AVPR1A and OXTR polymorphisms are associated with sexual and reproductive behavioral phenotypes in humans. Mutation in brief no. 981. Online

Distinct life history patterns have been observed and characterized in humans and appear to have a heritable component. The specific genetic variation responsible for the heritability is unknown. This study tested two plausible candidate genes for association with human life history characteristics using a sample of Caucasian men and women taken from a large Australian community survey. Associations were found between two polymorphisms within the AVPR1A gene and age of first sexual intercourse in men and women. An association was also found between a polymorphism in the OXTR gene with the tendency to parent children at an earlier age in females. This study is the first to report associations between AVPR1A and OXTR genetic variation with life history traits in humans.     

Left ventricular function in diabetes mellitus. II: Relation between clinical features and left ventricular function.

We have shown a close relation between clinical microvascular complications and abnormalities of left ventricular function in 185 established diabetics without clinical heart disease. In 50 insulin-dependent diabetics who presented at under 20 years of age there was a correlation between the duration of diabetes and the isovolumic relaxation time, minimal dimension to mitral valve opening, and ratio of pre-ejection period to left ventricular ejection time. Diabetics with mild microvascular complications were similar to diabetics with no complications except for minor prolongation of the diastolic time intervals. Those with severe complications were significantly different from diabetes with milder complications and normal controls in all variables of left ventricular function. A close relation between left ventricular function and the microvascular complications index (code 0 when no complications to code 7 when all present and severe) was found for the following variables: isovolumic relaxation time, the interval from minimal dimension to mitral valve opening, ratio of pre-ejection period to left ventricular ejection time, and pre-ejection period index. It is concluded that in diabetes abnormalities of left ventricular function are related to duration of disease and complications; and that a diabetic specific heart muscle disorder occurs frequently in patients with severe microvascular complications.     

Exploiting graft-versus-tumour responses using donor leukocyte infusions

Allogeneic stem cell transplantation (SCT) has become the treatment of choice for some patients with haematological malignancies, allowing dose escalation of chemo-radiotherapy beyond the limits imposed by bone marrow toxicity. However, it is now apparent that dose escalation alone does not eradicate the malignancy in many cases and that an associated immune-mediated graft-versus-malignancy effect may be equally important. Its presence is supported by the following observations: anecdotal reports that patients with relapsed leukaemia following SCT may re-enter remission after withdrawal of immunosuppressive drugs; the lower risk of relapse associated with the development of graft-versus-host-disease (GVHD); and an increased risk of relapse in patients receiving syngeneic transplants or T-cell depleted allogeneic marrow grafts. More directly compelling evidence has been provided by the efficacy of donor lymphocyte infusions, particularly for relapsed chronic-phase CML. Issues that remain to be resolved include the precise nature of the effector cells and their target antigens, the best strategies for separating graft-versus-malignancy from GVHD, the role of adjuvant chemotherapy/cytokines, and the role of non-myeloablative transplantation.     

Adaptive changes in vitamin B12 absorption in celiac disease and after proximal small-bowel resection in man

Resection of the proximal small bowel is known to cause mucosal hyperplasia and enhanced absorption in the ileum of experimental animals, but similar adaptive changes had not previously been studied in man. Since intrinsic-factor-bound vitamin B₁₂ (IF-B₁₂) absorption is confined to the ileum, as an index of ileal adaptation, we measured whole-body IF–⁵⁸ Co B₁₂ absorption in 24 control subjects, in 4 patients after proximal small-bowel resection, and in 9 patients with adult celiac disease (where mucosal damage is often limited to the proximal intestine and spares the ileum). Control subjects absorbed 20.4% (±1sd 6.2%) of the administered 5-g dose of vitamin B₁₂, while the corresponding 7-day retention values in patients with proximal resection (mean 42.3%; range 32–61%) and in 2 of the 9 celiac patients (44.1% and 54%, respectively), were above the normal range. The increased vitamin B₁₂ absorption in these patients suggests that functional adaptation also occurs in the ileum in man. The results also illustrate the application of a newly developed whole-body counting technique to study vitamin B₁₂ absorption in man.This work was supported by Grants from the Medical Research Council to the Intestinal Malabsorption Group and a Commonwealth Medical Fellowship.Presented in part at the European Society for Clinical Investigation (Elias et al: Eur J Clin. Invest 3:226 1973).     

Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: separation of graft-versus-leukemia responses from graft-versus-host disease

Infusions of large numbers (> 10(8)/kg) of donor leukocytes can induce remissions in patients with chronic myeloid leukemia (CML) who relapse after marrow transplantation. We wanted to determine if substantially lower numbers of donor leukocytes could induce remissions and, if so, whether this would reduce the 90% incidence of graft-versus-host disease (GVHD) associated with this therapy. Twenty-two patients with relapsed CML were studied: 2 in molecular relapse, 6 in cytogenetic relapse, 10 in chronic phase, and 4 in accelerated phase. Each patient received escalating doses of donor leukocytes at 4- to 33-week intervals. Leukocyte doses were calculated as T cells per kilogram of recipient weight. There were 8 dose levels between 1 x 10(5) and 5 x 10(8). Lineage-specific chimerism and residual leukemia detection were assessed using sensitive polymerase chain reaction (PCR) methodologies. Nineteen of the 22 patients achieved remission. Remissions were achieved at the following T-cell doses: 1 x 10(7) (n = 8), 5 x 10(7) (n = 4), 1 x 10(8) (n = 3), and 5 x 10(8) (n = 4). To date, 15 of the 17 evaluable patients have become BCR-ABL negative by PCR. The incidence of GVHD was correlated with the dose of T cells administered. Only 1 of the 8 patients who achieved remission at a T-cell dose of 1 x 10(7)/kg developed GVHD, whereas this complication developed in 8 of the 11 responders who received a T-cell dose of > or = 5 x 10(7)/kg. Three patients died in remission, 1 secondary to marrow aplasia, 1 of respiratory failure and 1 of complications of chronic GVHD. Sixteen patients who were mixed T-cell chimeras before treatment became full donor T-cell chimeras at the time of remission. Donor leukocytes with a T-cell content as low as 1 x 10(7)/kg can result in complete donor chimerism together with a potent graft-versus-leukemia (GVL) effect. The dose of donor leukocytes or T cells used may be important in determining both the GVL response and the incidence of GVHD. In many patients, this potent GVL effect can occur in the absence of clinical GVHD.     

A fatal case of autoimmune thrombocytopenia with an IgM anti-GPIb/IX following one antigen mismatched unrelated donor bone marrow transplantation

We report the case of a 32-year-old patient with ALL who developed autoimmune thrombocytopenia 2 months following allogeneic bone marrow transplantation. An IgM autoantibody against the platelet glycoprotein Ib/IX complex was observed. Treatment with high-dose steroids and intravenous immunoglobulin G failed to produce any benefit and the thrombocytopenia led to fatal gastrointestinal haemorrhage. The possible factors contributing to post-allograft thrombocytopenia and potential management strategies are discussed.     

Human herpesvirus-7 infection of the CNS with acute myelitis in an adult bone marrow recipient

The beta-herpesviruses, human herpesviruses-6 and -7 (HHV-6 and HHV-7), are closely related and have very similar biological behaviour. While HHV-6 is associated with encephalitis in immunosuppressed adults, HHV-7 is not recognised as a cause of neurological disease in such patients. This report describes the identification of a reactivated HHV-7 infection in the cerebrospinal fluid of an adult who presented with an acute myelitis 11 months after unrelated donor bone marrow transplant.