Increased occurrence of free immunoglobulin light chains in cerebrospinal fluid and serum in human immunodeficiency virus-1 infection

The presence of free immunoglobulin light chains (FLCs) in the cerebrospinal fluid (CSF) and sera of patients with human immunodeficiency virus-1 (HIV-1) infection, multiple sclerosis (MS), and neurologically healthy control individuals was investigated by paying special attention to ensure that only truly free light chains would be detected. The FLCs were extracted by specifically binding them to Sepharose-coupled anti-FLC monoclonal antibodies, and thereafter they were electrophoresed and immunoblotted with monoclonal antibodies to both light chain (LC) isotypes. A frequent occurrence of kappa and lambda FLCs was found in both CSF and sera of HIV-1 infected patients. In HIV-1 infection and in MS, the frequency of FLCs of the CSF was equal. In healthy controls, only occasional weak FLCs were observed in either CSF or serum. FLC bands of the CSF from patients with HIV-1 infection tended to be more intensive than those of the appropriately diluted sera. Both intrathecal synthesis of FLCs and their transudation from sera through the impaired blood-brain barrier (BBB) may contribute to this. Increasing severity of general HIV-1 infection was accompanied by an increase of FLC intensity in sera. A qualitative demonstration of FLC in the CSF may be meaningful only in the absence of altered BBB function.     

Human leukocyte antigen-B8-DR3 is a more important risk factor for severe Puumala hantavirus infection than the tumor necrosis factor-alpha(-308) G/A polymorphism

The tumor necrosis factor (TNF)-alpha(-308) G/A polymorphism (TNF-2) is in linkage disequilibrium with the human leukocyte antigen (HLA)-B8-DR3 haplotype. Both factors have been associated with severe Puumala hantavirus-induced nephropathia epidemica (NE). To examine which part of this extended haplotype might show the strongest association with the outcome of NE, the HLA-B, HLA-DRB1, and TNF-alpha(-308) alleles in 116 hospital-treated patients with NE were analyzed. The findings pointing to clinically severe NE were strongly associated with HLA-B8-DR3 haplotype. There was a trend toward severe disease in persons positive for TNF-2. This was probably due to strong linkage disequilibrium with HLA-B8-DR3, since there were no differences in the clinical severity of NE when TNF-2-positive/B8-DR3-negative persons were compared with TNF-2-negative/B8-DR3-negative persons. It is concluded that the HLA-B8-DR3 haplotype is an important contributor to the course of NE. The data indicate that the TNF-2 allele is not an independent risk factor for severe NE but a passive component in the extended haplotype.     

Regional differences in the prevalence of pre-eclampsia in relation to the risk factors for coronary artery disease in women in Finland.

AIMS: The aim of this study was to examine the prevalence of pre-eclampsia in Southern, Eastern, and Northern Finland, and the relationship between history of pre-eclampsia and maternal coronary artery disease (CAD) risk factors. METHODS AND RESULTS: Women aged 25-64 years, who participated in a cross-sectional population survey and had been pregnant (n=3650), were studied. The proportion of women who had ever had pre-eclampsia was lower in Southern (7.9%) compared with Northern Finland (13.9%) (P=0.001), but did not differ from Eastern Finland (11.1%). In the logistic regression model, the age-adjusted prevalence of pre-eclampsia was 1.92-fold in Northern (95% CI: 1.46-2.53, P<0.001) and 1.47-fold in Eastern Finland (95% CI: 1.11-1.96, P=0.008) compared with Southern Finland. The odds ratios (ORs) were 1.70 (95% CI: 1.21-2.38, P=0.002) and 1.16 (95% CI: 0.82-1.64, P=0.40), respectively, when adjusted for age at first birth, current age, parity, body mass index (BMI), increased blood cholesterol, hypertension, diabetes/impaired glucose tolerance, CAD, and mother's myocardial infarction. History of pre-eclampsia was associated with increased blood cholesterol, higher current BMI and blood pressure, and higher current prevalence of hypertension, diabetes/impaired glucose tolerance. CONCLUSIONS: Pre-eclampsia is most prevalent in the Northern part of Finland and could only be partly explained by higher prevalence of CAD risk factors.     

Combination of subcutaneous levonorgestrel implants and transdermal dihydrotestosterone gel for male hormonal contraception

The primary aim of the present study was to determine the therapeutic dose of subcutaneous levonorgestrel (LNG) to induce azoospermia or severe oligozoospermia (<3 x 10(6)/mL) in normal men requiring contraception. Transdermal 5 alpha-dihydrotestosterone (DHT) was combined to the treatments to maintain peripheral androgen level. Forty-three 21-45-year-old healthy men were enrolled in this phase II randomised and comparative clinical performance study. The subjects were allocated to five groups to receive: (1) transdermal DHT (Andractim(R), Besins Iscovesco, Paris, France) and one subdermal LNG implant (Jadelle, Leiras, Turku, Finland); (2) transdermal DHT and two subdermal LNG implants; (3) transdermal DHT and four subdermal LNG implants; (4) transdermal DHT and oral LNG (Microluton, Schering, Germany); or (5) transdermal DHT only. A total of 27 men completed the suppression phase. None of them reached azoospermia. One subject with oral LNG and transdermal DHT reached <3 million/mL at 5 months of suppression, but not repeatedly. Together 2/27 (7%) subjects, one with oral LNG and DHT and the other with four subdermal LNG implants and DHT reached <5 million/mL temporarily. Altogether 9/27 (33%) subjects reached <20 million/mL. Serum testosterone concentrations (S-T) decreased significantly during the first 3 months of treatment with one, two and four LNG implants and DHT and during the next 3 months S-T remained significantly lower with two or four implants. Serum oestradiol concentrations (S-E(2)) decreased significantly during the first 3 months only with four implants, but at 6 months S-E(2) was lower also in the group with two implants. Serum luteinizing hormone (LH) decreased significantly only with two LNG implants and DHT gel at 5 and 6 months. Serum FSH did not decrease in any of the groups. None of the subjects filled the criteria to continue to the efficacy phase. A total of 16 men discontinued for various reasons. Of the 27 men completing the suppression phase, all have recovered to sperm levels >20 million/mL. There were no changes in blood count, lipid profile, liver function tests, prostate-specific antigen (PSA), sex hormone binding globulin (SHBG), prolactin or cortisol. The mixed antiglobulin reaction (MAR)-IgG, MAR-IgA or tray agglutination test (TAT) did not change during any of the treatments. The present study shows that the LNG implants themselves are well-tolerated by men and safe, and might be suitable for replacing part of the testosterone used as injections to reduce the androgen dose during male hormonal contraception. The DHT gel was considered as quite or very uncomfortable by 66% of the men because of feeling cold during the time it was on the skin, but noncompliance in using the gel was not reported by the men.     

Increase in cerebral blood flow of right prefrontal cortex in man during orgasm

The functional anatomy of human emotional responses has remained poorly understood, mainly because invasive experiments in humans are unacceptable due to ethical reasons. The new functional imaging techniques such as positron emission tomography and single photon emission computed tomography have made it possible to study the neurophysiology of living humans non-invasively. We studied the regional cerebral blood flow with semi-quantitative ^99mTC-HMPAO single photon emission computed tomography in eight healthy right-handed heterosexual males during orgasm. The results showed decrease of cerebral blood flow during orgasm in all other cortical areas except in right prefrontal cortex, where the cerebral blood flow increased significantly (P < 0.005).     

Transgenic and knockout mouse models for the study of luteinizing hormone and luteinizing hormone receptor function

The main functions of luteinizing hormone (LH) are concerned with regulation of gonadal function, and these functions are today well delineated through previous physiological studies. However, novel information of less well-known aspects of actions of this hormone is currently emerging from studies on genetically modified mouse models, with either enhanced or suppressed LH/LH receptor (LHR) function. The novel functions of LH include its role, in specific situations, as promoter of formation and growth of gonadal and extragonadal tumors. Chronically elevated LH levels in transgenic (TG) mice can also induce responses to this hormone in extragonadal tissues. The knockout (KO) mouse for the LHR has elucidated various less well-known details in the function of LH during ontogeny and adult life. Finally, studies on LHR promoter function have revealed that the expression of this gene occurs in age, sex and tissues-specific fashion. The purpose of this brief review is to summarize some of our recent findings upon studies of TG and KO mice with altered function of LH or its receptor.     

Rat testis LH/hCG receptors and testosterone production after treatment with GnRH

Adult male rats were implanted subcutaneously for 1,2 or 4 days with Alzet^® osmotic minipumps, infusing synthetic gonadotropin-releasing hormone (GnRH) at a rate of 0.1 μg/h. Plasma LH increased significantly, reaching a maximum after 2 days treatment. Plasma and testicular testosterone levels increased to a maximum in 1 day, and decreased gradually thereafter, reaching the control level by day 4. Testicular specific [¹²⁵I]hCG binding decreased gradually during the treatment, being 57% of the controls by day 4. It is concluded that changes of physiologic magnitude in circulatory LH are able to induce a significant loss of testicular LH/hCG binding capacity. Furthermore, after a short stimulatory phase there is a lack of response in testicular steroidogenesis to the elevated LH levels.     

Immortalization by large T-antigen of the adult epididymal duct epithelium

The teleost brain is characterized by exceptionally high levels of aromatase, the enzyme that converts androgens into estrogens, and by its continuous growth throughout life. Gonadal estrogens have been implicated in sex differentiation and the control of reproduction in adult fish, but the role of neural estrogens during early development is far from clear. The present study describes the isolation and characterization of the cDNA sequence from brain aromatase (P450aromB) in the European sea bass (Dicentrarchus labrax L.), a well established model for neuroendocrine research in fish. P450aromB was cloned from a brain cDNA library and encoded a predicted protein of 505 residues, with a calculated molecular weight of 57.2 kDa. Comparisons of the deduced amino acid sequence to that of the ovarian aromatase (P450aromA) in the same species revealed 62% identity, lower than the 84% identity shared between sea bass and tilapia brain aromatases. Phylogenetic analysis showed the occurrence of a gene duplication for P450arom in the teleost lineage after its divergence from the tetrapods. Moreover, the low percentage of identity between brain and ovarian forms within the same species suggests that both genes evolved separately right after the appearance of the teleosts. Tissue-specific expression of P450aromA and P450aromB mRNA was studied in adult sea bass. P450aromB was preferentially expressed in brain of both males and females but also present at much lower levels in testis, ovary and head kidney, an organ known for its steroidogenic capabilities in fish. However, P450aromA expression was restricted to testis and ovary. A semiquantitative PCR was developed to measure P450aromB mRNA levels. Analysis of the expression of P450aromB in the brain of juvenile sea bass showed that females exhibited higher mRNA levels than males at 200 days post fertilization (dpf), by the time of gonadal sex differentiation. A switch in expression occurred thereafter, between 200 and 250 dpf, with males exhibiting higher levels than females. This situation was maintained by 300 dpf and is in agreement with measured levels of enzymatic activity in adults. These changes and sex-related differences in expression profiles may imply differences in the functionality of the enzyme between males and females, suggesting an important role for P450aromB in sea bass sex differentiation. However, due to the continuous growth of the teleost brain throughout life, a role in neurogenesis for brain aromatase should also be considered.