Sexual dimorphism of the extraorbital lacrimal glands in SF-1 knockout mice

Sexual dimorphism (SD) represents all the differences between males and females of the same species. SD of the murine lacrimal gland and the major effect of testosterone on its formation are well documented. Steroidogenic factor-1 (SF-1, NR5a1) is a nuclear receptor essential for the fetal development of steroid hormones producing organs and SF-1 knockout mice (Sf-1 KO) are therefore born without gonads and adrenal glands. The aim of this study was to investigate whether SD in lacrimal glands is present in the absence of exposure to sex hormones during development. Lacrimal glands from adult Sf-1 KO male and female mice without hormonal exposure, and from males that were treated with testosterone propionate (TP) prior to sacrifice, were examined. After sacrifice, glandular tissue was processed using standard histological procedures. Paraffin sections were analysed by stereology and immunostained against the androgen receptor (AR). Our results showed that there were no statistically significant differences in the mean volumes of acini, connective tissue or ductal system between males, females, and males on TP. The same pertains to the mean length of the ducts in all three groups. In the absence of sex hormones, sex chromosomes proved to be insufficient in inducing sexual dimorphism in LG. However, nuclei of the acinar cells in males on TP were positive for AR, whereas in males without TP no expression of AR was detected. Administration of TP induced the expression of AR in the nuclei of acinar cells of males but did not affect the morphology of LG. We conclude that SD in the lacrimal gland is not present in Sf-1 KO mice and this suggests that sex hormones have a major role in the development of SD in the lacrimal gland.     

Effect of accuracy constraint on joint coordination during pointing movements

Given the number of muscles and joints of the arm, more ways are available to produce an identical hand movement when pointing to a target than are strictly necessary. How the nervous system manages these abundant degrees of freedom was the focus of this study of pointing to targets of low and high indices of difficulty (ID). Two essential features of movement synergies were examined. The first reflects the preferred relations among the outputs of each movement element and was studied through principal component analysis. The second feature of synergy reflects the flexibility of those relationships evidenced by the use of multiple, goal-equivalent solutions to joint coordination. This second feature, which is the main focus of this report, was studied using the uncontrolled manifold approach. Motor abundance was defined operationally as the component of variance of joint combinations that left unchanged the value of important performance variables (goal-equivalent variability, GEV). This variance component was contrasted with the component of variance leading to a change in the value of these variables (non-goal-equivalent variability, NGEV). The difference between GEV and NGEV was evaluated with respect to the performance variables movement extent, movement direction, and path of the arm's center of mass. More than 90% of the variance of joint motions across the pointing trial were accounted for by one principal component, indicating a consistent temporal coupling among most joint motions in a single functional synergy. The flexible nature of this synergy was revealed by the variability analysis. All subjects had significantly higher GEV than NGEV for most of the movement path. Thus, variable patterns of joint coordination did not represent noise but the use of equivalent coordinative solutions related to stabilizing important performance variables. Higher GEV than NGEV was present regardless of the task's ID. One exception was at the time of peak velocity, leading to poorer control of movement extent than movement direction. Increasing the task's ID led to an overall reduction of joint configuraion variance, particularly GEV. These results support earlier work indicating that the use of goal-equivalent solutions to joint coordination is a common feature of the control of this and many other motor tasks. Functionally important performance variables appear to be controlled through flexible but task-specific coordination among the motor elements Electronic Publication     

Prefrontal enlargement of CSF spaces in agoraphobia: a qualitative CT-scan study.

1. This CT study was designed to assess brain morphology in 21 patients with agoraphobia and 21 normal control subjects matched for age and sex. 2. Internal and external CSF spaces were evaluated by qualitative assessment on a 3-point scale (normal, questionable, abnormal). 3. Patients showed bilateral enlargement of prefrontal CSF spaces (p < .05). The rating abnormal" was given in the left hemisphere to 6 (28.6%) of the patients, to 4 (19%) of the patients in the right hemisphere, but to none (0%) of the normal controls. 4. These findings suggest that alterations in brain morphology are involved in the etiology of agoraphobia.     

Potential preventive strategies and therapies in urinary tract infection

There are perhaps five strategies either presently advocated or under investigation for prevention of recurrent urinary tract infection (UTI): antibiotics, including natural peptides; functional foods; vaccines; probiotics; and miscellaneous, including avoidance of spermicides and maintenance of good hygiene. It is not possible to state the proportion of patients using antibiotics versus foods such as cranberry or using alternative approaches such as avoidance of spermicides. The majority of women who are referred to specialists will be prescribed long-term, low-dose antibiotics. However, given the magnitude of the problem, it is safe to state that large numbers of women are at least experimenting with alternative remedies such as drinking of cranberry juice or ingestion of herbal remedies with a view to enhancing their immune response. Vaccine development remains a long way from human use and has yet to be developed for organisms other than Escherichia coli. The use of probiotics to restore the normal vaginal flora and provide a competitive bacterial barrier to pathogens is close to becoming available as an alternative preventive approach. The next decade should see the introduction of new methods for reduction of the high incidence of UTI and better management of recurring urogenital infections.     

Human phase I vaccine trials of 3 recombinant asexual stage malaria antigens with Montanide ISA720 adjuvant

Two phase I vaccine trials were conducted to test the immunogenicity and safety of a vaccine containing three recombinant malaria antigens from the asexual stage of Plasmodium falciparum. The three antigens are a fragment of MSP1 (190LCS.T3); MSP2 and a portion of RESA and were formulated in Montanide ISA720 adjuvant. These trials investigated the dose response of each antigen for eliciting both antibody and T-cell responses and the immunogenicity of a mixture of the antigens compared with the antigens injected separately. All three antigens elicited both antibody and T-cell responses. Strong T-cell responses were observed with 190LCS.T3 and RESA with stimulation indices exceeding 100 for peripheral blood leucocytes in some individuals. The antibody responses were generally weak. The human antibody responses observed with MSP2 in Montanide ISA720 were not significantly different from those obtained in an earlier trial which used MSP2 with alum as the adjuvant. No antigenic competition was observed: volunteers receiving a mixture of antigens had similar responses to those receiving the three antigens at separate sites. Tenderness and pain at the injection site were common over the first few days following immunization. In some volunteers, especially those receiving the highest doses tested, there was a delayed reaction at the injection site with pain and swelling occurring approximately 10 days after injection.     

Retained intravitreal lens fragments after phacoemulsification: a clinicopathological correlation

AIMS: To explore the relation between clinical course and timing of vitrectomy with the nature and intensity of intraocular inflammatory response in eyes with retained intravitreal lens fragments following complicated phacoemulsification. METHODS: Prospective evaluation of 22 eyes with retained lens fragments with emphasis on corneal clarity, uveitis, intraocular pressure (IOP), timing of vitrectomy, and visual outcome. Numbers of different types of inflammatory cells in vitreous washings were counted, masked to clinical details, in three non-overlapping adjacent high power fields. Relations between clinical and pathological findings were assessed. RESULTS: The IOP was raised in 19 eyes before vitrectomy and remained high in nine postoperatively. The latter had higher median total cell count (104 cells/mm(2)) than those with normal postoperative IOP (37 cells/mm(2)) but this difference was not statistically significantly different (p=0.17). Nine of 22 eyes underwent vitrectomy within 1 week of cataract surgery. Median total cell count in these eyes was 20 cells/mm(2) compared with 140 cells/mm(2) in eyes vitrectomised later-this difference was statistically significant (p <0.001). Final visual acuity was 6/12 or better in 13 eyes, these had fewer intravitreal inflammatory cells than the remaining six with poor visual outcome and no pre-existing cause for this (three patients excluded) (p=0.02). Macrophages were the predominant inflammatory cell type. CONCLUSION: There was significantly less inflammatory cell activity in eyes which had retained lens fragments removed early (within 1 week). Later removal was associated with persistently elevated IOP and poorer visual outcome.     

Inhibition of uropathogenic biofilm growth on silicone rubber in human urine by lactobacilli – a teleologic approach

The ability of three Lactobacillus strains to inhibit the adhesion and growth of naturally occurring uropathogens on silicone rubber was investigated in human urine. The importance of biosurfactant production by Lactobacillus in discouraging uropathogen growth was determined in relation to the binding affinities of the lactobacilli for silicone rubber. L. fermentum B54 markedly inhibited uropathogen growth on the silicone rubber disks after 8 days for all five men included in the study, albeit to various extents ranging from 77% to 100%. In urine from women, however, this inhibition was less clear, as it was absent for two of the four women participating in this study. L. casei rhamnosus 36 completely discouraged uropathogen growth on the disks after 8 days for three of the four women, whereas its effect in urine from men was less pronounced (inhibition ranged from 48% to 100% and was absent for one man). L. casei rhamnosus ATCC 7469^T was the least inhibitory Lactobacillus strain tested and inhibition was absent for a number of both male and female participants, possibly as a result of the low binding affinity of this strain for silicone rubber and of its inability to release biosurfactants. We conclude that the inhibition of uropathogen growth is dependent on the Lactobacillus strain involved, and for L. fermentum B54 it was demonstrated to be sex-related. Hence, inhibition must be considered a multifactorial process.     

Large cleaved and immunoblastic lymphoma may represent two distinct clinicopathologic entities within the group of diffuse large B-cell lymphomas.

PURPOSE: The reliability of immunohistochemistry for subdividing diffuse large B-cell lymphomas (DLBCL) into germinal center B-cell-like (GCB) and non-GCB prognostic subgroups is debated. In this study we evaluated the prognostic significance of such subgrouping on a series of 153 DLBCL patients. Furthermore, we investigated whether both subgroups could comprise clinicopathologic entities recognized by their morphology and characterized by a distinct phenotype, specific genetic abnormalities, and clinical characteristics. PATIENTS AND METHODS: All samples from patients were reviewed and morphologically subdivided into large cleaved, immunoblastic, and not otherwise specified DLBCL. GCB and non-GCB immunohistochemical profiles were established. The presence of chromosomal translocations involving BCL2, BCL6, and MYC and/or rearrangements of these genes was investigated. RESULTS: Subdividing DLBCL with either a GCB or non-GCB immunophenotypic profile was not of prognostic significance. Nevertheless, CD10 expression was a predictor of favorable outcome, whereas high bcl-2 expression and BCL6 rearrangement were adverse predictors of disease-free survival. Interestingly, large cleaved DLBCL was clearly associated with a GCB immunophenotypic profile, CD10 expression, BCL2 rearrangement, age younger than 60 years, and low to low/intermediate International Prognostic Index risk, but was not of prognostic significance. In contrast, immunoblastic morphology was associated with a non-GCB profile and was a significant predictor of unfavorable DFS. CONCLUSION: Subdividing DLBCL into subgroups based on their immunohistochemical profile was not of prognostic significance. Nevertheless, it allowed the additional characterization of two lymphoma subgroups previously recognized in the Working Formulation. Both correspond to two distinct clinicopathologic entities within the DLBCL.     

Exome sequencing in individuals with cardiovascular laterality defects identifies potential candidate genes

The birth prevalence of laterality defects is about 1.1/10,000 comprising different phenotypes ranging from situs inversus totalis to heterotaxy, mostly associated with complex congenital heart defects (CHD) and situs abnormalities such as intestinal malrotation, biliary atresia, asplenia, or polysplenia. A proportion of laterality defects arise in the context of primary ciliary dyskinesia (PCD) accompanied by respiratory symptoms or infertility. In this study, exome sequencing (ES) was performed in 14 case-parent trios/quattros with clinical exclusion of PCD prior to analysis. Moreover, all cases and parents underwent detailed clinical phenotyping including physical examination, echocardiography by a skilled paediatric cardiologist and abdominal ultrasound examinations not to miss mildly affected individuals. Subsequent survey of the exome data comprised filtering for monoallelic de novo, rare biallelic, and X-linked recessive variants. In two families, rare variants of uncertain significance (VUS) in PKD1L1 and ZIC3 were identified. Both genes have been associated with laterality defects. In two of the remaining families, biallelic variants in LMBRD1 and DNAH17, respectively, were prioritized. In another family, an ultra-rare de novo variant in WDR47 was found. Extensive exome survey of 2,109 single exomes of individuals with situs inversus totalis, heterotaxy, or isolated CHD identified two individuals with novel monoallelic variants in WDR47, but no further individuals with biallelic variants in DNAH17 or LMBRD1. Overall, ES of 14 case-parent trios/quattros with cardiovascular laterality defects identified rare VUS in two families in known disease-associated genes PKD1L1 and ZIC3 and suggests DNAH17, LMBRD1, and WDR47 as potential genes involved in laterality defects.Subject terms: Disease genetics, Genetic counselling, Biological sciences