The hematopoietic cell-specific Rho GTPase inhibitor ARHGDIB/D4GDI limits HIV type 1 replication

Rho GTPases are able to influence the replication of human immunodeficiency virus type 1 (HIV-1). However, little is known about the regulation of HIV-1 replication by guanine nucleotide dissociation inhibitors (GDIs), one of the three major regulators of the Rho GTPase activation cycle. From a T cell-based cDNA library screening, ARHGDIB/RhoGDIβ, a hematopoietic lineage-specific GDI family protein, was identified as a negative regulator of HIV-1 replication. Up-regulation of ARHGDIB attenuated the replication of HIV-1 in multiple T cell lines. The results showed that (1) a significant portion of RhoA and Rac1, but not Cdc42, exists in the GTP-bound active form under steady-state conditions, (2) ectopic ARHGDIB expression reduced the F-actin content and the active forms of both RhoA and Rac1, and (3) HIV-1 infection was attenuated by either ectopic expression of ARHGDIB or inhibition of the RhoA signal cascade at the HIV-1 Env-dependent early phase of the viral life cycle. This is in good agreement with the previous finding that RhoA and Rac1 promote HIV-1 entry by increasing the efficiency of receptor clustering and virus-cell membrane fusion. In conclusion, the ARHGDIB is a lymphoid-specific intrinsic negative regulator of HIV-1 replication that acts by simultaneously inhibiting RhoA and Rac1 functions.     

Pituitary lymphoma developing within pituitary adenoma

Lymphoma occurring in the pituitary gland is an exceedingly infrequent event. Here, we describe a case of pituitary lymphoma complicating recurrent pituitary adenoma. A 56-year-old male with a history of pituitary adenoma was diagnosed with diffuse large B-cell lymphoma (DLBCL) of the left ocular adnexa, which was successfully treated by standard chemotherapy and local radiotherapy. Eight months later, he complained of diplopia and bitemporal hemianopia. Brain magnetic resonance imaging detected a suprasellar tumor. Transsphenoidal biopsy of the mass was performed, and histopathological examination revealed DLBCL admixed with pituitary adenoma. On a review of the literature, we found that pituitary lymphoma developing within adenoma is a recurrent phenomenon. The composite tumor is likely to be characterized by suprasellar involvement and presentation of visual disturbances. Moreover, in the present case, the suprasellar tumor remained visible after autologous peripheral stem cell transplant, likely due to the residual pituitary adenoma. We therefore recommend that refractory pituitary lymphoma should be vigorously biopsied in search of possibly underlying adenoma.     

IgG4-related disease of the thyroid glands

Recent reports on Hashimoto's thyroiditis (HT) with increased numbers of IgG4-positive plasma cells suggest that this type of HT may have a close relationship to IgG4-related disease (IgG4-RD). This unique subgroup of HT is termed as IgG4 thyroiditis and reveals distinct clinical, serological, and sonographic features from the non-IgG4 thyroiditis group. On the basis of immunostaining for IgG4, HT was divided into an IgG4 thyroiditis group and a non-IgG4 thyroiditis group. Clinically, IgG4 thyroiditis was associated with younger age group, lower female-male ratio, higher levels of thyroid autoantibodies, diffuse low echogenicity, more rapid progress requiring surgical treatment and more subclinical hypothyroidism. Serum IgG4 concentrations elevated in IgG4 thyroiditis and decreased significantly after a thyroidectomy. Histopathologically, IgG4 thyroiditis showed a higher grade of stromal fibrosis, lymphoplasmacytic infiltration, and follicular cell degeneration than non-IgG4 thyroiditis. IgG4 thyroiditis may represent IgG4-RD of thyroid gland, because it shares common histopathological characteristics with IgG4-RD in other organs. The identification of IgG4-RD of the thyroid gland opens new insights not only for patient's treatment with HT but also for the development of new therapeutic approaches for this rapidly progressive destructive subtype of HT. This article mainly focuses on reviewing the unique histopathological, clinical, and serological features of IgG4 thyroiditis group of HT. The etiology and genetic changes of HT are also discussed.     

Investigation of the prognosis of patients with papillary thyroid carcinoma by tumor size

In papillary thyroid carcinoma (PTC), extrathyroid extension (Ex) and clinical lymph node metastasis (N) significantly affect the prognosis. We investigated the prognosis of patients with PTC 1 cm or less (1,220 patients), 1.1-2 cm (2,101 patients), 2.1-3 cm (1,249 patients), 3.1-4 cm (645 patients), and larger than 4 cm (563 patients). We classified N factor into three categories: N0, no clinical node metastasis: N1, clinical node metastasis smaller than 3 cm and without extranodal tumor extension requiring at least partial excision of adjacent organs for node dissection: and N2, clinical node metastasis 3 cm or larger or showing extranodal tumor extension. N2 markedly affected lymph node and distant recurrence-free survivals and cause-specific survival, regardless of the tumor size. N1 also adversely affected lymph node and distant recurrence-free survival but not cause-specific survival. Ex did not affect patients' prognosis with PTC 1 cm or less. It became a prognostic factor with PTC larger than 1 cm, and worsened lymph node and distant recurrence-free survival not only for N0 but also for N1 PTC larger than 3 cm and larger than 2 cm, respectively. However, its influence is limited for N2 PTC patients. Furthermore, Ex worsened the CSS with PTC larger than 2 cm in combination with N2. We have to note that the prognostic significance for lymph node and distant recurrence-free and cause-specific survival of Ex and N varies according to the tumor size in order to accurately predict the clinical outcomes and establish therapeutic strategies for PTC patients.     

Spontaneous atrial fibrillation initiated by tyramine in canine atria with increased sympathetic nerve sprouting

Sympathetic Activation and Atrial Fibrillation. Background: Chronic left ventricular myocardial infarction (LVMI) promotes atrial and pulmonary veins (PV) sympathetic nerve sprouting. Objectives: To test the hypothesis that sympathetic stimulation with tyramine initiates atrial fibrillation (AF) by early afterdepolarization (EAD)‐mediated triggered activity at the left atrial PV (LAPV) junction. Methods: LVMI was created in 6 dogs and 6 dogs served as controls. Six to 8 weeks later the activation pattern of the isolated LAPV was optically mapped using dual voltage and intracellular Ca⁺² (Ca_i²⁺)‐sensitive epifluorescent dyes before and after tyramine (5 μM) perfusion. Results: Tyramine initiated spontaneous AF in 5 of 6 atria but none in the control group (P < 0.01). The AF was initiated by late phase 3 EAD‐mediated triggered activity that arose from the LAPV junction causing functional conduction block in LA, reentry, and AF. The AF was subsequently maintained by mixed reentrant and focal mechanisms. The EADs arose during the late phase 3, when the Ca_i²⁺ level was 64 ± 12% of the peak systolic Ca_i²⁺ transient amplitude, a property caused by tyramine's simultaneous shortening of the action potential duration and lengthening of the Ca_i²⁺ transient duration in the LVMI group but not in the control. Tyrosine hydroxylase and growth associated protein 43 positive nerve sprouts were significantly increased in the sinus node, LAA, and the LSPV in the LVMI group compared to control (P < 0.01). Conclusions: Increased atrial sympathetic nerve sprouts after LVMI makes the LAPV junction susceptible to late phase 3 EAD‐mediated triggered and AF during sympathetic stimulation with tyramine.     

Interleukin-1β measurement in stimulated whole blood cultures is useful to predict response to anti-TNF therapies in rheumatoid arthritis

Objective. In RA, response to TNF blockers may be associated with a profile of cytokine production unique to each patient. This study sought to predict the response to biologic agents by examining pro-inflammatory cytokine synthesis in stimulated whole blood cultures (WBCs). Methods. We measured the concentration of TNF-α, IL-1β and IL-6 in supernatants of lipopolysaccharide (LPS)-stimulated WBCs obtained from RA patients (n?=?41) before anti-TNF therapy (infliximab, 13; etanercept, 26; and adalimumab, 2) and from healthy controls (n?=?12). At 24 weeks after biologics, whole bloods were again drawn from 14 of 41 patients. Response was defined by the European League Against Rheumatism response criteria after 24 weeks of therapy. Results. Among 41 patients, 32 were responders (good 14/moderate 18), while 9 were non-responders. All cytokines measured were significantly lower in RA patients than in controls. In RA, IL-1β production was lower in non-responders than in responders [median (interquartile range): 3.5 (1.5-9.4) vs 10.0 (5.1-93.1) pg/ml, P?=?0.048]. The area under the curve from a receiver operating characteristic curve analysis for the prediction of response using IL-1β was 0.717 (95% CI 0.520, 0.914). The sensitivity and specificity of IL-1β (cut-off value 4.84?pg/ml) was 78.1 and 77.8%, respectively. All cytokines were significantly higher 6 months later compared with their respective baseline. Conclusion. IL-1β measurement in LPS-stimulated WBC is useful to predict responsiveness to anti-TNF agents. Cytokine production capacities in LPS-stimulated WBCs are up-regulated by biologics.     

Risk factors for failure of resolving optic disc pit maculopathy after primary vitrectomy without laser photocoagulation

Japanese Journal of Ophthalmology - To determine factors significantly correlated with the failure of macular reattachment by pars plana vitrectomy (PPV) without laser photocoagulation of the optic...     

Intraoperative optical coherence tomography-assisted displacement of prepapillary membrane in eyes with optic disc pit maculopathy

Graefe's Archive for Clinical and Experimental Ophthalmology - To determine the efficacy of displacing a prepapillary membrane during vitrectomy assisted by intraoperative optical coherence...     

Decreased expression of aquaporin 2 in the collecting duct of mice lacking the vasopressin V1a receptor

Background

Vasopressin V1a receptor null (V1aR^?/?) mice recently showed incomplete urinary concentration due to higher urine volume during control and water diuresis (euhydration), but showed normal response during dehydration (Aoyagi et al., Am J Physiol 295: F100–7, 2008).

Methods

Water balance, plasma vasopressin, plasma and urine osmolality, and aquaporin 2 (AQP2) expression in the kidney of wild-type (WT) and V1aR^?/? mice were therefore further examined using improved methods of urine collection (urinary bladder urine).

Results

V1aR^?/? mice demonstrated a lower urine osmolality (3,360 ± 138 vs. 3,610 ± 47 mOsm/kgH₂O) and a higher plasma osmolality (354.3 ± 1.3 vs. 342.5 ± 1.5 mOsm/kgH₂O) after dehydration for 24 h compared to WT mice (P < 0.05). In contrast, the plasma vasopressin concentration was significantly (P < 0.001) higher in the V1aR^?/? mice (48.8 ± 4.8 vs. 22.1 ± 2.4 pg/ml). On the other hand, although the AQP2 protein expression in the kidney was increased after dehydration, the basal (control) and dehydration-induced AQP2 protein levels were significantly lower in V1aR^?/? mice compared to WT mice (by Western blotting). Staining by an anti-AQP2 antibody in the luminal membrane of the collecting ducts was increased in both V1aR^?/? and WT mice after dehydration, but was relatively weaker in the V1aR^?/? mice (by immunohistochemistry). Moreover, urinary excretion of AQP2 protein, an index of the luminal AQP2 expression, was significantly (P < 0.05) lower in the V1aR^?/? mice.

Conclusion

V1aR signaling may be fundamentally important for the expression of AQP2 in the collecting ducts during control conditions and dehydration.