Molecular diagnostics of gliomas: the clinical perspective.

Significant progress has been made in the molecular diagnostic subtyping of brain tumors, in particular gliomas. In contrast to the classical molecular markers in this field, p53 and epidermal growth factor receptor (EGFR) status, the clinical significance of which has remained controversial, at least three important molecular markers with clinical implications have now been identified: 1p/19q codeletion, O⁶-methylguanine methyltransferase (MGMT) promoter methylation and isocitrate dehydrogenase-1 (IDH1) mutations. All three are favorable prognostic markers. 1p/19q codeletion and IDH1 mutations are also useful to support and extend the histological classification of gliomas since they are strongly linked to oligodendroglial morphology and grade II/III gliomas, as opposed to glioblastoma, respectively. MGMT promoter methylation is the only potentially predictive marker, at least for alkylating agent chemotherapy in glioblastoma. Beyond these classical markers, the increasing repertoire of anti-angiogenic agents that are currently explored within registration trials for gliomas urgently calls for efforts to identify molecular markers that predict the benefit derived from these novel treatments, too.

Observations on the Pharmacokinetics and Pharmacodynamics of Dexmedetomidine. Clinical Studies on Healthy Volunteers and Intensive Care Patients

Patients treated in intensive care units require sedation and analgesia. However, sedative drugs also have potential adverse effects, and there is no single ideal sedativeanalgesic drug for these patients. Dexmedetomidine is an apha2-adrenoceptor agonist licenced for sedation of intensive care patients and patients undergoing surgery and other invasive procedures. Several routes of parenteral administration (intravenous, intramuscular, subcutaneous and intranasal) have been utilized. In the present series of studies, the pharmacokinetics and pharmacodynamics of intranasally administered dexmedetomidine as well as the gastrointestinal effects of intravenous dexmedetomidine were determined in healthy volunteers. Pharmacokinetics of dexmedetomidine during long lasting, high-dose infusions were characterized in intensive care patients. The bioavailability of intranasal dexmedetomidine was relatively good (65%), but interindividual variation was large. Dexmedetomidine significantly inhibited gastric emptying and gastrointestinal transit. In intensive care patients, the elimination half-life of dexmedetomidine was somewhat longer than reported for infusions of shorter duration and in less ill patients or healthy volunteers. Dexmedetomidine appeared to have linear pharmacokinetics up to the studied dose rate of 2.5 μg/kg/h. Dexmedetomidine clearance was decreasing with age and its volume of distribution was increased in hypoalbuminaemic patients, resulting in a longer elimination half-life and context-sensitive half-time. Intranasally administered dexmedetomidine was efficacious and well tolerated, making it appropriate for clinical situations requiring light sedation. The clinical significance of the gastrointestinal inhibitory effects of dexmedetomidine should be further evaluated in intensive care patients. The possibility of potentially altered potency and effect duration should be taken into account when administering dexmedetomidine to elderly or hypoalbuminaemic patients.

Clinical impact of Achromobacter xylosoxidans colonization/infection in patients with cystic fibrosis

The rate of diagnosis of colonization/infection of the airways with Achromobacter xylosoxidans has increased in cystic fibrosis patients, but its clinical significance is still controversial. This retrospective, case-control study aimed to evaluate the clinical impact of A. xylosoxidans colonization/infection in cystic fibrosis patients. Individuals who were chronically colonized/infected (n=10), intermittently colonized/infected (n=15), and never colonized/infected with A. xylosoxidans (n=18) were retrospectively evaluated during two periods that were 2 years apart. Demographic characteristics, clinical data, lung function, and chronic bacterial co-colonization data were evaluated. Of the total study population, 87% were pediatric patients and 65.1% were female. Individuals chronically colonized/infected with A. xylosoxidans had decreased forced expiratory volume in 1 s (51.7% in the chronic colonization/infection group vs 82.7% in the intermittent colonization/infection group vs 76% in the never colonized/infected group). Compared with the other two groups, the rate of co-colonization with methicillin-resistant Staphylococcus aureus was higher in individuals chronically colonized/infected with A. xylosoxidans (P=0.002). Changes in lung function over 2 years in the three groups were not significant, although a trend toward a greater decrease in lung function was observed in the chronically colonized/infected group. Compared with the other two groups, there was a greater number of annual hospitalizations in patients chronically colonized/infected with A. xylosoxidans (P=0.033). In cystic fibrosis patients, there was an increased frequency of A. xylosoxidans colonization/infection in children, and lung function was reduced in patients who were chronically colonized/infected with A. xylosoxidans. Additionally, there were no differences in clinical outcomes during the 2-year period, except for an increased number of hospitalizations in patients with A. xylosoxidans.

Evaluation of clinical periodontal conditions in smokers and non-smokers

Given that tobacco smoking habit is a risk factor for periodontal diseases, the aim of this study was to compare clinical periodontal aspects between smokers and non-smokers. The clinical status were assessed in 55 patients, 29 smokers and 26 non-smokers, aged 30 to 50 years, with mean age of 40. The clinical parameters used were: probing depth (PD), plaque index (PI), gingival index (GI), clinical attachment level (CAL), gingival recession (GR) and gingival bleeding index (GBI) for arches (upper and lower ) and teeth (anterior and posterior). Tooth loss was also evaluated in both groups. Multiple regression analysis showed: tendency of greater probing depth and clinical attachment level means for smokers; greater amount of plaque in smokers in all regions; greater gingival index means for non-smokers with clinical significance (p<0.05) in all regions. Although, without statistical significance, the analysis showed greater gingival bleeding index means almost always for nonsmokers; similar gingival recession means in both groups and tendency of upper tooth loss in smokers and lower tooth loss in non-smokers. The findings of this study showed that clinical periodontal parameters may be different in smokers when compared to non-smokers and that masking of some periodontal signs can be a result of nicotine's vasoconstrictor effect.

Incidence of the ossified pterygoalar ligament in Brazilian human skulls and its clinical implications

The ossified pterygoalar ligament is formed between the lateral lamina of the pterygoid process and the infratemporal surface of the sphenoid bone or its greater wing and was not connected to the sphenoid spine. The aim of this study was to evaluate the incidence of the ossified pterygoalar ligament in Brazilian human skulls and analyzing its clinical importance. 183 Brazilian adult (between 30 to 60 years old) dry human skulls were evaluated. Was evaluated the incidence of skulls with complete or partial ossification of the pterygoalar ligament, bilaterally and unilaterally and in the presence on the right and left sides. Were found 5 skulls had the ossified pterygoalar ligament, resulting in an overall incidence of 2.73%. There was 1 skull in the presence of the incomplete ossification of the pterygoalar ligament, unilaterally and on the left side resulting in incidence of 0.54%. There were 4 skulls in the presence of the complete ossification of the pterygoalar ligament, unilaterally and on the right side resulting in incidence of 2.18%. The ossified pterygoalar ligament is a major cause of the entrapment of the lingual nerve or a branch of the mandibular nerve and may cause mandibular neuralgia. The incidence of the ossified pterygoalar ligament and the pterygoalar foramen is low in the Brazilian population. However, these structures have clinical significance as this ligament establish relationships with the ovale foramen and difficulty in accessing in this foramen in a therapeutic approach.

A split-mouth randomized clinical trial of conventional and heavy flowable composites in class II restorations

Objective: The aim of this study was to evaluate the 2-year clinical performance of class II restorations made with a composite resin with two different viscosities.Methods: 47 patients received two class II restorations (n = 94), one made with GrandioSO (conventional viscosity CV), and the other with GrandioSO Heavy Flow (flowable viscosity FV), subjecting both materials to the same clinical conditions. The self-etching adhesive Futurabond M was used for all restorations. The composites were inserted using the incremental technique. The restorations were evaluated using the modified USPHS criteria according to the periods: baseline, 6 months, 1 year and 2 years after restorative procedures.Results: After 24 months, 40 patients attended the recall and 78 restorations were evaluated. In all periods, no secondary caries was observed. After 6 months, there were slightly overall changes of scores for most parameters. After 24 months, the higher number of changes from score Alfa to Bravo was observed for marginal discolouration (32.5% CV and 39.5% FV) and colour match (15% CV and 31.6% FV), followed by proximal contact (25% CV and 23.7% FV) and marginal adaptation (20% CV and 21.1% FV). For wear, surface texture and postoperative sensitivity the changes were very small. Just two restorations were lost during the 24-month follow up. Less than 5% of all restorations showed postoperative sensitivity. Chi-square test showed no significant differences between the two materials for all parameters analysed.Conclusion: After 2 years of clinical service, no significant differences were observed between GrandioSO conventional and GrandioSO Heavy Flow for the parameters analysed. Both materials provided acceptable clinical behaviour in class II restorations. Clinical Significance: This study presents the possibility of using a flowable composite with high filler content, for performing class II restorations. (C) 2014 Elsevier Ltd. All rights reserved.

Five-year clinical performance of the dentine Deproteinization Technique in non-carious cervical lesions

Objective: The aim of this study was to evaluate the 5-year clinical performance of composite restorations of non-carious cervical lesions (NCCL) using a total-etch adhesive system with or without collagen removal with 10% sodium hypochlorite (NaOCl).Methods: In this study randomized controlled split-mouth clinical trial, one-hundred and thirty-eight NCCL were restored into 30 patients. Each patient received at least one pair of composite restorations (Filtek A110/3M ESPE), bonded either with 2 techniques: Conventional Technique - acid etching with 37% phosphoric acid + Prime & Bond NT (Denstply DeTrey); Deproteinization Technique - acid etching with 37% phosphoric acid + 10% NaOCl for 1 min + Prime & Bond NT. The two techniques were evaluated using the United States Public Health Service (USPHS) criteria at baseline, 18 months, 3 and 5 years. After five years, one-hundred and six restorations were evaluated in 24 patients. Data were analyzed using the Chi-Square test (p < 0.05).Results: There were no statistically significant differences between the two techniques regarding the evaluated parameters (p > 0.05).Conclusion: After 5 years, the application of 10% NaOCl deproteinization on etched dentine did not affect the clinical performance of composite restorations placed in NCCL when compared to the conventional total-etch technique.Clinical significance: Clinical studies evaluating the performance of the Deproteinization Technique are scarce. In this study, this technique showed similar clinical performance at the end of 5 years when compared to a conventional total-etch technique. (C) 2014 Elsevier Ltd. All rights reserved.

Comparative effects of photodynamic therapy mediated by curcumin on standard and clinical isolate of Streptococcus mutans

Aim: The aim of this study was investigate the effect of photodynamic therapy (PDT) using curcumin (C) as a photosensitizing agent irradiated with an LED (L) in the blue wavelength as a light source on a standard and clinical isolate of Streptococcus mutans (S. mutans) in a planktonic suspension model. Materials and methods: Suspensions of both strains were divided into 4 groups as follows: absence of C and L (control group: C–L–), with C and without L (C group: C+L–), absence of C with L (L group: C–L+) and presence of C and L (PDT group: C+L+). Three different concentrations of curcumin (0.75 mg/ml, 1.5 mg/ml and 3 mg/ml) and three light fluences of studied light source (24, 48 and 72 J cm–2) were tested. Aliquots of each studied group was plated in BHI agar and submitted to colony forming units counting (CFU/ml) and the data transformed into logarithmical scale. Results: A high photoinactivation rate of more than 70% was verified to standard S. mutans strain submitted to PDT whereas the clinical isolate showed a lower sensitivity to all the associations of curcumin and LED. A slight bacterial reduction was verified to C+L– and C–L+, demonstrating no toxic effects to the isolated application of light and photosensitizer to both S. mutans strains tested. Conclusion: Photodynamic therapy using a combination of curcumin and blue LED presented a substantial antimicrobial effect on S. mutans standard strain in a planktonic suspension model with a less pronounced effect on its clinical isolate counterparts due to resistance to this alternative approach. Clinical significance: Alternative antimicrobial approaches, as photodynamic therapy, should be encouraged due to optimal results against cariogenic bacteria aiming to prevent or treat dental caries.

Can repair increase the longevity of composite resins? Results of a 10-year clinical trial

The aim of this double-blind clinical trial was to assess the longevity of repairs to localized clinical defects in composite resin restorations that were initially planned to be treated with a restoration replacement. Methods Twenty-eight patients aged 18–80 years old with 50 composite resin restorations (CR) were recruited. The restorations with localized, marginal, anatomical deficiencies and/or secondary caries adjacent to CR that were “clinically judged” to be suitable for repair or replacement according to the USPHS criteria were randomly assigned to Repair (n = 25) or Replacement (n = 25) groups, and the quality of the restorations was scored according to the modified USPHS criteria. The restorations were blind and two examiners scored them at baseline (Cohen Kappa agreement score 0.74) and at ten years (Cohen Kappa agreement score 0.87) restorations. Wilcoxon tests were performed for comparisons within the same group (95% CI), and Friedman tests were utilized for multiple comparisons between the different years within each group. Results Over the decade, the two groups behaved similarly on the parameters of marginal adaptation (MA) (p > 0.05), secondary caries (SC) (p > 0.05), anatomy (A) (p < 0.05), and colour (C) (p > 0.05). Conclusions Given that the MA, SC, A and C parameters behaved similarly in both groups, the repair of composite resins should be elected when clinically indicated, because it is a minimally invasive treatment that can consistently increase the longevity of restorations. Clinical significance The repair of defective composite resins as an alternative treatment to increase their longevity proved to be a safe and effective treatment in the long term.

Distal extension removable partial denture with resilient attachment connect to an anterior fixed implant-supported prosthesis: a clinical report

Background: Considering the limited qualitative and quantitative bone in the posterior arch, this modality of prosthetic treatment could provide a positive emotional factor reestablished by immovability of the anterior fixed implant-supported segment. Objective: This clinical report demonstrates the possibility of achieving positive results with a removable partial denture connected to an implant-supported fixed prosthesis associated to an extra resilient attachment. Clinical significance: In cases of posterior mandibular and maxilla atrophy added to the patients desire against the bone graft, this kind of prosthetic treatment has an important place as an alternative.

Parvovirus 4 infection and clinical outcome in high-risk populations

Parvovirus 4 (PARV4) is a DNA virus frequently associated with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections, but its clinical significance is unknown. We studied the prevalence of PARV4 antibodies in 2 cohorts of HIV- and HCV-infected individuals (n = 469) and the correlations with disease status. We found that PARV4 infection frequently occurred in individuals exposed to bloodborne viruses (95% in HCV-HIV coinfected intravenous drug users [IDUs]). There were no correlations between PARV4 serostatus and HCV outcomes. There was, however, a significant association with early HIV-related symptoms, although because this was tightly linked to both HCV status and clinical group (IDU), the specific role of PARV4 is not yet clear.

Characterization and Clinical Relevance of ALDHbright Populations in Prostate Cancer

PURPOSE High aldehyde dehydrogenase (ALDH) has been suggested to selectively mark cells with high tumorigenic potential in established prostate cancer cell lines. However, the existence of cells with high ALDH activity (ALDH(bright)) in primary prostate cancer specimens has not been shown so far. We investigated the presence, phenotype, and clinical significance of ALDH(bright) populations in clinical prostate cancer specimens. EXPERIMENTAL DESIGN We used ALDEFLUOR technology and fluorescence-activated cell-sorting (FACS) staining to identify and characterize ALDH(bright) populations in cells freshly isolated from clinical prostate cancer specimens. Expression of genes encoding ALDH-specific isoforms was evaluated by quantitative real-time PCR in normal prostate, benign prostatic hyperplasia (BPH), and prostate cancer tissues. ALDH1A1-specific expression and prognostic significance were assessed by staining two tissue microarrays that included more than 500 samples of BPH, prostatic intraepithelial neoplasia (PIN), and multistage prostate cancer. RESULTS ALDH(bright) cells were detectable in freshly excised prostate cancer specimens (n = 39) and were mainly included within the EpCAM((+)) and Trop2((+)) cell populations. Although several ALDH isoforms were expressed to high extents in prostate cancer, only ALDH1A1 gene expression significantly correlated with ALDH activity (P < 0.01) and was increased in cancers with high Gleason scores (P = 0.03). Most importantly, ALDH1A1 protein was expressed significantly more frequently and at higher levels in advanced-stage than in low-stage prostate cancer and BPH. Notably, ALDH1A1 positivity was associated with poor survival (P = 0.02) in hormone-naïve patients. CONCLUSIONS Our data indicate that ALDH contributes to the identification of subsets of prostate cancer cells of potentially high clinical relevance.

The subjective present and its modulation in clinical contexts

Time is a basic dimension in psychology, underlying behavior and experience. Timing and time perception constitute implicit processes that are often inaccessible to the individual person. Research in this field has shown that timing is involved in many areas of clinical significance. In the projects presented here, we combine timing with seemingly different fields of research, such as psychopathology, perceptual grouping, and embodied cognition. Focusing on the time scale of the subjective present, we report findings from three different clinical studies: (1) We studied perceived causality in schizophrenia patients, finding that perceptual grouping (‘binding’, ‘Gestalt formation’), which leads to visual causality perceptions, did not distinguish between patients and healthy controls. Patients however did integrate context (provided by the temporal distribution of auditory context stimuli) less into perceptions, in significant contrast to controls. This is consistent with reports of higher inaccuracy in schizophrenia patients’ temporal processing. (2) In a project on auditory Gestalt perception we investigated auditory perceptual grouping in schizophrenia patients. The mean dwell time was positively related to how much patients were prone to auditory hallucinations. Dwell times of auditory Gestalts may be regarded as operationalizations of the subjective present; findings thus suggested that patients with hallucinations had a shorter present. (3) The movement correlations of interacting individuals were used to study the non-verbal synchrony between therapist and patient in psychotherapy sessions. We operationalized the duration of an embodied ‘social present’ by the statistical significance of such associations, finding a window of roughly 5.7 seconds in conversing dyads.We discuss that temporal scales of nowness may be modifiable, e.g., by mindfulness. This yields promising goals for future research on timing in the clinical context: psychotherapeutic techniques may alter binding processes, hence the subjective present of individuals, and may affect the social present in therapeutic interactions.

Etomidate - a review of robust evidence for its use in various clinical scenarios

Etomidate is an intravenous hypnotic with a favourable clinical profile in haemodynamic high-risk scenarios. Currently, there is an active debate about the clinical significance of the drug's side effects and its overall risk-benefit ratio. Etomidate-induced transient adrenocortical suppression is well documented and has been associated with increased mortality in sepsis. In surgical patients at risk of hypotensive complications, however, a review of current literature provides no robust evidence to contraindicate a single-bolus etomidate induction. Large randomised controlled trials as well as additional observational data are required to compare safety of etomidate and its alternatives.

Chronic lymphocytic leukemia: A study of the changing patterns of the natural history, clinical factors associated with prognosis, and risk of second cancers

A retrospective cohort study was conducted among 1542 patients diagnosed with CLL between 1970 and 2001 at the M. D. Anderson Cancer Center (MDACC). Changes in clinical characteristics and the impact of CLL on life expectancy were assessed across three decades (1970–2001) and the role of clinical factors on prognosis of CLL were evaluated among patients diagnosed between 1985 and 2001 using Kaplan-Meier and Cox proportional hazards method. Among 1485 CLL patients diagnosed from 1970 to 2001, patients in the recent cohort (1985–2001) were diagnosed at a younger age and an earlier stage compared to the earliest cohort (1970–1984). There was a 44% reduction in mortality among patients diagnosed in 1985–1995 compared to those diagnosed in 1970–1984 after adjusting for age, sex and Rai stage among patients who ever received treatment. There was an overall 11 years (5 years for stage 0) loss of life expectancy among 1485 patients compared with the expected life expectancy based on the age-, sex- and race-matched US general population, with a 43% decrease in the 10-year survival rate. Abnormal cytogenetics was associated with shorter progression-free (PF) survival after adjusting for age, sex, Rai stage and beta-2 microglobulin (beta-2M); whereas, older age, abnormal cytogenetics and a higher beta-2M level were adverse predictors for overall survival. No increased risk of second cancer overall was observed, however, patients who received treatment for CLL had an elevated risk of developing AML and HD. Two out of three patients who developed AML were treated with alkylating agents. In conclusion, CLL patients had improved survival over time. The identification of clinical predictors of PF/overall survival has important clinical significance. Close surveillance of the development of second cancer is critical to improve the quality of life of long-term survivors. ^