Practical implementation of the partial ordering continual reassessment method in a Phase I combination-schedule dose-finding trial.

There is a growing medical interest in combining several agents and optimizing their dosing schedules in a single trial in order to optimize the treatment for patients. Evaluating at doses of several drugs and their scheduling in a single Phase I trial simultaneously possess a number of statistical challenges, and specialized methods to tackle these have been proposed in the literature. However, the uptake of these methods is slow and implementation examples of such advanced methods are still sparse to date. In this work, we share our experience of proposing a model-based partial ordering continual reassessment method (POCRM) design for three-dimensional dose-finding in an oncology trial. In the trial, doses of two agents and the dosing schedule of one of them can be escalated/de-escalated. We provide a step-by-step summary on how the POCRM design was implemented and communicated to the trial team. We proposed an approach to specify toxicity orderings and their a-priori probabilities, and developed a number of visualization tools to communicate the statistical properties of the design. The design evaluation included both a comprehensive simulation study and considerations of the individual trial behavior. The study is now enrolling patients. We hope that sharing our experience of the successful implementation of an advanced design in practice that went through evaluations of several health authorities will facilitate a better uptake of more efficient methods in practice.

Searching for gene expression differences in primary fibroblasts between patients with one and two neoplasms in childhood.

Genetic factors are important for developing primary and subsequent malignancies in children. This study investigated the role of genetic factors involved in DNA-repair. Designed as a feasibility study, it addressed the possibility of obtaining samples for genetic analyses from former patients through the German Childhood Cancer Registry. Testing feasibility was as important as the biological question itself. We analyzed the expression of DNA-repair genes in untreated primary fibroblasts of 20 individuals with a second neoplasm compared to 20 matched single neoplasm cases using customized cDNA microarrays (1344 gene sequences, about 800 genes). Matching was by first neoplasm, age, and year of first diagnosis. Forty-six percent of the 52 contacted second neoplasm cases and 18% of the 132 single neoplasm patients participated in the study. The DNA-repair gene results show small differences in the basal gene expression of FTH1 and CDKN1A. To our knowledge, this is the first study using gene expression arrays in untreated primary fibroblasts regarding second neoplasms after a childhood neoplasm. We were able to recruit childhood cancer patients for genetic analyses long after diagnosis. The biological importance of the differences in the DNA-repair gene expression has to be elucidated yet.

Genetic signatures shared in embryonic liver development and liver cancer define prognostically relevant subgroups in HCC.

Multiple activations of individual genes during embryonic liver and HCC development have repeatedly prompted speculations about conserved embryonic signatures driving cancer development. Recently, the emerging discussion on cancer stem cells and the appreciation that generally tumors may develop from progenitor cells of diverse stages of cellular differentiation has shed increasing light on the overlapping genetic signatures between embryonic liver development and HCC. However there is still a lack of systematic studies investigating this area. We therefore performed a comprehensive analysis of differentially regulated genetic signaling pathways in embryonic and liver cancer development and investigated their biological relevance.Genetic signaling pathways were investigated on several publically available genome wide microarray experiments on liver development and HCC. Differentially expressed genes were investigated for pathway enrichment or underrepresentation compared to KEGG annotated pathways by Fisher exact evaluation. The comparative analysis of enrichment and under representation of differentially regulated genes in liver development and HCC demonstrated a significant overlap between multiple pathways. Most strikingly we demonstrated a significant overlap not only in pathways expected to be relevant to both conditions such as cell cycle or apoptosis but also metabolic pathways associated with carbohydrate and lipid metabolism. Furthermore, we demonstrated the clinical significance of these findings as unsupervised clustering of HCC patients on the basis of these metabolic pathways displayed significant differences in survival.These results indicate that liver development and liver cancer share similar alterations in multiple genetic signaling pathways. Several pathways with markedly similar patterns of enrichment or underrepresentation of various regulated genes between liver development and HCC are of prognostic relevance in HCC. In particular, the metabolic pathways were identified as novel prognostically relevant players in HCC development.

Multiple testing in candidate gene situations: a comparison of classical, discrete, and resampling-based procedures.

In candidate gene association studies, usually several elementary hypotheses are tested simultaneously using one particular set of data. The data normally consist of partly correlated SNP information. Every SNP can be tested for association with the disease, e.g., using the Cochran-Armitage test for trend. To account for the multiplicity of the test situation, different types of multiple testing procedures have been proposed. The question arises whether procedures taking into account the discreteness of the situation show a benefit especially in case of correlated data. We empirically evaluate several different multiple testing procedures via simulation studies using simulated correlated SNP data. We analyze FDR and FWER controlling procedures, special procedures for discrete situations, and the minP-resampling-based procedure. Within the simulation study, we examine a broad range of different gene data scenarios. We show that the main difference in the varying performance of the procedures is due to sample size. In small sample size scenarios,the minP-resampling procedure though controlling the stricter FWER even had more power than the classical FDR controlling procedures. In contrast, FDR controlling procedures led to more rejections in higher sample size scenarios.

Prognostic factors and outcomes of patients with hepatocellular carcinoma in non-cirrhotic liver.

OBJECTIVES: To report the outcome of patients with hepatocellular carcinoma (HCC) in non-cirrhotic liver depending on the mode of primary treatment and to define clinicopathological factors influencing patients' prognosis. METHODS: A retrospective analysis of an unselected cohort of 105 patients was performed. Overall survival (OS) was estimated by the Kaplan-Meier method and potentially prognostic factors were analyzed in Cox regression models. RESULTS: OS of the whole cohort at 1, 3, and 5 years was 66%, 47%, and 29%, respectively. Tobacco consumption, ECOG >0, macroscopic vascular invasion, continuous tumor diameter, and treatment other than resection were predictors of decreased OS in the whole cohort. Resection was performed in 64% of patients with 1-, 3-, and 5-year OS rates of 84%, 69%, and 42%, respectively. Siderosis and BCLC stage were associated with decreased OS after resection. Recurrence occurred in 57% of patients with 1-, 3-, and 5-year disease-free survival (DFS) rates of 63%, 39%, and 31%, respectively. Viral hepatitis and macroscopic vascular invasion were associated with decreased DFS. One-, 3-, and 5-year OS rates in patients with non-surgical approaches (transarterial chemoembolization, systemic therapy, best supportive care) were 38%, 11%, and 7%, respectively. Tobacco consumption and Okuda stage were associated with decreased OS in these patients. CONCLUSIONS: OS and DFS of patients with HCC in non-cirrhotic liver depend most notably on tumor-related, demographic, and etiological factors. Features of the non-neoplastic liver tissue play only a minor role. Liver resection leads to a significantly better prognosis than non-surgical treatment approaches.

Designing phase I oncology dose escalation using dose-exposure-toxicity models as a complementary approach to model-based dose-toxicity models.

One of the objectives of oncology phase I dose-escalation studies has been to determine the maximum tolerated dose (MTD). Although MTD is no longer set as the dose for further development in contemporary oncology drug development, MTD determination is still important for informing the therapeutic index. Bayesian adaptive model-based designs are becoming mainstream in oncology first-in-human trials. Herein, we illustrate via simulations the use of systemic exposure in Bayesian adaptive dose-toxicity models to estimate MTD. We extend traditional dose-toxicity models to incorporate pharmacokinetic exposure, which provides information on exposure-toxicity relationships. We pursue dose escalation until the maximum tolerated exposure (corresponding to the MTD) is reached. By leveraging pharmacokinetics, dose escalation considers exposure and interindividual variability on a continuous rather than discrete domain, offering additional information for dose-escalation decisions. To demonstrate this, we generated 1000 simulations (starting dose of 1/25th the reference dose and six dose levels) for several different scenarios. Both rule-based and model-based designs were compared using metrics of potential safety, accuracy, and reliability. The mean results over simulations and different toxicity scenarios showed that model-based designs were better than rule-based methods and that exposure-toxicity model-based methods have the potential to valuably complement dose-toxicity model-based methods. Exposure-toxicity model-based methods had decreased underdose risk accompanied by a relatively smaller increase in overdose risk, resulting in improved net reliability. MTD estimation accuracy was compromised when exposure variability was large, emphasizing the importance of appropriate control of pharmacokinetic variability in phase I dose-escalation studies.

Association analysis of serotonin receptor 1B (HTR1B) and brain-derived neurotrophic factor gene polymorphisms in Borderline personality disorder.

The purpose of this study was to test for association between Borderline personality disorder (BPD) and variants of the HTR1B and the brain-derived neurotrophic factor (BDNF) gene. We genotyped four HTR1B and the functional BDNF G196A marker in 161 Caucasian BPD patients and 156 healthy controls. There were no significant differences between groups in genotype or haplotype distribution of HTR1B markers or in genotype distribution of the BDNF marker. Logistic regression analyses revealed an over-representation of the BDNF 196A allele in HTR1B A-161 allele carrying BPD patients.

Impact of several histopathological prognosticators and local tumour extension on oncological outcome in pT3b/c N0M0 renal cell carcinoma.

OBJECTIVE: To investigate the prognostic relevance of different histopathological features and local tumour extension in patients with pT3b/c N0M0 renal cell carcinoma (RCC), as recently new proposals of reclassifying tumour fat invasion in pT3b/c RCC have been made but the effect of other histopathological tumour characteristics and combinations thereof with tumour invasion has yet to be determined in these patients. PATIENTS AND METHODS: Between 1990 and 2006, 1943 patients underwent surgical treatment for renal tumours in our institution, of which 175 patients (8.7%) had pT3b/c RCC. After exclusion of 57 patients (32.6%) with lymph node and/or distant metastases at the time of diagnosis, 118 (67.4%) remained for retrospective analysis. Different histopathological features and local tumour extension were studied for their association with cancer-specific-survival (CSS) and progression-free-survival (PFS) by univariate and multivariate analyses. Histopathology was reviewed and revised according to the 2002 Tumour-Nodes-Metastasis (TNM) classification system by one pathologist (S.B.). CSS and PFS were estimated by the Kaplan-Meier method. RESULTS: Follow-up data were obtained from 110 patients at a median (range) of 3.2 (0.3-16.1) years. In univariate analysis, microvascular invasion (MVI) and capsular invasion increased the risk of tumour progression by 2.05- and 2.72-times (P = 0.037 and P < 0.001). Overall, tumour fat invasion (TFI) and the presence of areas composed by cells with eosinophilic cytoplasm were associated with a higher risk of progression (P = 0.001 and P = 0.011) and reduced CSS (P = 0.037 and P = 0.017). In multivariate analysis, MVI and capsular invasion were associated with a two-fold increased risk of dying from cancer (hazard risk ratio, HR 2.22, P = 0.045 and HR 2.31, P = 0.011). TFI in general (P = 0.004) and specifically coexistent perirenal fat invasion (PFI) and renal sinus fat invasion (RSFI) were associated with a three-fold increased risk of developing tumour progression (HR 3.36, P = 0.001). The 10-year CSS and PFS rates were 39% and 36% for all patients, 47% and 45% for pT3b/c RCC with no PFI or RSFI, and 25% and 10% for PFI + RSFI. CONCLUSION: Patients with pT3b/c RCC with MVI, capsular invasion, TFI and especially PFI + RSFI, have a markedly reduced prognosis compared with patients with pT3b/c RCC without these features. When these results are corroborated by additional studies and external validation, modification of the TNM classification system would be a sensible consequence.

Interaction between gene variants of the serotonin transporter promoter region (5-HTTLPR) and catechol O-methyltransferase (COMT) in borderline personality disorder.

Borderline personality disorder (BPD) is characterized by a heterogeneous symptomatology with instability in impulse control, interpersonal relationships and self-image. BPD patients display repeated self-injury, chronic suicidal tendencies and emotional dysregulation, mainly dysregulation of negative affect. In its etiology, genetic and environmental factors have been suggested. Recently, an investigation in male healthy volunteers found gene-gene effects of the catechol-O-methyl-transferase (COMT) low-activity (Met(158)) and the low-expression allele of the deletion/insertion (short/long or S/L, respectively) polymorphism in the serotonin transporter-linked promoter region (5-HTTLPR) on the central processing of aversive stimuli. The purpose of the present study was to test for association between BPD and the COMT Val(158)Met single nucleotide polymorphism (SNP), the 5-HTTLPR S/L variant and the interaction of these two gene variants. One hundred sixty one well-defined Caucasian BPD patients and 156 healthy controls were recruited from central Germany. In BPD patients, the genotype COMT Met(158)Met was over-represented compared to healthy controls (P = 0.0085; adjusted P = 0.034). We observed no differences in 5-HTTLPR genotypes between BPD and controls (P = 0.286). Additionally, the COMT Met(158)Met genotype was significantly over-represented in BPD patients carrying at least one 5-HTTLPR S allele (P = 0.0007; adjusted P = 0.028). Logistic regression analysis confirmed an interaction of the COMT Met(158) and the 5-HTTLPR S allele (P = 0.001). These data suggest an involvement of altered dopaminergic and/or noradrenergic neurotransmission as well as an interactive effect of COMT and 5-HTTLPR gene variants in the etiology of BPD, and underline the usefulness of analyses of gene-gene effects in diseases of complex inheritance with multiple genes involved.

Association analysis of SCN9A gene variants with borderline personality disorder.

Borderline personality disorder (BPD) is a serious psychiatric disorder affecting about 1-2% of the general population. Key features of BPD are emotional instability, strong impulsivity, repeated self-injurious behavior (SIB) and dissociation. In the etiology of BPD and its predominant symptoms, genetic factors have been suggested. The voltage-gated sodium channel Nav1.7 is expressed in sensory neurons and in the hippocampus, a key region of the limbic system probably dysfunctional in BPD and dissociative disorders. The alpha-subunit of Nav1.7 is encoded by the SCN9A gene on chromosome 2 and variations of SCN9A can lead to complete inability to sense pain. The aim of the present study was to test for associations between SCN9A gene variants and BPD as well as BPD-related phenotypes. We genotyped ten tagging single nucleotide polymorphisms (SNPs) within the SCN9A gene in 161 well-defined Caucasian BPD patients and 156 healthy controls. We found no globally significant association of SCN9A markers with BPD at level 5%. However, in the female and in the male subsample, different SCN9A markers and individual haplotypes showed uncorrected p-values<0.05. In addition, p-values<0.05 were observed in the analysis of associations between SCN9A markers and dissociative symptoms. Although our results were largely negative, replication studies in an independent sample are warranted to follow up on the potential role of SCN9A gene variants in BPD and dissociative symptoms, paying special attention to a possible gender different etiology.

A case control study of statin and magnesium administration in patients after aneurysmal subarachnoid hemorrhage: incidence of delayed cerebral ischemia and mortality.

OBJECTIVE: To analyse the effect of the implementation of statin and magnesium treatment on delayed cerebral ischemia (DCI) and 14 day mortality in patients with subarachnoid hemorrhage (SAH). METHODS: Retrospective, single-center, observational case control study. One hundred SAH patients received either simvastatin and magnesium, solely statin or no treatment. RESULTS: Eighteen percent (n=5) of patients receiving statin and magnesium treatment developed a DCI whereas 24% (n=5) in the statin group and 16% (n=8) in the control group had DCI. Dead by day 14 was registered in 18% (n=5) of patients in the statin and magnesium group, in 10% (n=2) in the statin group and in 27% (n=14) in the control group. None of the results reached a statistical significance level of 0.05. CONCLUSION: A trend towards a lower mortality within 14 days in patients receiving solely simvastatin and those receiving statin and magnesium as compared with the control group was found. A higher incidence for DCI was found in the statin group, whereas patients without statin and magnesium tended to have less often DCI. None of the results was statistically significant.

Dynamic contrast-enhanced MRI before and after transcatheter occlusion of patent foramen ovale.

OBJECTIVE: The purpose of this study was threefold: to evaluate the diagnostic accuracy of dynamic contrast-enhanced MRI compared with transesophageal echocardiography (TEE) in the detection of patent foramen ovale (PFO) and of residual shunts after occlusion of PFO, to define cutoff values for semiquantitative analysis of signal intensity-time curves, and to compare the diagnostic accuracy of visual detection with that of semiquantitative analysis. SUBJECTS AND METHODS: Forty-three patients (18 women, 25 men; mean age, 51 +/- 14 years) who underwent TEE for suspicion of PFO (n = 26, 19 patients with and seven without PFO) or for routine assessment for residual shunt after transcatheter PFO occlusion (n = 17, nine patients with and eight without residual shunt) were consecutively enrolled to undergo contrast-enhanced MRI (saturation recovery steady-state free precession sequence). The images were analyzed both visually and semiquantitatively for arrival of contrast agent in the left atrium before arrival in the pulmonary veins during a Valsalva maneuver. TEE results were used as the clinical reference. RESULTS: With an area under the signal intensity-time curve of 0.85, height of the first initial peak in signal intensity in the left atrium proved to be the best discriminator in right-to-left shunt detection. For a cutoff value of 129% (from baseline signal intensity) for this parameter, sensitivity and specificity were 90% (17/19) and 100% (7/7) in patients without PFO devices and 56% (5/9) and 88% (7/8) in patients with PFO devices. The diagnostic accuracy of both visual assessment and semiquantitative analysis was consistently superior before PFO device implantation than after device implantation. The diagnostic accuracy of visual shunt assessment was better than that of semiquantitative shunt assessment in patients with PFO occluders (sensitivity, 67% [6/9] correctly diagnosed; specificity, 88% [7/8]) and those without PFO occluders (sensitivity, 95% [18/19]; specificity, 100% [7/7]). CONCLUSION: At present, MRI cannot replace TEE for the exclusion of potential embolic sources, such as thrombus in the left atrial appendage. However, MRI can be an attractive alternative noninvasive technique if TEE is technically unfeasible or is declined by patients.

Cochlear origin of early hearing loss in vestibular schwannoma.

OBJECTIVE: To test whether early hearing loss (HL) is cochlear in origin in patients with vestibular schwannoma (VS). STUDY DESIGN: Retrospective case review in an academic tertiary referral center. METHODS: A group of 19 VS patients with normal/symmetrical hearing and a group of 20 VS patients with mild HL (threshold at any tested frequency better than 45 dB HL) on the tumor ear side. Differences of the amplitudes of the distortion products of otoacoustic emissions (DPOAEs) between the tumor ear and the nontumor ear were studied at frequencies of 1, 1.4, 2, 2.8, and 4 kHz. The Wilcoxon test was used to compare the ears for both groups and to test for possible differences in tumor size between groups. RESULTS: DPOAE amplitudes do not differ strongly between the ears in VS patients with normal/symmetrical hearing (two-sided P values: .050 at 1 kHz, .182 at 1.4 kHz, .378 at 2 kHz, .293 at 2.8 kHz, and .238 at 4 kHz) but are decreased compared with the nontumor ear at frequencies 1, 1.4, 2, and 2.8 kHz in VS patients with even mild HL (two-sided P values: .013 at 1 kHz, .007 at 1.4 kHz, .033 at 2 kHz, .010 at 2.8 kHz, and .156 at 4 kHz). Tumor size did not differ significantly between the two groups (P = .436). CONCLUSION: Amplitudes of DPOAEs begin to decrease even at the early stages of HL in VS patients, which suggests a cochlear origin of early HL in these patients. DPOAEs may be used in a clinical setting to monitor progression of cochlear damage at the early stages of hearing impairment in VS patients.

Dynamic posturography findings predict balance status in vestibular schwannoma patients.

OBJECTIVE: To test whether condition 5 score (C5S) and condition 6 score (C6S) of the sensory organization test of computerized dynamic platform posturography (CDPP) differ between vestibular schwannoma (VS) patients with and without vestibular symptoms. STUDY DESIGN: Retrospective review of prospectively collected data. SETTING: Tertiary academic referral center. PATIENTS: Two hundred and sixteen consecutive patients with a histological diagnosis of a VS (103 women; 113 men; age range, 18-78 years; median, 54 years) who had been preoperatively evaluated by CDPP. A hundred and twelve patients had a history of vertigo, dizziness, and/or imbalance, and 104 patients had neither present nor past vestibular symptoms at all. INTERVENTION: Diagnostic. Preoperative CDPP in VS patients with and without vestibular symptoms. MAIN OUTCOME MEASURES: Condition 5 score and C6S of the sensory organization test of CDPP of VS patients. To test whether C5S and C6S differ between VS patients with and without vestibular symptoms, the Wilcoxon-Mann-Whitney rank sum test was applied. RESULTS: Both C5S (p = 0.001) and C6S (p < 0.0005) were significantly lower in VS patients with vestibular symptoms than in VS patients without vestibular symptoms. CONCLUSION: There is a significant difference in the distribution of C5S and C6S between VS patients with and without vestibular symptoms. Thus, patients with symptoms tend to have lower C5S and C6S than patients without symptoms, although this trend is not sufficient for reliable discrimination for all patients.

Comparison of electronystagmography results with dynamic posturography findings in patients with vestibular schwannoma.

CONCLUSION: Condition-5-score (C5S) and condition-6-score (C6S) of computerized dynamic platform posturography (CDPP) can detect the presence of a functional deficit of the lateral semicircular canal (and the superior vestibular nerve), irrespective of the central vestibular compensatory status, in vestibular schwannoma (VS) patients. OBJECTIVES: To test whether CDPP findings differ between VS patients with and without asymmetry on caloric and/or rotational ENG studies. PATIENTS AND METHODS: This was a retrospective review of 216 consecutive patients with VS. C5S and C6S of CDPP (Equitest) were compared among patients with normal caloric and rotational studies, patients with asymmetry on caloric studies and normal rotational studies, and patients with asymmetric caloric and rotational studies using the Wilcoxon-Mann-Whitney test. RESULTS: C5S and C6S of VS patients with normal caloric and rotational studies were significantly higher than in VS patients with either asymmetry on both rotational and caloric test results (p<0.001 for both C5S and C6S) or normal rotational studies and asymmetry on caloric testing (p<0.001 for both C5S and C6S). Neither C5S nor C6S were significantly different between patients with asymmetry on caloric testing and normal rotational studies and patients with asymmetry on both rotational and caloric testing.

Usefulness of combining clinical and radiological dental findings for a more accurate noninvasive age estimation.

The aim of this study was to establish correlations of clinical and radiological dental findings, alone or in combination, with chronological age in adults. Dental findings and orthopantomograms of 984 patients (aged 20-60 years; 524 females/460 males) were analyzed. DMF-T index and distance (alveolar bone level, ABL) between cemento-enamel junction and alveolar bone margin were recorded. Additionally, clinical and radiological findings at each tooth crown and root were collected according to the actual status of destruction and restoration, and a total score for each dentition (TSD) was calculated. After univariate correlation analysis, correlation coefficients for ABL and TSD were improved by using square root (sqrt). However, the determination accuracy was still not satisfactory; 90% of the residuals were in the range of about +/-10. The present study showed that clinical and radiological dental findings could not be used, not even in combination, for accurate age estimation as a single method, but that they could support other methods.

Transient evoked otoacoustic emissions in vestibular neuritis.

OBJECTIVES: Partial or total degeneration of the vestibulocochlear anastomosis at its takeoff from the saccular ganglion and regenerating efferent neural buds under the cochlear outer hair cells (OHCs) have been found in the temporal bones of human patients with a history of vestibular neuritis (VN). We sought to test whether VN has any functional impact on the ipsilateral OHCs by means of transient evoked otoacoustic emission (TEOAE) testing. METHODS: We retrospectively analyzed prospectively collected TEOAE data of 28 patients (19 female, 9 male; age range, 21 to 60 years; median age, 42.5 years). The pure tone air conduction hearing thresholds at each standard audiometric frequency (0.125 to 8 kHz) and the amplitudes of the TEOAEs at the 1-, 2-, 3-, and 4-kHz frequency bands were compared between the lesional and contralateral sides by use of the nonparametric sign test for 2 paired samples. RESULTS: No significant difference was found in the pure tone air conduction hearing thresholds between the lesional and contralateral ears at any of the 11 standard tested frequencies. No significant difference was found between the TEOAE amplitudes of the lesional and contralateral sides. CONCLUSIONS: Subclinical OHC functional impairment is not present in VN. Moreover, no apparent significant changes in medial olivocochlear bundle resting activity accompany VN.

Impact of infectious burden on extent and long-term prognosis of atherosclerosis.

BACKGROUND: Recent findings suggest a causative role of infections in the pathogenesis of atherosclerosis. In hypothesizing an association between infectious agents and the development of atherosclerosis, we would expect a correlation to the extent of atherosclerosis. Moreover, this effect could be multiplied by the number of pathogens to which an individual had been exposed. METHODS AND RESULTS: In 572 patients, IgG or IgA antibodies to herpes simplex virus 1 and 2, cytomegalovirus, Epstein-Barr virus, Hemophilus influenzae, Chlamydia pneumoniae, Mycoplasma pneumoniae, and Helicobacter pylori were measured. The extent of atherosclerosis was determined by coronary angiography, carotid duplex sonography, and evaluation of the ankle-arm index. Elevated IgA antibodies against C pneumoniae (P<0.04) and IgG antibodies against H pylori (P<0.02), cytomegalovirus (P<0.05), and herpes simplex virus 2 (P<0.01) were associated with advanced atherosclerosis (> or =2 vascular regions), adjusted for age, sex, cardiovascular risk factors, and highly sensitive C-reactive protein. Infectious burden divided into 0 to 3, 4 to 5, and 6 to 8 seropositivities was significantly associated with advanced atherosclerosis, with an odds ratio (95% CI) of 1.8 (1.2 to 2.6) for 4 to 5 (P<0.01) and 2.5 (1.2 to 5.1) for 6 to 8 seropositivities (P<0.02) (adjusted). After a mean follow-up of 3.2 years, cardiovascular mortality rate was 7.0% in patients with advanced atherosclerosis and seropositive for 0 to 3 pathogens compared with 20.0% in those seropositive for 6 to 8 pathogens. CONCLUSIONS: Our results support the hypothesis that infectious agents are involved in the development of atherosclerosis. We showed a significant association between infectious burden and the extent of atherosclerosis. Moreover, the risk for future death was increased by the number of infectious pathogens, especially in patients with advanced atherosclerosis.

Intratympanic dexamethasone and hyaluronic acid in patients with low-frequency and Ménière's-associated sudden sensorineural hearing loss.

BACKGROUND: Steroids are widely used for the treatment of cochleovestibular disorders. Direct steroid application in the middle ear cavity, when combined with a round window membrane permeability-modulating substance, increases the level of the steroid reaching the target cells. We measured hearing in patients with idiopathic isolated low-frequency sensorineural hearing loss and in patients with sudden sensorineural hearing loss and a history of Ménière's disease. Contradictory reports about effectiveness of intratympanic steroid therapy on vertigo control and hearing improvement in patients with Ménière's disease exist in the literature. METHODS: Eighteen patients with isolated low-frequency idiopathic sudden sensorineural hearing loss and 21 patients with sudden sensorineural hearing loss and a history of Ménière's disease were prospectively evaluated. The acute effect of the intratympanic application of dexamethasone with hyaluronic acid on hearing outcome after failure of an initial standard treatment with intravenous steroid and vasoactive substances was assessed. Evaluation was based on standard pure-tone audiometry findings. RESULTS: After intratympanic injection of dexamethasone and hyaluronic acid, 14 of the 18 patients with isolated low-frequency sensorineural hearing loss showed a significant improvement in hearing. After intratympanic therapy, 15 patients with a previous history of Ménière's disease and idiopathic isolated low-frequency sensorineural hearing loss showed an improvement in hearing on pure-tone audiometry, four remained unchanged, and two showed a tendency toward a slight deterioration. CONCLUSION: Intratympanic combined dexamethasone/hyaluronic acid application provides a reliable and safe therapeutic option for improvement of hearing in patients with isolated low-frequency idiopathic sudden sensorineural hearing loss or sensorineural hearing loss resulting from Ménière's disease who have failed intravenous steroid and vasoactive treatments.

Sympathetic vasomotor response of the radial artery in patients with diabetic foot syndrome.

OBJECTIVE: Neurophysiological assessment of the peripheral autonomic system is characterized by various limitations. An alternative approach to laser Doppler and venous plethymography is the assessment of the sympathetic vasomotor response of the radial artery obtained by continuous wave Doppler sonography. Nomogram data have been established and demonstrate the temporary disappearance of diastolic flow after coughing or deep inspiration. RESEARCH DESIGN AND METHODS: We assessed the sympathetic vasomotor response in 25 patients (mean age 64 years, range 43-76) with diabetic foot syndrome. The Doppler data were correlated with nerve conduction studies of the median and peroneal nerve, the extent of radiologically diagnosed media sclerosis, and compared with nomogram values (n = 41). RESULTS: Although similar mean flow velocities were found under baseline conditions, the flow pattern was characterized by higher pulsatility in the diabetic group (resistance index [RI] 1.1 vs. 0.7). No significant difference in RI was observed after coughing. The latency of onset of the response was prolonged (2.1 vs. 1.5 s), while the duration of the response did not differ (18 vs. 15 s). Only the nerve conduction velocity of the peroneal nerve correlated inversely with the RI. The extent of radiologically proven calcification tended to correlate with the pulsatility of the baseline signal and the response latencies. CONCLUSIONS: The data obtained by this study suggest the concurrent existence of reduced vessel elasticity due to media sclerosis and dysfunction of the autonomic vasomotor system.