Treatment of immature teeth with nonvital pulps in adults: a prospective comparative clinical study comparing MTA with Ca(OH)2.

AIM: To evaluate and compare the influence of various predictors on outcomes of apexification using either mineral trioxide aggregate (MTA) or calcium hydroxide (CH) in permanent immature anterior teeth with necrotic pulps and periapical lesions of adults. METHODOLOGY: Ninety immature teeth with necrotic pulps and periapical lesions on adult patients (aged 18-40 years) were treated with MTA (45 teeth) or CH (45 teeth) between 2015 and 2018. Patients of both groups were recalled for follow-up examinations after the first intervention at 1,3,6 and 12 months for the first year, every 6 months for the second year and every year thereafter until the end of the study (median 32.3 months). The treatment outcome based on clinical and radiographic criteria was assessed by calibrated examiners and dichotomized as 'healed+healing' or 'not healed'. The age, gender, stage of root development, preoperative signs and symptoms of apical periodontitis and size of periapical lesion were recorded. The cumulative success proportion and mean time were analysed with the Kaplan-Meier test. The generalized logrank statistic was used to describe prognostic clinical variables. Fisher's exact test was applied for the evaluation of the healing rates. RESULTS: Thirty-nine of the 45 teeth treated with MTA were available for recall. Of these, 29 teeth (74%) revealed calcific apical barrier formation with complete resolution of periapical lesions, 7 teeth (18%) were healing, and 3 teeth (8%) had persistent disease. Thirty-four of the 45 teeth in the CH group were available for recall. Of these, 27 teeth (79%) had complete healing of periapical lesions and had calcific barrier formation, 4 teeth (12%) were healing, and the remaining 3 teeth (9%) had not healed. The survival rate of teeth treated with MTA was similar to the survival rates observed in teeth treated with CH (90% and 91%, respectively, P > 0.05). The generalized logrank statistic revealed that the cumulative success rate of both materials was not significantly different (P > 0.05). None of the tested predictors had an influence on the treatment outcomes of teeth in both groups (P > 0.05). CONCLUSIONS: Apexification with both MTA and CH was associated with similar treatment outcomes. MTA may be proposed as a material for apexification treatment in immature teeth of adult patients due to the shorter treatment time associated with its use.

Regenerative Endodontic Therapy with Platelet Rich Fibrin: Case Series.

Regenerative endodontic therapy (RET) provides a novel treatment modality for the immature teeth with pulp necrosis. The aim of this case series was to evaluate RET of immature permanent teeth using platelet rich fibrin (PRF) at 36-month follow-up periods. In the present case series, three immature maxillary incisors diagnosed with pulp necrosis and apical periodontitis were treated with RET. The root canals were irrigated with 1.5% sodium hypochlorite (NaOCl) and medicated with triple antibiotic paste(TAP). At the second visit, TAP was removed and root canals were conditioned with 17% EDTA. PRF was used as a scaffold. MTA was placed over PRF and the teeth were restored with composite resin. Periapical radiographs and cone beam computerized tomography(CBCT) were used to evaluate the healing. At the end of the 36-month follow-up periods, there was no response to pulp sensibility tests with cold and electric pulp tester, but all teeth showed decreased periapical lesions or evidence of healing.

Werner syndrome: clinical evaluation of two cases and a novel mutation.

Werner syndrome (WS) is a premature aging disorder, inherited in an autosomal recessive pattern and caused by the mutation in the WRN gene. In this report we describe two male patients with negative family history who demonstrate characteristic findings of WS, with different mutations, including one novel mutation. The first case was a 47-year-old man who had been suffering from large, ischemic ulcers on both legs for 7 years. Physical examination revealed a thin and short man with severe wasting of all extremities. He had a high-pitched voice, hoarseness, a characteristic bird-like facies, bilateral cataracts, generalized osteoporosis, hypotrichosis, atrophic and poikilodermic skin, flexion contractures of hands, feet and knees, and soft tissue calcifications. Laboratory investigations revealed anemia, high erythrocyte sedimentation rate, low creatinine clearance, and high liver enzymes. Genetic analysis showed a homozygous novel 1bp-deletion in exon 19 of WRN, 2426/27delG, causing frameshift and protein truncation R809SfsX2, which has not been described before. The second case was a 23-year-old man who was referred for large callosities on both feet, present for 7 years. He complained of weakness, weight loss, wasting of muscles, and early graying of hair. The entire skin was thin, wrinkled and dry. Generalized hypotrichosis, scattered ephelid-like macules, sclerotic fingers, calcinosis cutis on ears, hyperpigmentation on elbows were the other alterations of skin. Skeletal survey revealed osteoporosis. Genetic analysis showed a homozygous known pathogenic splice site mutation c.3460-2A>G, causing skipping of Exon 30 in WRN.

The improved killing of both androgen-dependent and independent prostate cancer cells by etoposide loaded SPIONs coupled with NIR irradiation.

Etoposide (Eto) is a toxic drug that shows promise in treating prostate cancer (PCa) but confers significant side effects, and has poor solubility and bioavailability. Nanoparticles are quite successful in overcoming such problems. Multifunctional nanoparticles that provide an opportunity to perform combination therapy have attracted great interest in recent years. Superparamagnetic iron oxide nanoparticles (SPIONs) are popular in various biomedical applications, including magnetic resonance imaging, drug delivery, magnetic hyperthermia and recently in photothermal therapy, combining imaging with therapy. Here, for the enhanced killing of PCa cells that are either androgen-dependent or not, the combination of SPION based Eto delivery and mild hyperthermia triggered by laser irradiation is proposed for the first time in the literature. For the encapsulation of Eto, highly stable, small, polyacrylic acid coated SPIONs were conjugated with bovine serum albumin (BSA) (Eto-BSA@PAA@SPION). Eto-BSA@PAA@SPION with 9% drug content produced better chemotherapeutic outcomes than free Eto on both androgen-dependent/castration sensitive LNCaP and androgen-independent/castration-resistant PC3 and DU145 PCa cells by enhancing drug internalization. Single and short irradiation of Eto-BSA@PAA@SPION treated cells at 808 nm improved the drug release and sensitized cells for Eto, hence, increasing the toxicity dramatically in all studied PCa cell lines. Caspase-mediated apoptosis, DNA damage, and ROS generation were detected in the treated cells, increasing with the Eto dose and laser treatment. The IC50 for Eto is reduced to 0.08 µg mL-1, 0.13 µg mL-1 and 2.8 µg mL-1 with laser/Eto-BSA@PAA@SPION for LNCaP, DU145 and PC3 cells, respectively. These are the lowest IC50 values seen in the literature for Eto on these cell lines so far, suggesting that the demonstrated nanoparticles and treatment approaches have great potential to treat various PCa cells at low doses of the drug under mild laser treatment conditions.

IL-15 and IL-2: a matter of life and death for T cells in vivo.

Interleukin (IL)-2 and IL-15 are redundant in stimulating T-cell proliferation in vitro. Their precise role in vivo in governing T-cell expansion and T-cell homeostasis is less clear. Each may have distinct functions and regulate distinct aspects of T-cell activation. The functional receptors for IL-2 and IL-15 consist of a private alpha-chain, which defines the binding specificity for IL-2 or IL-15, and shared IL-2 receptor beta- and gamma-chains. The gamma-chain is also a critical signaling component of IL-4, IL-7 and IL-9 receptors. Thus, the gamma-chain is called the common gamma or gamma-c. As these receptor subunits can be expressed individually or in various combinations resulting in the formation of receptors with different affinities, distinct signaling capabilities or both, we hypothesized that differential expression of IL-2 and IL-15 receptor subunits on cycling T cells in vivo may direct activated T cells to respond to IL-2 or IL-15, thereby regulating the homeostasis of T-cell response in vivo. By observing in vivo T-cell divisions and expression of IL-2 and IL-15 receptor subunits, we demonstrate that IL-15 is a critical growth factor in initiating T cell divisions in vivo, whereas IL-2 limits continued T-cell expansion via downregulation of the gamma-c expression. Decreased gamma-c expression on cycling T cells reduced sustained Bcl-2 expression and rendered cells susceptible to apoptotic cell death. Our study provides data that IL-2 and IL-15 regulate distinct aspects of primary T-cell expansion in vivo.

A comparison of travoprost, latanoprost, and the fixed combination of dorzolamide and timolol in patients with pseudoexfoliation glaucoma.

PURPOSE: To compare the intraocular pressure (IOP) lowering effect and safety of latanoprost, travoprost given every evening, and the fixed combination dorzolamide + timolol (DTFC) given twice daily in pseudoexfoliation glaucoma (PXG). METHODS: This randomized, prospective, investigator-masked study has been conducted with 50 PXG patients. Patients were assigned to one of three groups: travoprost 0.004%, fixed combination of dorzolamide 2%+timolol 0.5%, or latanoprost 0.005% for 6 months. At baseline and 0.5, 1, 2, 3, 4, 5, and 6 months of therapy, IOP (8 am, 10 am, 4 pm), blood pressures, and pulse rates were measured, and ophthalmologic examination was performed. The side effects were recorded at each visit. RESULTS: Forty-two of the 50 patients initially enrolled completed this study. Withdrawn patients included one (latanoprost) for lack of efficacy, five (three travoprost, one latanoprost, one DTFC) for adverse events, and two (one latanoprost, one DTFC) for loss of follow-up. Each of the three drugs considerably reduced the IOP in PXG cases throughout the 6 months. Mean IOP reduction at 6 months was -9.3+/-2.9 mmHg in the travoprost group, -8.2+/-1.2 mmHg in the latanoprost group, and 11.5+/-3.3 mmHg in the DTFC group. Comparing the groups, DTFC is more effective than latanoprost and travoprost in lowering IOP (p<0.05). There was no difference between travoprost and latanoprost. The most common treatment-related adverse event was conjunctival hyperemia. Intensity of ocular hyperemia was greater in the travoprost group compared with the latanoprost and DTFC groups (p<0.05). There were no significant effects on systemic safety parameters. CONCLUSIONS: The results demonstrated that DTFC is more effective in reducing IOP than latanoprost and travoprost. Latanoprost and travoprost had similar ocular hypotensive effects in patients with PXG. All three drugs were well tolerated; there were fewer ocular side effects attributable in the latanoprost group.

Cystoid macular edema associated with latanoprost after uncomplicated cataract surgery.

PURPOSE: To report clinically symptomatic and angiographically documented cystoid macular edema (CME) associated with the use of latanoprost in two pseudophakic eyes after uncomplicated cataract surgery. METHODS: Retrospective review of two patients who had history of latanoprost use and uncomplicated cataract surgery and described blurred vision in the first postoperative month. RESULTS: Ocular examination revealed CME, which was confirmed by fluorescein angiography. The visual acuities of patients improved and the CME was angiographically resolved after discontinuation of latanoprost and the initiation of nonsteroidal anti-inflammatory eye-drops and oral acetazolamide. CONCLUSIONS: Until a causal relationship between CME and latanoprost is proved or disproved, caution in its use in pseudophakic patients would be prudent.

Fibrosis in chronic rejection of human liver allografts: expression patterns of transforming growth factor-TGFbeta1 and TGF-beta3.

Activation and transformation of lipocytes (Ito cells, stellate cells) into alpha-actin-positive myofibroblast-like cells is an essential step in the initiation of liver fibrosis. Transforming growth factor-beta (TGF-beta) is considered an important mediator of this process. In order to determine mechanisms of fibrotic deposition in a hepatic transplant setting, we analyzed 10 chronically rejected human liver allografts for the expression of extracellular matrix (ECM) molecules, myofibroblast-like cells (alpha-actin), macrophages, and TGF-beta1 and -beta3. Using single- and double-immunohistochemical staining techniques, all specimens investigated showed increased deposition of the ECM proteins fibronectin, tenascin, undulin, and collagen VI with a characteristic densification especially in pericentral areas. Likewise, strong accumulation of alpha-actin-positive cells and TGF-beta1-expressing macrophages was observed in the same fields, supporting the concept of lipocyte activation/transformation and subsequent ECM production fostered by macrophage-derived TGF-beta1. In contrast, TGF-beta3 was found to be mainly expressed by a markedly increased number of lipocytes. Interestingly, distribution of TGF-beta3 corresponded to that of tenascin, an ECM molecule known to be involved in early matrix organization, suggesting that TGF-beta3 may likewise act mainly in early stages of fibrogenesis. Furthermore, TGF-beta3 restriction to high numbers of a single cell type (i.e., lipocytes) implied a possible role in cell proliferation through autocrine loops. In conclusion, fibrosis in chronic rejection seems to follow similar mechanisms as in non-transplanted livers but additionally suggests differential temporal and functional roles for the TGF-beta isoforms 1 and 3 in the course of a multistep process leading to lipocyte transformation and ECM production.

Rapamycin induces transforming growth factor-beta production by lymphocytes.

BACKGROUND: Under certain conditions rapamycin and transforming growth factor- (TGF) beta have similar immunoregulatory effects, suggesting a potential functional link between rapamycin and TGF-beta. METHODS: Splenic leukocytes were stimulated in vitro with anti-CD3 or with allogeneic cells in vivo in the presence or absence of rapamycin. TGF-beta production by activated lymphocytes was quantitated using ELISA. RESULTS: Splenic leukocytes from BALB/c mice that were primed with allogeneic cells and conditioned with rapamycin in vivo as well as splenic leukocytes that were treated with rapamycin in vitro produced significantly higher levels of TGF-beta upon anti-CD3 stimulation as compared with untreated controls. CONCLUSION: Our data suggest that rapamycin can program activated lymphocytes to produce TGF-beta. Thus, the immunosuppressive effects of rapamycin may be partially mediated by TGF-beta.

Expression patterns of integrin receptors and extracellular matrix proteins in chronic rejection of human liver allografts.

The beta1-integrin family of adhesion molecules is supposed to mediate cell-to-matrix interactions involved in a variety of immune reactions, especially in those associated with tissue remodelling. In an attempt to determine the role of beta1-integrins in the initiation and maintenance of fibrotic deposition observed in chronic rejection after liver transplantation, we immunohistochemically analysed the expression of different extracellular matrix components and the very late antigen (VLA) family of beta1-integrins in 11 samples of chronically rejected human liver allografts and compared results to findings in acutely rejected transplants and nontransplanted chronic inflammatory livers. In contrast to normal liver specimens, chronically rejected human liver allografts displayed a general overexpression of matrix components along sinusoids throughout the tissue and an additional characteristic accumulation in pericentral areas. Accordingly, VLA-1, -5 and -6 demonstrated a linear upregulation or de novo expression on sinusoidal lining cells, VLA-1 and VLA-4 additionally displayed concentration within pericentral fibrotic deposits. VLA-2 and -3 were only sporadically found. In accordance with findings in chronic rejection, chronic inflammatory livers showed overexpression of VLA-1, -5 and -6 within sinusoids and accumulation of VLA-1 and -4 in fibrotic septa. In contrast, acutely rejected allografts displayed slight overexpression of ECM components without characteristic accumulates, hence beta1-integrins were seen to be equally distributed throughout the parenchyma. Altogether, our analysis showed an upregulation of integrin receptors which corresponded to the extent of ECM deposition and thus suggested an important role for these molecules in the iniation of fibrosis observed in these specimens. Individual integrins showed different expression patterns within sinusoids and fibrotic areas, indicating distinct roles in differential stages of matrix accumulation, but induction patterns were generally similar in chronic inflammatory and chronically rejected livers, suggesting independence of the underlying disease.

Striking dichotomy of PD-L1 and PD-L2 pathways in regulating alloreactive CD4(+) and CD8(+) T cells in vivo.

Programmed death-1 (PD-1) is a recently identified coinhibitory molecule that belongs to the CD28 superfamily. PD-1 has two ligands PD-L1 and PD-L2. There is some evidence that PD-L1 and PD-L2 serve distinct functions, but their exact function in alloimmunity remains unclear. In the present study, we used a GVHD-like model that allows detailed analyses of T-cell activation at a single cell level in vivo to examine the role of PD-1/PD-L1 and PD-1/PD-L2 interactions in regulating proliferation of CD4(+) and CD8(+) T cells in response to alloantigen stimulation. We found that both CD4(+) and CD8(+) T cells proliferated vigorously in vivo and that PD-L1 and PD-L2 exhibit strikingly different effect on T-cell proliferation. While blocking PD-L1 did not affect the in vivo proliferation of CD4(+) and CD8(+) T cells regardless of CD28 costimulation, blocking PD-L2 resulted in a marked increase in the responder frequency of CD8(+) T-cells in vivo. The effect of PD-L2 on the CD8(+) T-cell proliferation is regulated by CD28 costimulation and by the CD4(+) T cells. We conclude that PD-L1 and PD-L2 function differently in regulating alloreactive T-cell activation in vivo, and PD-L2 is predominant in this model in limiting alloreactive CD8(+) T-cell proliferation.

A comparison of travoprost, latanoprost, and the fixed combination of dorzolamide and timolol in patients with pseudoexfoliation glaucoma.

PURPOSE: To compare the intraocular pressure (IOP) lowering effect and safety of latanoprost, travoprost given every evening, and the fixed combination dorzolamide + timolol (DTFC) given twice daily in pseudoexfoliation glaucoma (PXG). METHODS: This randomized, prospective, investigator-masked study has been conducted with 50 PXG patients. Patients were assigned to one of three groups: travoprost 0.004%, fixed combination of dorzolamide 2%+timolol 0.5%, or latanoprost 0.005% for 6 months. At baseline and 0.5, 1, 2, 3, 4, 5, and 6 months of therapy, IOP (8 am, 10 am, 4 pm), blood pressures, and pulse rates were measured, and ophthalmologic examination was performed. The side effects were recorded at each visit. RESULTS: Forty-two of the 50 patients initially enrolled completed this study. Withdrawn patients included one (latanoprost) for lack of efficacy, five (three travoprost, one latanoprost, one DTFC) for adverse events, and two (one latanoprost, one DTFC) for loss of follow-up. Each of the three drugs considerably reduced the IOP in PXG cases throughout the 6 months. Mean IOP reduction at 6 months was -9.3+/-2.9 mmHg in the travoprost group, -8.2+/-1.2 mmHg in the latanoprost group, and11.5+/-3.3 mmHg in the DTFC group. Comparing the groups, DTFC is more effective than latanoprost and travoprost in lowering IOP (p<0.05). There was no difference between travoprost and latanoprost. The most common treatment-related adverse event was conjunctival hyperemia. Intensity of ocular hyperemia was greater in the travoprost group compared with the latanoprost and DTFC groups (p<0.05). There were no significant effects on systemic safety parameters. CONCLUSIONS: The results demonstrated that DTFC is more effective in reducing IOP than latanoprost and travoprost. Latanoprost and travoprost had similar ocular hypotensive effects in patients with PXG. All three drugs were well tolerated; there were fewer ocular side effects attributable in the latanoprost group. (Eur J Ophthalmol 2006; 15: 73-80).

Cystoid macular edema associated with latanoprost after uncomplicated cataract surgery.

PURPOSE: To report clinically symptomatic and angiographically documented cystoid macular edema (CME) associated with the use of latanoprost in two pseudophakic eyes after uncomplicated cataract surgery. METHODS: Retrospective review of two patients who had history of latanoprost use and uncomplicated cataract surgery and described blurred vision in the first postoperative month. RESULTS: Ocular examination revealed CME, which was confirmed by fluorescein angiography. The visual acuities of patients improved and the CME was angiographically resolved after discontinuation of latanoprost and the initiation of nonsteroidal anti-inflammatory eyedrops and oral acetazolamide. CONCLUSIONS: Until a causal relationship between CME and latanoprost is proved or disproved, caution in its use in pseudophakic patients would be prudent. (Eur J Ophthalmol 2005; 15: 158-61).

Secretory IgA epitopes in basal tears of extended-wear soft contact lens wearers and in non-lens wearers.

PURPOSE: To determine secretory IgA epitopes in tears of extended-wear soft contact lens wearers and non-wearing controls. METHODS: We developed enzyme-linked immunosorbent assays (ELISA) to determine the tear concentrations of two epitopes of secretory IgA, the IgA alpha-chain and the secretory component. These epitopes were measured in basal tears of 20 individuals in 6 nights of extended wear of etafilcon A soft contact lenses and in 19 non-lens-wearing individuals. RESULTS: Levels of IgA alpha-chain immunoreactivity were significantly decreased in the lens-wearing group compared to non-lens wearers. However, the level of secretory component immunoreactivity was not significantly different between groups. IgA alpha-chain and secretory component immunoreactvity were highly correlated; however, some samples showed a marked variation between these two values. CONCLUSION: Tear concentrations of sIgA epitopes are significantly reduced in extended-wear contact lens wearers, and may contribute to the increased susceptibility to ocular infection seen in this group.