Astrocyte decrease in the subgenual cingulate and callosal genu in schizophrenia

Decreases in glial cell density and in GFAP mRNA in the anterior cingulate cortex have been reported in schizophrenia, bipolar disorder and major depressive disorder. Our study examines astrocyte and oligodendrocyte density in the white and grey matter of the subgenual cingulate cortex, and at the midline of the genu of the corpus callosum, in schizophrenia, bipolar disorder, depression and normal control cases. Serial coronal sections were stained with H and E for anatomical guidance, cresyl haematoxylin for oligodendrocyte identification and GFAP immunohistochemistry for astrocyte identification. Oligodendrocyte and astrocyte density was measured using systematic anatomical distinctions and randomised counting methods. A significant decrease in astrocyte density was observed in schizophrenia compared with normal controls in the cingulate grey matter, cingulate white matter and the midline of the corpus callosum (p = 0.025). Bipolar disorder and depression cases showed no significant changes in astrocyte density. Oligodendrocytes did not show any changes between diagnostic groups. In subgenual cingulate cortex, the ratio of oligodendrocytes to astrocytes was decreased between the controls and the three disease groups, suggesting a specific glial cell type specific change in schizophrenia.     

Substrate modification combined with pulmonary vein isolation improves outcome of catheter ablation in patients with persistent atrial fibrillation: a prospective randomized comparison.

AIMS: To investigate the effectiveness of additional substrate modification (SM) by left atrial (LA) linear lesions as compared with pulmonary vein isolation (PVI) alone in patients with persistent atrial fibrillation (AF) in a prospective randomized study. Percutaneous PVI has evolved as an accepted treatment for paroxysmal AF but seemed to be less effective in patients with persistent AF. The benefit of PVI alone and additional linear lesions has not been validated in a randomized study so far. METHODS AND RESULTS: Sixty-two patients with persistent AF (median duration 7, range 1-18 months) were randomly assigned to either PVI alone (n = 30) or additional SM (n =32) consisting of a roof line connecting both left superior and right superior PV and LA isthmus ablation between left inferior PV and mitral annulus. Procedures including SM were performed using a three-dimensional mapping system (EnSite NavX, St Jude Medical, St Paul, MN, USA). Anti-arrhythmic drugs were discontinued within 8 weeks after ablation in both groups. Follow-up included daily trans-telephonic ECG transmitted irrespective of the patient's symptoms. PVI was successful in 98% of all targeted veins in both groups. Additional SM did not increase fluoroscopy time (72.1+/-18.7 vs. 72.9+/-17.3 min, P=0.92) because of the use of three-dimensional navigation in the PVI+SM group. AF recurrences within the first 4 weeks following ablation were more common after PVI alone (77%) than additional SM (44%, P=0.002). After a follow-up time of 487 (429-570) days, only 20% of patients undergoing stand alone PVI remained in sinus rhythm when compared with 69% following PVI combined with SM (P=0.0001). Two patients assigned to PVI+SM experienced procedure-related complications (cardiac tamponade and minor stroke) which resolved without sequelae. CONCLUSION: PVI alone is insufficient in the treatment of persistent AF. However, additional left linear lesions increase the success rate significantly. Early AF-relapses are associated with a negative outcome after PVI alone but not following additional SM.     

Thiotepa, busulfan, and cyclophosphamide: a new preparative regimen for autologous marrow or blood stem cell transplantation in high-risk multiple myeloma

Forty patients with multiple myeloma received thiotepa (750 mg/m2), busulfan (10 mg/kg), and cyclophosphamide (120 mg/kg) (TBC) followed by autologous bone marrow or blood stem cell support. Granulocyte-Colony stimulating factor (G-CSF) was administered to accelerate hematopoietic recovery. Sixty-five percent of all patients responded to this treatment. Eighty-eight percent of patients transplanted in partial remission had a further reduction of the myeloma and 53% achieved a complete remission. Forty-eight percent of patients with refractory myeloma responded. All responding patients transplanted during partial remission or with primary refractory myeloma remain free of progression for a period of 4 to 24 months post-transplant, but the remission duration of patients treated in refractory relapse was short (4 months). Five of 24 patients transplanted with marrow and none of 16 receiving blood stem cells died of treatment-related complications. Use of blood stem cells resulted in more rapid granulocyte and platelet recovery. We conclude that TBC is an effective, relatively well tolerated, preparative regimen for patients with multiple myeloma.     

Cyclic guanosine monophosphate-dependent protein kinase is targeted to intermediate filaments and phosphorylates vimentin in A23187-stimulated human neutrophils

The effects of the calcium ionophore, A23187, on human neutrophil activation were studied in relation to the signaling mechanism of cyclic guanosine monophosphate (cGMP)-dependent protein kinase (G- kinase). Immunocytochemistry demonstrated that G-kinase translocated from a diffuse localization in the cytoplasm to the cytoskeleton after stimulation with A23187. Over a period of 5 minutes, G-kinase was transiently colocalized with the intermediate filament protein, vimentin. At 3 minutes' stimulation with A23187, colocalization of G- kinase and vimentin was predominantly confined to filaments that extended into the uropod. The time of colocalization of G-kinase and vimentin was reduced in the A23187-stimulated cell from 3 minutes to 1 minute by 8-Br-cGMP. Coincident with colocalization was an increase in cGMP levels and transient phosphorylation of vimentin in adhered A23187- stimulated cells. Phosphorylation of vimentin was maximal after 3 minutes with A23187, and was essentially over at 5 minutes. The time of phosphorylation of vimentin was also reduced from 3 minutes to 1 minute when cells were preincubated with 8-Br-cGMP and then stimulated with A23187, which suggests that cyclic adenosine monophosphate (cAMP)- dependent protein kinase does not phosphorylate vimentin in A23187- treated neutrophils. Phosphorylation of vimentin was not observed in nonactivated cells treated only with 8-Br-cGMP. The presence of the protein kinase C inhibitors, staurosporine or H-7, did not inhibit vimentin phosphorylation in A23187-treated cells, which provides supportive data that protein kinase C is not the phosphorylating enzyme. These results suggest that vimentin and G-kinase are colocalized in a Ca(2+)-dependent manner in neutrophils, and that vimentin is transiently phosphorylated by G-kinase in response to the colocalization of the two proteins. The transient redistribution of compartmentalized G-kinase represents one type of neutrophil activation mechanism.     

Regulation of autoimmune anti-platelet antibody-mediated adhesion of monocytes to platelet GPIIb/GPIIIa: effect of armed monocytes and the Mac-1 receptor

Platelet autoantigen-autoantibody-monocyte interaction was studied by utilization of a specific monoclonal antibody (MoAb) 10E5 to trap and immobilize the GPIIb-GPIIIa complex on microtiter plates. Peripheral blood mononuclear cells (PBMC) or purified monocytes formed distinct morphologic clusters after incubation with immobilized antigen for 18 hours at 37 degrees C. PBMC of 18 and 19 patients with autoimmune thrombocytopenic purpura (ATP) formed 48 +/- 6.8 (SEM) clusters/well compared with 7.4 +/- 1.0 for control subjects, P less than .001. The number of clusters per well correlated inversely and exponentially with platelet count, r = -.8, n = 21, indicating that the GPIIb-GPIIIa autoantigen is pathophysiologically relevant. Binding of ATP PBMC to immobilized GPIIb-GPIIIa could be inhibited by F(ab')2 fragments of immunoglobulin (Ig) G of ATP patients, indicating that monocyte IgG bound to autoantigen by its F(ab')2 domain. Optimal cluster formation could be obtained with normal monocytes if preincubated with ATP IgG but not with F(ab')2 fragments of ATP IgG, indicating that ATP IgG binds to monocytes by its Fc domain. Armed monocytes (ie, normal monocytes preincubated with ATP IgG) bound to immobilized autoantigen 5.8-fold greater than normal monocytes incubated with immobilized autoantigen opsonized with ATP IgG. Armed monocyte adhesion could be inhibited 81% from 18.9 +/- 1.6 to 3.6 +/- 0.5 clusters/well by prior fixation with 0.1% formalin, whereas fixation of IgG before arming of monocytes was not inhibitory. MoAb MM41, directed against the alpha m- chain of the Mac-1 adhesive protein receptor of monocytes, inhibited cluster formation by 79%. Thus, (1) armed monocyte interaction with autoantigen is considerably more effective than monocyte interaction with opsonized autoantigen; (2) armed monocyte interaction requires specific F(ab')2-antigen recognition; and (3) monocyte-autoantigen interaction requires a secondary nonimmunologic adhesive event.     

Risk factors for HIV infection among circumcised men in Uganda: a case-control study

Introduction

Male circumcision (MC) reduces the risk of HIV infection. However, the risk reduction effect of MC can be modified by type of circumcision (medical, traditional and religious) and sexual risk behaviours post-circumcision. Understanding the risk behaviours associated with HIV infection among circumcised men (regardless of form of circumcision) is critical to the design of comprehensive risk reduction interventions. This study assessed risk factors for HIV infection among men circumcised through various circumcision approaches.

Methods

This was a case-control study which enrolled 155 cases (HIV-infected) and 155 controls (HIV-uninfected), all of whom were men aged 18–35 years presenting at the AIDS Information Center for HIV testing and care. The outcome variable was HIV sero-status. Using SPSS version 17, multivariable logistic regression was performed to identify factors independently associated with HIV infection.

Results

Overall, 83.9% among cases and 56.8% among controls were traditionally circumcised; 7.7% of cases and 21.3% of controls were religiously circumcised while 8.4% of cases and 21.9% of controls were medically circumcised. A higher proportion of cases than controls reported resuming sexual intercourse before complete wound healing (36.9% vs. 14.1%; p<0.01). Risk factors for HIV infection prior to circumcision were:being in a polygamous marriage (AOR: 6.6, CI: 2.3–18.8) and belonging to the Bagisu ethnic group (AOR: 6.1, CI: 2.6–14.0). After circumcision, HIV infection was associated with: being circumcised at >18 years (AOR: 5.0, CI: 2.4–10.2); resuming sexual intercourse before wound healing (AOR: 3.4, CI: 1.6–7.3); inconsistent use of condoms (AOR: 2.7, CI: 1.5–5.1); and having sexual intercourse under the influence of peers (AOR: 2.9, CI: 1.5–5.5). Men who had religious circumcision were less likely to have HIV infection (AOR: 0.4, 95% CI: 0.2–0.9) than the traditionally circumcised but there was no statistically significant difference between those who were traditionally circumcised and those who were medically circumcised (AOR: 0.40, 95% CI: 0.1–1.1).

Conclusions

Being circumcised at adulthood, resumption of sexual intercourse before wound healing, inconsistent condom use and having sex under the influence of peers were significant risk factors for HIV infection. Risk reduction messages should address these risk factors, especially among traditionally circumcised men.     

“Men are always scared to test with their partners … it is like taking them to the Police”: Motivations for and barriers to couples’ HIV counselling and testing in Rakai,Uganda: a qualitative study

Introduction

Uptake of couples’ HIV counselling and testing (couples’ HCT) can positively influence sexual risk behaviours and improve linkage to HIV care among HIV-positive couples. However, less than 30% of married couples have ever tested for HIV together with their partners. We explored the motivations for and barriers to couples’ HCT among married couples in Rakai, Uganda.

Methods

This was a qualitative study conducted among married individuals and selected key informants between August and October 2013. Married individuals were categorized by prior HCT status as: 1) both partners never tested; 2) only one or both partners ever tested separately; and 3) both partners ever tested together. Data were collected on the motivations for and barriers to couples’ HCT, decision-making processes from tested couples and suggestions for improving couples’ HCT uptake. Eighteen focus group discussions with married individuals, nine key informant interviews with selected key informants and six in-depth interviews with married individuals that had ever tested together were conducted. All interviews were audio-recorded, translated and transcribed verbatim and analyzed using Nvivo (version 9), following a thematic framework approach.

Results

Motivations for couples’ HCT included the need to know each other''s HIV status, to get a treatment companion or seek HIV treatment together – if one or both partners were HIV-positive – and to reduce mistrust between partners. Barriers to couples’ HCT included fears of the negative consequences associated with couples’ HCT (e.g. fear of marital dissolution), mistrust between partners and conflicting work schedules. Couples’ HCT was negotiated through a process that started off with one of the partners testing alone initially and then convincing the other partner to test together. Suggestions for improving couples’ HCT uptake included the need for couple- and male-partner-specific sensitization, and the use of testimonies from tested couples.

Conclusions

Couples’ HCT is largely driven by individual and relationship-based factors while fear of the negative consequences associated with couples’ HCT appears to be the main barrier to couples’ HCT uptake in this setting. Interventions to increase the uptake of couples’ HCT should build on the motivations for couples’ HCT while dealing with the negative consequences associated with couples’ HCT.     

Combination of short CAG and GGN repeats in the androgen receptor gene is associated with acne risk in North East China

Background Acne vulgaris is one of the most common skin disorders, and androgen is known to play a key role in the development of acne. However, the exact genetic mechanism by which androgen receptor (AR) gene affects acne development is still unclear. Objective Our study aimed to investigate whether CAG and GGN polymorphism of the AR gene are associated with acne risk. Patients and methods Two hundred thirty‐eight patients and 207 controls were included in the study. The repeat lengths of the AR gene were determined by GeneScan analysis. Results Men with CAG < 23 and women with CAG < 24 had significant risk compared to those men with CAG ≥ 23 [odds ratio (OR), 2.07; 95% confidence interval (95% CI), 1.21–3.54] and women with CAG ≥ 24 (OR, 2.05; 95% CI, 1.18–3.56). In males, GGN repeats, considered independently of the CAG repeat, have no significant effect on the acne risk; however, when combined with CAG repeats, the acne patients exhibited significantly higher frequency of the haplotypes CAG < 23/GGN ≤ 23 (OR, 3.33; 95% CI, 1.10–10.07; P < 0.05) compared with the controls. Conclusion Our results of this study strongly indicated that a shorter CAG repeat length and specific haplotypes of AR attributed to the risk of acne development and thus could serve as a susceptibility marker.