High risk pregnancies in hypopituitary women

BACKGROUND: Various short papers have suggested that pregnancies in women with hypopituitarism are high risk but no formal assessment of pregnancy outcome has yet been reported. METHODS: An audit was carried out concerning the outcome of 18 pregnancies in nine women who underwent ovulation induction in a single centre over 20 years. RESULTS: The live birth rate was 61%, miscarriage rate 28% and mid-trimester uterine death rate 11% with no survivors from four sets of twins. The Caesarian section rate was 100% and half of the live births were on or below the 10th centile for weight. One woman successfully breast-fed. CONCLUSIONS: Women with hypopituitarism have high-risk pregnancies, perhaps because of a uterine defect secondary to endocrine deficiency. Fertility treatment must strive for singleton pregnancies with application of particularly strict criteria to avoid twin pregnancies. Early elective Caesarian section is probably warranted in this group.     

Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1.

We report the identification of mutations in lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) genes in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17. Linkage disequilibrium analysis of six families affected by NCIE permitted us to reduce a recently reported interval of 8.4 cM on chromosome 17p13.1 to a 600 kb region around the marker D17S1796, which contains LOX genes. LOX products have long been implicated in skin disorders. Two point mutations and one deletion were found in ALOXE3 and three point mutations were found in ALOX12B in these consanguineous families from the Mediterranean basin. ALOXE3 and ALOX12B are two genes which are physically linked and functionally related. They are separated by 38 kb, have one more exon than the other LOX genes and are mainly expressed in epithelial cells including keratinocytes. Although the main substrate(s) of the two enzymes is (are) still unknown, the products of ALOX12B obtained in experimental systems have been demonstrated to be of R-chirality. It seems likely that the product of one of these enzymes may be the substrate of the other, and that they belong to the same metabolic pathway.     

Heritability and clinical features of multigenerational families with obsessive-compulsive disorder and hoarding.

To date, only one complete genome screen for obsessive-compulsive disorder (OCD) has been published. That study identified a region of suggestive linkage (maximum lod score of 2.25) with a relatively small sample size (N = 56; 27 with OCD). Additional complete genome screens are needed to confirm this finding and identify other regions of linkage. We present the clinical characteristics and power to detect linkage of 11 multigenerational families with OCD and hoarding (N = 92; 44 with OCD), as well as heritability estimates for several quantitative traits. Families with at least two individuals with OCD were identified through probands with childhood-onset OCD. Expected lod scores were calculated for simulated genetic marker data under an additive and two dominant models assuming a dense SNP marker map. All affected individuals had an early age of onset (18 or younger). Hoarding was present in 46% of subjects. Obsessive-compulsive symptoms and hoarding were highly heritable. The maximum mean expected lod score was 3.31 for OCD and 1.39 for hoarding. We found reasonable power to detect regions of interest (lod = 2) for OCD in these families, but will need to expand our family collection to have adequate power to detect regions of interest for hoarding.     

The vascular lesions in vascular and mixed dementia: the weight of functional neuroanatomy

Vascular dementia appears rarer than previously thought, but the contribution of vascular lesions to cognitive impairment in Alzheimer's disease (AD) affected patients (mixed dementias) is now recognized as frequent. The role of strategic areas of the brain involved in the cognitive decline induced by vascular lesions and their relative contributions to the severity of the dementing process remain poorly understood. We determined the relationship between the severity of clinical dementia and the volume of different brain areas affected by infarcts in a prospective clinicopathological study in elderly patients. A volumetric study of the functional zones of Mesulam's human brain map affected by vascular lesions was made and correlations between quantified neuropathological data and the severity of dementia were performed in cases with large vascular lesions only, pure AD, and both lesions. The severity of cognitive impairment was significantly correlated with the total volume of infarcts but in a multi-variate model the volume destroyed in the limbic and heteromodal association areas, including the frontal cortex and in the white matter explained 50% of the variability in MMSE and GDS. The total volume of ischemic lesions explained only 0.1-5% of the variability in MMSE and GDS. Age only explained an extra of 0.1-1.6%. This study confirms that infarcts located in strategic areas have a role in the mechanism of cognitive impairment and brings a key for their quantification. It may be useful for developing neuropathological criteria in multi-infarct and mixed dementias.     

Failure to produce conditioning with low-dose trimethylthiazoline or cat feces as unconditioned stimuli

Trimethylthiazoline (TMT), a derivative of fox feces, has been reported to fail to produce aversive conditioning as an unconditioned stimulus (UCS) when presented in large amounts (I. S. McGregor, L. Schrama, P. Ambermoon, & R. A. Dielenberg, 2002). Experiment I evaluated very low TMT levels that nonetheless produced defensive behaviors in rats during exposure. Although each level (0.01, 0.05, and 0.10 microl TMT) produced significant change in defensiveness, none resulted in significant changes the following day in the absence of TMT. Experiment 2 evaluated cat urine, cat feces, and cat fur/skin odor against a no-odor control. Urine produced no significant changes, but feces and fur/skin odors elicited virtually identical changes in defensive behaviors during exposure. When tested the next day in the absence of odor, the fur/skin odor-exposed group showed significant differences on the same behaviors as during exposure, but the feces-exposed group showed no differences on any measure. Results suggest that lack of conditioning to TMT may relate to the type of predator odor rather than the amount, predator species, or possible lack of odor components in TMT that are present in natural feces. Predator feces may also be less effective as a UCS because they are poorly predictive of the actual presence of the predator, suggesting the need for a reevaluation of UCS functions in aversive conditioning.     

Increased and highly stable levels of functional soluble interleukin-6 receptor in sera of patients with monoclonal gammopathy

Soluble human interleukin-6 receptor (sIL-6R) was measured in the serum of 30 healthy individuals, 32 individuals with monoclonal gammopathy of undetermined significance (MGUS), 20 patients with early multiple myeloma (MM) and 54 patients with overt MM. The serum activity recognized by an immunoradiometric assay was determined to be sIL-6R, because of its binding capacity to IL-6 and its molecular mass of 55 kDa. All sera of healthy individuals contained sIL-6R (mean value: 89 ng/ml, range 17-300 ng/ml). Serum sIL-6R levels were increased by 51% in patients with MGUS (mean value: 135 ng/ml, p<0.005), by 44% in patients with early myeloma (mean value: 128 ng/ml, p<0.001) and by 116 % in patients with overt MM (mean value: 193 ng/ml, p<0.001). In patients with MM, a complete lack of correlation (p>0.7) was found between serum sIL-6R levels and other previously recognized prognostic factors in this disease, particularly serum IL-6 levels and those factors related to tumor cell mass. The independence of serum sIL-6R levels on tumor cell mass was directly demonstrated by studying four patients with MM treated with autologous bone marrow transplantation for periods of between 320 and 760 days. These levels were found to be remarkably stable and constant, independent of whether patients relapsed or achieved complete remission. Finally, physiological concentrations of sIL-6R were found to increase by tenfold the sensitivity of human myeloma cell lines to IL-6. These observations suggest a high control of the sIL-6R level in vivo, and, possibly, an important functional role of this circulating protein in patients with monoclonal gammopathies.     

Inability to activate muscles maximally during cocontraction and the effect on joint stiffness

In order to determine the maximum joint stiffness that could be produced by cocontraction of wrist flexor and extensor muscles, experiments were conducted in which healthy human subjects stabilized a wrist manipulandum that was made mechanically unstable by using positive position feedback to create a load with the characteristics of a negative spring. To determine a subject's limit of stability, the negative stiffness of the manipulandum was increased by increments until the subject could no longer reliably stabilize the manipulandum in a 1° target window. Static wrist stiffness was measured by applying a 3° rampand-hold displacement of the manipulandum, which stretched the wrist flexor muscles. As the load stiffness was made more and more negative, subjects responded by increasing the level of cocontraction of flexor and extensor muscles to increase the stiffness of the wrist. The stiffness measured at a subject's limit of stability was taken as the maximum stiffness that the subject could achieve by cocontraction of wrist flexor and extensor muscles. In almost all cases, this value was as large or larger than that measured when the subject was asked to cocontract maximally to stiffen the wrist in the absence of any load. Static wrist stiffness was also measured when subjects reciprocally activated flexor or extensor muscles to hold the manipulandum in the target window against a load generated by a stretched spring. We found a strong linear correlation between wrist stiffness and flexor torque over the range of torques used in this study (20–80% maximal voluntary contraction). The maximum stiffness achieved by cocontraction of wrist flexor and extensor muscles was less than 50% of the maximum value predicted from the joint stiffness measured during matched reciprocal activation of flexor and extensor muscles. EMG recorded from either wrist flexor or extensor muscles during maximal cocontraction confirmed that this reduced stiffness was due to lower levels of activation during cocontraction of flexor and extensor muscles than during reciprocal contraction.     

The cellular structure and lipid/protein composition of adipose tissue surrounding chronically stimulated lymph nodes in rats

To test the hypothesis that chronic immune stimulation of a peripheral lymph node induces the formation of additional mature adipocytes in adjacent adipose tissue, one popliteal lymph node of large male rats was stimulated by local injection of 10 microg or 20 microg lipopolysaccharide three times a week for 6 weeks. Adipocyte volumes in sites defined by their anatomical relations to the stimulated and homologous unstimulated popliteal lymph nodes were measured, plus adipocyte complement of the popliteal depot, and the lipid and protein content of adipocytes and adipose stroma. The higher dose of lipopolysaccharide doubled the mass of the locally stimulated lymph node and the surrounding adipose tissue enlarged by the appearance of additional mature adipocytes. Similar but smaller changes were observed in the popliteal adipose depot of the unstimulated leg and in a nodeless depot. The lipid content of the adipocytes decreased and that of the stroma increased dose-dependently in all samples measured but the changes were consistently greater in the depot surrounding the stimulated lymph node. The protein content of both adipocytes and stroma increased in samples surrounding the stimulated node. We conclude that chronic immune stimulation of lymphoid tissues induces the formation of more adipocytes in the adjacent adipose tissue. These findings suggest a mechanism for the selective hypertrophy of lymphoid-containing adipose depots in the HIV-associated adipose redistribution syndrome.     

Quantitation of antigen-specific immune responses in human immunodeficiency virus (HIV)-infected individuals by limiting dilution analysis

The lymphocyte proliferative response to recall antigens is lost following HIV infection. We sought to devise a means by which the functional immune status of persons in the early stages of HIV infection could be monitored quantitatively. The response to tetanus toxoid was examined in 45 HIV-infected individuals and 11 controls using conventional lymphocyte proliferative assays concurrently with limiting dilution analysis utilizing the secretion of interleukin-2 as the measure of a response. Our data show that the limiting dilution analysis detects tetanus toxoid-reactive T cells in 80% of those tested, as compared to only 44% by proliferation. However, the frequency of tetanus-reactive T cells in HIV-infected individuals (median frequency = 1/59,156) is decrease five-fold as compared to seronegative controls (median frequency = 1/11,599). Longitudinal studies demonstrated a time-dependent decrease in the frequency of tetanus-specific T cell responses in the HIV-infected individuals. Thus, the limiting dilution analysis is a quantitative approach for detecting antigen-specific T cells in HIV-infected individuals, and may be used to monitor changes in T cell function in HIV infection.