Jerzy Wasserman

Lymphocyte and granulocyte reactions during sleep deprivation.

&NA; The possible influence of 48 hr of sleep deprivation on in vitro DNA synthesis of blood lymphocytes and on the adhesiveness and intracellular, stainable activity of alkaline phosphatase in blood granulocytes was studied in twelve young male volunteers. Following the sleep deprivation, all 12 subjects showed marked reductions of DNA synthesis after stimulation with phytohemagglutinin. Pre‐exposure levels were regained 5 days after terminating the vigil. No changes were noted in granulocyte adherence or alkaline phosphatase activity. The results suggest that sleep deprivation may decrease cell‐mediated immune reactions and thereby impair some aspects of host defense.

The CRHR1 gene: a marker for suicidality in depressed males exposed to low stress

The risk of suicide, which causes about 1 million deaths each year, is considered to augment as the levels of stress increases. Dysregulation in the stress response of the hypothalamic‐pituitary‐adrenocortical (HPA) axis, involving the corticotrophin‐releasing hormone (CRH) and its main receptor (CRHR1), is associated with depression, frequent among suicidal males. Here we have analyzed single nucleotide polymorphisms (SNPs) in these genes, in family trios with suicide attempter offspring (n = 542), by using the transmission disequilibrium test both in a two‐staged screening/replication sample design and in detailed reanalysis in the entire sample. Stratification based on the levels of lifetime stress showed reproducible association and linkage of an SNP in the CRHR1 gene (rs4792887) to suicide attempters exposed to low levels of stress (P = 0.002), among whom most males were depressed (P = 0.001). The identified allele may represent a part of the genetic susceptibility for suicidality by increasing HPA axis activity upon exposure to low levels of stress.

Neuroendocrine and immunologic effects of unemployment and job insecurity.

We prospectively followed a cohort of 354 blue-collar men and women, some of whom lost their jobs. Results show marked effects during the anticipatory and early unemployment phase on mental well-being, serum cortisol, prolactin, total cholesterol, HDL cholesterol, and phytohemagglutinin reactivity of lymphocytes. Most of these changes appear to be of short-term duration. However, changes in cardiovascular risk factors are observed at least 2 years following the loss of ones job. Coping style appears to be a major determinant whether or not and how people will react to unemployment.

Oral candida albicans in HIV infection.

The prevalence of oral colonization with Candida albicans was studied in 225 homosexual men, 99 of whom had HIV antibodies and in 175 heterosexual men. Oral candidal carriage was most prevalent among HIV seropositive homosexual men (77.8%). Rich growth of C. albicans in culture and findings of pseudomycelial elements in oral mucosal smear also correlated with HIV seropositivity. Pseudomycelial forms of C. albicans were demonstrated in mucosal smear from all patients with oral mucosal lesions suspected for candidiasis. However, 26/53 patients (49.1%) with positive smear had no clinical signs of oral candidiasis. The oral yeast flora was sampled twice in 85 homosexual men at an interval of 12-18 months. 71/85 patients (83.5%) were grouped into the same category of candidal colonization; carrier or noncarrier state, on both occasions. No statistically significant differences in numbers of CD 4 cells or CD 8 cells were observed between patients with respect to candidal colonization, when HIV seropositive and seronegative homosexual men were considered separately.

Immunological changes in primary HIV-1 infection

Homosexual men with symptomatic primary HIV-1 infection displayed a pronounced lymphopaenia with significantly depressed numbers of CD3+, CD4+ and CD8+ cells and B cells during the first week of illness. Subsequently, the CD8+ cell counts rose in parallel with numbers of CD3+ cells, atypical lymphocytes and activated (CD38+ and HLA-Dr+) cells to attain maximal levels about a month following onset of illness. In contrast CD4+ and B cell numbers remained low for an extended period of time. Early signs of a host response included a transient appearance of interferon-alpha in the blood and raised levels of neopterin and beta 2-microglobulin (beta 2-M). Neither CD4+/CD8+ cell ratio nor beta 2-M resumed completely normal values during a follow-up period of 2 years. These findings shed some light on pathogenetic events during early HIV-1 infection and suggest that the infection, following the acute symptomatic stage, usually enters a stage of chronic active rather than latent infection.

Depression in suicidal males: genetic risk variants in the CRHR1 gene

Dysregulation in the stress response of the hypothalamic–pituitary–adrenal axis, involving the corticotrophin‐releasing hormone and its main receptor (CRHR1), is considered to play a major role in depression and suicidal behavior. To comprehensively map the genetic variation in CRHR1 in relation to suicidality and depression, as a follow‐up to our initial report on SNP rs4792887, we analyzed six new single nucleotide polymorphisms (SNPs), in an extended sample of family trios (nu2003=u2003672) with suicide attempter offspring, by using family‐based association tests. The minor T‐allele of exonic SNP rs12936511, not previously studied in the context of psychiatric disorders and suicidal behaviors, was significantly transmitted to suicidal males with increased Beck Depression Inventory (BDI) scores (nu2003=u2003347; Pu2003=u20030.0028). We found additional evidence of association and linkage with increased BDI scores among suicidal males with an additional SNP, located proximally to the index SNP rs4792887, as well as with two distal SNPs, which were correlated with index SNP rs4792887. Analysis of haplotypes showed that each of the risk alleles segregated onto three separate haplotypes, whereas a fourth ‘nonrisk’ haplotype (‘CGC’) contained none of the risk alleles and was preferentially transmitted to suicidal males with lowered BDI scores (Pu2003=u20030.0007). The BDI scores among all suicidal males, who carried a homozygous combination of any of the three risk haplotypes (non‐CGC/non‐CGC; nu2003=u2003160), were significantly increased (Pu2003=u20030.000089) compared with suicidal male CGC carriers (nu2003=u2003181). Thus, while the characteristics of the suicide female attempters remained undetermined, the male suicidal offspring had increased depression intensity related to main genetic effects by exonic SNP rs12936511 and homozygous non‐CGC haplotypes.

Genetics of HPA-axis, depression and suicidality

The ultimate consequence of mental ill-health, suicidal behavior (SB), is a significant problem in most societies of the world. Suicide causes about one million deaths worldwide each year, and 10-20 times more people attempt suicide. The causes of why certain people engage in SB are complex, involving for e.g., both environmental and genetic factors, and interactions in-between. Well-established environmental risk factors are events causing significant psychological stress, which are particularly difficult to cope with, e.g. exposure to physical and sexual abuse. Excessive stress have the potential to induce unfavorable effects in a variety of higher brain-functions, incurred as side-effects to maladaptive responses in the genetically controlled stress-responsive neurosystems, e.g. the hypothalamic-pituitary-adrenal (HPA) axis; a major and systemic stress-modulator, which is mainly controlled by the regulatory corticotrophin releasing hormone receptor 1 (CRHR1) gene. Variation in-between individuals in such stress-regulatory genes such as CRHR1, may underlie the causes of the increased susceptibility of certain individuals towards SB. Here we review some of the current knowledge on what is known about the roles of the HPA axis in SB, with a focus on CRHR1.

Nature and nurture in suicidal behavior, the role of genetics: some novel findings concerning personality traits and neural conduction.

Suicide affects about one million people each year, a phenomenon characterized by heterogeneous and complex causes. Often environmental factors such as negative life events may act as a significant contributor to suicidal behavior. However, in many cases the exposure to the same environmental stress does not result in increased suicidality. It is now well established that there is also a substantial genetic contribution to suicidal behavior. Here, functional and association studies which implicate specific genes in psychological traits and environmental factors are discussed, interactions which are related to completed suicide or suicide attempt, and our novel findings which need replication are presented. We found that genetic variation in the noradrenergic tyrosine hydroxylase gene was associated with the angry/hostility personality trait and vulnerability to stress. Similarly, we recently discovered that genetic variation in components of the stress-related hypothalamic pituitary adrenocortical axis, T-box 19 and corticotropin releasing hormone receptor 1, showed association and linkage to high anger/hostility in and male depression the suicidal offspring, respectively. Further results from our studies have revealed that genetic variation in genes with roles in basal mechanisms of neural conduction, voltage-gated sodium channel type VIII alpha and vesicle-associated membrane 4 protein, showed association and linkage among suicide attempters. Additionally, we have results which give support to the findings of others, implicating the serotonin transporter and serotonin receptor 1A in suicidal behavior. Our future studies aim at identifying and resolving complex patterns and mechanisms of neurobiological gene-environment interactions, which may contribute to suicide.

The serotonin 1A receptor C(-1019)G polymorphism in relation to suicide attempt

BackgroundSerotonergic neurotransmission has been implicated in suicidal behavior. Association between suicidal completers and a regulatory C(-1019)G polymorphism (rs6295) in the serotonin 1A receptor (HTR1A) gene was previously reported, whereas a following study showed no association in a sample of suicide attempters.MethodsThe involvement of the implicated G-allele of the 5-HTR1A C(-1019)G polymorphism (rs6295) was analyzed with the transmission disequilibrium test (TDT) in a sample of 272 suicide attempter families.ResultsNo overtransmission of the G-allele was found in the entire sample of suicide attempters (p = 0.1460; n = 272 trios). However, a strong trend for overtransmission of the G-allele was observed in a sub-sample selected for a high level of previous traumatic and/or stressful life events prior to the suicide attempt (p = 0.0630, two-tail; n = 94 trios).ConclusionThe current results show that variation at the rs6295 polymorphism of the HTR1A gene is not associated with suicide attempts generally. However, the results indicate a possible role of the G-allele in suicidal behavior in connection with high exposure to traumatic and/or stressful life events, which is in need of future investigation.

Suicide attempt and basic mechanisms in neural conduction: Relationships to the SCN8A and VAMP4 genes

Family and twin studies show that genetic variation influences suicidal behavior, but do not indicate specific genes. We investigated the relationship between genetic variation and suicide attempt by screening 250 genetic markers using transmission disequilibrium test (TDT) analysis. Analysis of 77 triplets (suicide attempters and both their parents), indicated that gene‐variants in, or adjacent to, the sodium channel, voltage gated, type VIII, alpha polypeptide (SCN8A) (Pu2009=u20090.008), vesicle‐associated membrane protein 4 (VAMP4) (Pu2009=u20090.004), and prenylated Rab acceptor 1 (RABAC1) (Pu2009=u20090.006) genes are over‐transmitted in suicide attempt. Replication in a separate sample, consisting of 190 triplets, confirmed the exploratory data for the SCN8A (Pu2009=u20090.005) and VAMP4 (Pu2009=u20090.019) genes, but failed to confirm the data for the RABAC1 gene. Our results indicate that genetic variation in the SCN8A and VAMP4 genes may contribute to risk for suicide attempt, possibly through alterations in neural conduction.