thereafter as well as at different times during the day, including after a standardized lunch. Dexamethasone (0.5 mg) suppression of cortisol was also measured. The rise of morning cortisol values was positively associated with body mass index (r: 0.45, p=0.016), waist/hip ratio (r: 0.54, p=0.003), abdominal sagittal diameter (r: 0.54, p=0.003), glucose (r: 0.54, p=0.003), insulin (r: 0.57, p=0.002) and triglycerides (r: 0.46, p=0.014). The morning rise also correlated positively with the elevation of cortisol following lunch (r: 0.45, p=0.043) but not with other cortisol measurements or dexamethasone suppression. Elevation of cortisol immediately after awakening has previously been found to provide a simple indicator of HPA axis regulation, as suggested also by the results of this study, and an elevated rise has been reported after exposure to frequent or chronic perceived stress. The rise of cortisol immediately after awakening might be an indicator of an increased risk of developing serious, prevalent diseases via the metabolic syndrome.

Objective: Elevated androgens in women are associated with type 2 diabetes and are dependent on the conversion to estrogens by aromatase cytochrome P450. Polymorphisms of a tetranucleotide repeat [TTTA]n in the fourth intron of the CYP19 gene are associated with endocrine-dependent diseases and were examined in relation to hormone levels and disease risk factors in premenopausal women. Research Methods and Procedures: A population sample of women born in 1956 (n = 270) were genotyped for this polymorphism and the results set in relation to steroid hormones, including saliva cortisol, anthropometric variables, estimates of insulin, glucose and lipid metabolism, and blood pressure. Results: Seven tetranucleotide repeat [TTTA]n alleles were detected with allelic sizes of 168 to 195 bp, with a TCT deletion/insertion (168/171 bp) upstream of this microsatellite. Smoking was associated with elevated androgens (p = 0.005 to 0.019). Using the median (average stretch, 177.5 bp) as a dividing line, nonsmoking women with the shorter microsatellite had higher free testosterone (p = 0.018) and lower sex hormone binding globulin (p = 0.033). These differences were pronounced with the 168-bp allele. Such women were also characterized by a less-substantial decrease of morning cortisols (“unwinding”; p = 0.035) and central obesity (abdominal sagittal diameter, p = 0.049) and had waist/hip circumference ratios of borderline significance (p = 0.064). Discussion: The results indicate that, in premenopausal women, a short microsatellite in the fourth intron of the CYP19 gene, caused by a TCT deletion upstream the [TTTA]n tract, is associated with elevated androgens, perturbed regulation of the hypothalamic-pituitary-adrenal axis, and abdominal obesity.

Limited therapeutic options remain for patients with relapsing lymphoma following chemotherapy and autologous stem cell transplantation (ASCT), hence motivating investigations of complementary treatments. The aim of the present study was to evaluate feasibility and immunological effects of an immunotherapy schedule administered during chemotherapy-induced remission of aggressive non-Hodgkińs lymphoma (NHL). Repeated cycles of rIL-2, rIFN-alpha and histamine were administered to a patient with a grade III follicle center cell lymphoma, following relapse and high-dose chemotherapy with stem cell support. T-cell cytokine production and repertoire alterations were monitored by flow cytometry together with assessment of natural killer (NK) cell-mediated cytotoxicity. The treatment schedule induced significant increases in frequencies of CD4+ T cells expressing intracellular IFN-gamma or IL-4, thus a T helper (Th) 1 and Th 2 type of response were observed. CD8+T cells showed enhancement mainly of TNF-alpha production. Such induction of T-cell effector functions was accompanied by an augmentation of NK-cell cytotoxicity and a pronounced reduction of possibly regulatory CD57 expressing lymphocytes. The results indicate synergistic T- and NK-cell activation by tolerable doses of the combined immunotherapy, administered during remission after chemotherapy and ASCT in NHL.

Summary. To analyse autologous lymphocyte cytolytic activities of potential importance for cell-based immunotherapy in multiple myeloma (MM), in vitro differentiated dendritic cells (DCs) loaded with patient-specific monoclonal immunoglobulin (mIg) were used as autologous target cellsin cytotoxicity assays. Effector populations consisted of purified natural killer (NK) cells (CD56+, CD3–) and T cells (CD3+). The MM patients' NK cells cultured in the presence of interleukin 2 (IL-2) showed pronounced cytotoxic activity towards autologous mature DCs. Autologous MM DC targets displayed similar susceptibility to NK cell lysis, compared with allogeneic control DC targets, despite high surface expression of self major histocompatibility complex (MHC) antigens. However, some degree of classic MHC class I-mediated negative regulation was implicated in the NK–DC interactions, as indicated by class I blocking experiments. NK-mediated lysis was also discerned towards primary autologous MM cells. The results indicated that the major effector mechanism was mediated through the perforin–granzyme exocytosis pathway. In conclusion, NK cells from MM patients displayed significant and consistent cytotoxicity towards autologous mature DCs, suggesting that innate immunity could be implicated in MM and may influence the outcome of the administration of tumour antigen-pulsed DCs in treatment trials.

Objective: In the current obesity epidemic, the ability to remain lean is beginning to be uncommon. Therefore, it was considered of interest to characterize such subjects. Research Methods and Procedures: From a population of premenopausal women (n = 270), all 40 years of age, those with a similar body mass index (BMI) as women at the age of 21 years, born the same year (BMI = 21.1 kg/m2) were selected among nonsmokers and compared with the remaining nonsmoking women. Results: Lean women showed, as expected, low waist-to-hip circumference ratio and abdominal sagittal diameter as well as absence of other disease risk factors. Compared with the remaining women, 17β-estradiol was high and androgens were low, whereas insulin-like growth factor I and thyroid hormones showed no differences. Dihydroepiandrosterone sulfate was lower, whereas cortisol, measured in saliva repeatedly over a day, and adrenocorticotropin hormone were not different. Results from questionnaires indicated higher education and socioeconomic status, frequent sports activities, and better psychosocial adaptation and psychological health. A tetranucleotide repeat polymorphism in the fifth intron of the aromatase P450 gene was longer among the lean (187 base pairs) than the rest of the women. Women with opposite phylogenetic characteristic have a short microsatellite (168 base pairs) in this gene locus. Discussion: Lean, nonsmoking women enjoy an excellent health in not only anthropometric and metabolic factors, but also in neuroendocrine, endocrine, and psychological variables. The endocrine measurements suggest a well-functioning aromatase, which in turn might have a genetic background, contributing to health. The aromatase gene might be important for regulation of body fat mass.

Rhabdomyolysis is a rare complication in haematological malignancies, and a diverse range of factors has been implicated in the etiology of the syndrome. In the present study we analysed muscle morphology and antibody reactivities to skeletal muscle proteins in a patient diagnosed with lambda (λ) light chain-secreting multiple myeloma (MM) and amyloidosis, who developed a progressive rhabdomyolysis. The muscle tissue analysis showed focal amyloid depositions and a low degree of atrophy and inflammation. Antibody reactivities against muscle proteins of approximately 42, 51 and 66 kD, respectively, were present in the patient's serum. The antibody specificities were revealed by λ light chain- or IgM-specific antibodies. The results indicate a possible etiologic link between antibody reactivities towards muscle proteins and muscle tissue disorder in a patient with the unique combination of rhabdomyolysis, amyloidosis and MM of the light chain type.

Several studies have reported an association between anxiety-related personality traits and a promoter polymorphism in the human serotonin transporter (5-HTT) gene (5-HTT gene-linked polymorphic region, 5-HTTLPR). In the present study, a population of 251 subjects was assessed with the Karolinska Scales of Personality (KSP) and genotyped both for the 5-HTTLPR and for a variable number of tandem repeats polymorphism in the second intron of the same gene. The interpretation of previous studies has to some extent been confounded by the studied subjects differing with respect to ethnicity, sex, and age. To circumvent this problem, all included subjects were Caucasians, women, and born in the same year (1956). Associations were found between the 5-HTTLPR and four of the five anxiety-related KSP scales (psychic anxiety, muscular tension, psychasthenia, and lack of assertiveness), subjects being homozygous for the short allele displaying higher anxiety scores than those of the long/long or long/short genotype. In addition, an association was found between the intron 2 polymorphism and one anxiety-related personality trait (somatic anxiety). © 2001 Wiley-Liss, Inc.

To elucidate the possible role of genetic variation in androgen receptor (AR), estrogen receptor α (ERα), and ERβ on serum androgen levels in premenopausal women, the CAG repeat polymorphism of the AR gene, the TA repeat polymorphism of the ERα gene, and the CA repeat polymorphism of the ERβ gene were studied in a population-based cohort of 270 women. Total testosterone, free testosterone, dehydroepiandrosterone sulfate, androstenedione, 17-hydroxyprogesterone, 3α-androstanediol glucuronide, 17β-estradiol, LH, FSH, and sex steroid hormone-binding globulin (SHBG) were measured in serum samples obtained in the follicular phase of the menstrual cycle. Women with relatively few CAG repeats in the AR gene, resulting in higher transcriptional activity of the receptor, displayed higher levels of serum androgens, but lower levels of LH, than women with longer CAG repeat sequences. The CA repeat of the ERβ gene also was associated with androgen and SHBG levels; women with relatively short repeat regions hence displayed higher hormone levels and lower SHBG levels than those with many CA repeats. In contrast, the TA repeat of the ERα gene was not associated with the levels of any of the hormones measured. Our results suggest that the serum levels of androgens in premenopausal women may be influenced by variants of the AR gene and the ERβ gene, respectively.

This study sought to examine the potential influence of personality disorders (PD) on anthropometry, hormones and metabolism in women. In a population sample of women born in 1956 (no.=270), estimates of PD:s by Structured Clinical Interview for DSM-III-R, Axis II, were correlated with anthropometric, endocrine, and metabolic factors. The PD:s were grouped into three thematic clusters: cluster A (characterized by oddness or eccentricity), cluster B (characterized by self-centeredness, emotionality, and erratic behavior) and cluster C (characterized by anxiety and fear). Subjects with cluster A PD:s had significantly increased body mass index (BMI, kg/m2) and abdominal sagittal diameter (cm) as well as lower salivary cortisol after dexamethasone (DEX) compared to controls. Subjects with cluster B also had a significantly higher abdominal sagittal diameter and significantly lower salivary cortisol levels after DEX than controls. In addition, subjects with cluster B PD:s had decreased levels of ACTH, and significantly higher concentrations of lactate and triglycerides, while high-density lipoprotein (HDL) cholesterol was significantly lower compared to controls. A significantly higher waist/hip ratio was seen among subjects with cluster C PD:s. In addition, these subjects had higher levels of insulin, glucose, lactate, triglycerides, total cholesterol and low-density lipoprotein (LDL) cholesterol than controls. Moreover, IGF-I and HDL cholesterol were significantly decreased in the former group. These results suggest that PD:s are involved in the development of obesity and abdominal fat accumulation in women, with different endocrine and metabolic profiles depending on the type of PD.

Circulating immune complexes (CIC) are frequently found in postinfarction patients. The constituents of these CIC are mostly unknown.The objective of the current study was to assess whether CIC containing alimentary proteins and antibodies against these proteins are implicated in precocious myocardial infarction (MI).Seventy-six survivors (67 men and 9 women, mean age 39 years) of a first MI before the age of 45 years were enrolled in this study. Two control groups were included. One group consisted of age-matched, randomly selected, population-based healthy individuals, 79 men and 11 women, without features of coronary heart disease. An additional control group was used only for the determination of serum antibodies against some of the alimentary proteins and consisted of 139 healthy blood donors, 95 men and 44 women, with a mean age of 42 years. Sucrose density gradient centrifugation, gel filtration and precipitation by polyethylene glycol were used for the isolation of CIC, and enzyme-linked immunosorbent assay (ELISA) was used to measure the immunoglobulin levels and specific antibodies against alimentary proteins in both sera and isolated CIC. Sodium dodecylsulfate (SDS) polyacrylamide gel electrophoresis and Western blotting were used to determine alimentary proteins in the CIC.Alimentary antigens/antibodies were present in immune complex form in seven out of 14 (50%) postinfarction patients who had persistent high concentrations of CIC, the latter constituting 18% of the entire group. Antibodies of the IgG isotype predominated. A rise in CIC, signs of activation of the classical complement pathway, and a rise in plasma concentrations of von Willebrand factor antigen (vWFAg) were evident within 1 week in four patients subjected to a 2-week elimination diet followed by a single challenge with cow's milk.This study suggests that dietary proteins occasionally give rise to persistent CIC, which may predispose to MI at a young age.

Multiple myeloma (MM) is a B-cell malignancy characterized by an accumulation of malignant plasma cells in the bone marrow. It is unclear whether genetic background could have an etiological impact on MM or influence the course of the disease. Interleukin-10 (IL-10) has been implicated in the growth and differentiation of normal B cells, and has also been shown to enhance the proliferation of MM cells. To address the putative involvement of IL-10 genetic variation in MM, we analyzed previously defined loci for bi-allelic polymorphism at position -1082 and two microsatellite loci (IL10.G and IL10.R) in the IL-10 promoter region. Seventy-three patients with MM, 27 with monoclonal gammopathy of undetermined significance, and 109 ethnically matched individuals as controls were included in the study. Significantly increased frequencies of the IL10.G genotype 136/136 and the IL10.R genotype 112/114, in addition to a decreased frequency of the IL10.R genotype 114/116, were found among the MM patients. Increased production of IL-10 was detected in the supernatants of lipopolysaccharide-stimulated peripheral blood mononuclear cells from MM patients who were homozygotes (136/136) and heterozygotes (136/non-136) for the IL10.G allele 136, as compared with the other IL10.G genotype carriers (non-136/non-136). These results suggest that the genetic variation in the IL-10 promoter region may play a role in the development of MM. © 2001 Wiley-Liss, Inc.

The association between the catechol-O-methyltransferase Val158Met polymorphism and panic disorder was studied in a Swedish sample of 211 patients and 452 controls. We found a significant excess of the Val allele in both male and female patients, the latter but not the former finding being in line with previous studies.

Hyperandrogenemia is the primary biochemical abnormality in women with polycystic ovary syndrome (PCOS). Despite numerous studies looking for differences in the levels of testosterone and other sex steroid hormones between women with PCOS and control populations, no definitive diagnostic endocrine markers for this syndrome have been identified. The investigators hypothesized that measurement of serum levels of sex steroid hormones with mass spectrometry would provide a more comprehensive profile of these hormones, and might show higher levels in women with PCOS than in controls. This cross-sectional study measured serum levels of sex steroid hormones in women with PCOS and controls, using a specific and sensitive mass spectrometry-based technique, to determine whether higher levels of some of these hormones could be diagnostic markers for the syndrome. The study population was comprised of women with PCOS (study group, n = 74) and a control group (n = 31). Levels of serum sex steroid precursors, estrogens, androgens, and glucuronidated androgen metabolites were measured in both groups. Immunoassays were performed to determine levels of sex hormone binding globulin, luteinizing hormone (LH), and follicle-stimulating hormone (FSH); and the LH/FSH ratio was calculated. Multivariate analysis was used to adjust for covariables. Before and after adjustment for age and body mass index, serum levels of androgens and estrogens, sex steroid precursors, and glucuronidated androgen metabolites were higher in women with PCOS compared to controls. Levels of LH and the LH/FSH ratio were also higher in women with PCOS. Multivariate logistic regression analyses showed that both estrone and free testosterone were independently associated with PCOS; the odds ratios per standard deviation increase were 23.8 for estrone, with a 95% confidence interval (CI) of 4.1 to 139.7, and 12.0 for free testosterone, with a 95% CI of 3.0 to 49.0. In combination, the association was even stronger. Estrone levels greater than 50 pg/mL and free testosterone levels more than 3.3 pg/mL discriminated between women with and without PCOS, with high specificity and sensitivity. In receiver operating characteristic analyses of the ability of estrone and free testosterone to detect PCOS, both had high sensitivity and specificity; the area under the curve was 0.93 for estrone (95% CI, 0.88-0.98) and 0.91 for free testosterone (95% CI, 0.86―0.97). These findings show that comprehensive analysis of serum sex steroid levels, with specific and sensitive mass spectrometry techniques is able to distinguish women with PCOS from controls. Serum levels of sex steroid precursors, androgens, glucuronidated androgen metabolites, and estrogens are higher compared to controls. Estrone and free testosterone—individually and especially in combination—are independently associated with PCOS.

Objective: To investigate possible differences, between generally and abdominally obese men, in activity and regulation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. Research Methods and Procedures: Fifty non-diabetic, middle-aged men were selected to obtain two groups with similar body mass index (BMI) but different waist/hip circumference ratio (WHR). Measurements were performed of the activity of the HPA axis and the sympathetic nervous system, as well as metabolic and endocrine variables. Results: Men with a high WHR, in comparisons with men with a low WHR, had higher insulin, glucose, and triglyceride values in the basal state and higher glucose and insulin after an oral glucose tolerance test. Men with high WHR had elevated diurnal adrenocorticotropic hormone (ACTH) values but similar cortisol values, except lower cortisol values in the morning. Diurnal growth hormone concentrations showed reduced peak size. Stimulation of the HPA axis with corticotropin-releasing hormone (CRH) and laboratory stress showed no difference in ACTH values between groups, but cortisol values were lower in men with high WHR. In comparison with men with a low WHR, men with a high WHR had elevated pulse pressure and heart rate in the basal state and after challenges by CRH and laboratory stress. They also had increased urinary excretion of catecholamine metabolites. Discussion: These results suggest a mild dysregulation of the HPA axis, occurring with elevated WHR independent of the BMI. The results also indicate a central activation of the sympathetic nervous system, such as in the early phases of hypertension, correlating with insulin resistance.

Recent animal studies indicate that leptin is involved in the regulation of blood pressure through the leptin receptor. Therefore, 51-yr-old men (N = 284) were selected; and anthropometric, endocrine, metabolic, and hemodynamic variables were examined in relation to polymorphisms of the leptin receptor gene (LEPR), by restriction fragment length polymorphism technique. Three polymorphisms were examined: Lys109Arg in exon 4, Gln223Arg in exon 6, and Lys656Asn in exon 14. In comparison with Lys109 homozygotes, Arg109 homozygotes (9%) showed lower body mass index (BMI) and abdominal sagittal diameter, as well as lower systolic (10.0 mm Hg) and diastolic (7.8 mm Hg) blood pressure. Additionally, Arg223 homozygotes (26.8%) showed lower blood pressure (7.6/5.7 mm Hg) than Gln223 homozygotes. These lower blood pressure levels were independent of other variables. No differences were found with the Lys656Asn polymorphism. Measurements of body fat mass correlated with leptin concentration in Lys109 homozygotes and in Lys109 heterozygotes but not in Arg109 homozygotes. Blood pressure correlated with leptin only in men carrying the wild-type allele Lys109. With both elevated BMI and leptin, Lys109 homozygotes had higher blood pressure than the Arg109 homozygous men (12.4/6.9 mm Hg). Men with blood pressure > or = 140/90 mm Hg had, in comparison with normotensive men, increased BMI and leptin levels, and Lys109 homozygotes were significantly more prevalent. These results suggest that leptin is associated with blood pressure regulation in men through the leptin receptor. When BMI and leptin are elevated, increased blood pressure is found only with the most prevalent LEPR genotype at codons 109 and 223, whereas variants of this receptor seem to protect from hypertension. This might explain why not all obese men are hypertensive.

Abdominal obesity affects many aspects of women's health, and recent studies indicate that hyperandrogenicity (HA) may contribute to the excess of body fat in women. As hormone behavior research attributes male-like play patterns in childhood to the effects of androgens, the aim of the present study was to assess the potential association of such behavior with obesity in adult women. In a randomly selected sample of 40-year-old women (n = 1464), 78% volunteered to respond to a questionnaire collecting information on the effect of other variables on childhood behavior. Self-reported body weight, height, and waist and hip circumferences were used to calculate body mass index (BMI) and waist/hip ratio (WHR). Age at menarche showed an inverse association with overweight (BMIor = 25) (odds ratio [OR] = 0.82). Reports of gender-related behavior as a child showed that playing with girls and girl toys was negatively related to both overweight and abdominal obesity (WHRor = 0.85). Among respondents who were overweight, relationships were found for playing with boys (OR = 0.90) and fighting (OR = 1.70). The OR of playing with boy toys and fighting among respondents with abdominal obesity were increased 1.12 and 1.65, respectively. Interests in athletics as a child seemed to decrease the risk for overweight (OR = 0.89) and abdominal obesity (OR = 0.91). Furthermore, dose-response analysis between the individual exposure levels and the OR for overweight showed a negative trend for playing with girls (p = 0.002) and girl toys (p = 0.017) and a positive trend for playing with boys (p = 0.011) and fighting (p = 0.031). Among respondents with abdominal obesity, positive dose-response effects were found for playing with boys (p = 0.026) and boy toys (p = 0.036) and fighting (p = 0.008). Thus, women with an elevated WHR showed a preference to play with boys and boy toys and also fought frequently as children. This might be a sign of a relative HA in childhood ("tomboyism"). These preliminary observations suggest that HA may originate in childhood.

Proinflammatory cytokines such as interleukin 6 (IL-6), tumour necrosis factor α (TNF-α) and IL-1β are considered to be involved in the pathogenesis of multiple myeloma (MM). In the present study, we examined a G/C polymorphism at position −174 in the promoter region of IL-6, a biallelic polymorphism at position −308 in the promoter region of TNF-α, the TaqI restriction fragment length polymorphism in exon 5 of IL-1β and a variable number of identical tandem repeat polymorphisms in intron 2 of IL-1 receptor antagonist (IL-1Ra) genes. The alleles of these loci are known to influence the level of production of the cytokines and the IL-1Ra. Seventy-three patients with MM, 27 with monoclonal gammopathy of undetermined significance (MGUS) and 129 healthy individuals were included. No difference was found between patients and healthy controls or between MM and MGUS patients in the distributions of genotypes and frequencies of alleles of the IL-6 (−174), TNF-α (−308), IL-1βTaqI and IL-1Ra gene polymorphisms. No associations between the polymorphisms at the loci under study and clinical factors such as age, sex, clinical stage at onset and M-protein type were observed. Our results indicate that the cytokine (IL-6, TNF-α and IL-1β) and IL-Ra gene polymorphisms do not confer susceptibility to the development of MM.

Summary Aims Type 2 diabetes mellitus (DM) develops when insulin resistance overcomes the capacity of compensatory insulin secretion. Insulin resistance may be induced via psychoneuroendocrine pathways, a possibility which has received little previous attention. Methods We have used salivary cortisol measurements to monitor the activity of the hypothalamic–pituitary–adrenal (HPA) axis, the major controller of hormones involved in the regulation of peripheral insulin sensitivity under everyday conditions. The influence of external challenges, as well as the sensitivity of feedback regulation, were followed in randomly selected middle-aged population samples. Results In health there is a rhythmicity of cortisol secretion, with a high plasticity and efficient feedback control. In contrast, a group of subjects were identified with a flat, rigid day curve and poor feedback control, who showed consistent abnormalities in stress-related cortisol secretion, including inhibited secretions of sex steroids and growth hormone; insulin resistance; abdominal obesity; elevated leptin levels; hyperglycaemia; dyslipidaemia and hypertension with elevated heart rate. The endocrine abnormalities are probably responsible for the anthropometric and metabolic abnormalities. The circulatory perturbations seem to be induced by a parallel activation of the central sympathetic nervous system suggesting an ‘hypothalamic arousal syndrome’, gradually developing into an independent risk for disease. An associated cluster of environmental factors, including psychosocial and socio-economic stress, traits of depression and anxiety, alcohol consumption and smoking, all factors known to activate hypothalamic centres, has been identified. A polymorphism of the glucocorticoid receptor gene, with 13.7% homozygotes in the male Swedish population, parallels receptor dysfunction, and may be responsible for the associated insulin resistance, central obesity and hypertension. Conclusions This is the first detailed examination of psychoneuroendocrinological processes in the natural environment on a population basis in relation to somatic health. The results suggest that an hypothalamic arousal syndrome, with parallel activation of the HPA axis and the central sympathetic nervous system, is responsible for development of endocrine abnormalities, insulin resistance, central obesity, dyslipidaemia and hypertension, leading to frank disease, including Type 2 DM. We suggest that this syndrome is probably based on environmental pressures in genetically susceptible individuals. Diabet. Med. 16, 373–383 (1999)