[Morphological retinal characteristics of patients with low vision due to diabetic macular edema]. / Morphologische retinale Charakteristika von Patienten mit einer Sehbehinderung infolge eines diabetischen Makulaödems.

BACKGROUND: The World Health Organisation (WHO) defines low vision as a best corrected visual acuity (BCVA) in the better eye between ≥0.5 logMAR and ≤1.3 logMAR. In diabetic macular edema (DME) the correlation between retinal morphology and function is not completely understood in patients with advanced visual impairment. OBJECTIVE: The aim of the study was to describe the pathomorphological similarities of DME in patients with low vision and to correlate them with clinical parameters. MATERIAL AND METHODS: Optical coherence tomography (OCT) and fluorescence angiography (FA) images were graded according to the SAVE protocol and correlated with BCVA, cataract grade and clinical parameters in order to elucidate joint features. RESULTS: Out of a total collective of 65 patients 24 had low vision and 18 of these 24 patients (75%) showed typical signs of atrophic edema according to SAVE protocol criteria (SAVE group 4); however, 6 patients were afflicted with less progressive forms of DME but still suffered from low vision. Common pathomorphological findings were a discontinuity of the ellipsoid zone (EZ; n = 18), loss of pseudosepta (n = 7), layer-disrupting cysts (n = 7) and hard exudates (n = 10). CONCLUSION: It is suggested that a disruption of the EZ, loss of pseudosepta and layer-disrupting cysts are signs of an advanced chronic DME causing low vision. A definition of characteristic pathomorphological patterns of chronic damage in OCT is important for a possible treatment discontinuation in the clinical routine.

Ultrasound measurements of carotid intima-media thickness by two semi-automated analysis systems.

Increased carotid intima-media thickness (cIMT) is associated with an increased risk of cardiac events and stroke. Several semi-automated edge-detection techniques for measuring cIMT are used for research and in clinical practice. Our aim was to compare two currently available semi-automated techniques for the measurement of cIMT. Carotid ultrasound recordings were obtained from 99 subjects (mean age 54·4 ± 8·9 years, range 33-69) without known cardiovascular diseases using a General Electric (GE) Vivid 7 ultrasound scanner, 8-MHz transducer. The far-wall cIMT was evaluated 1-2 cm proximal to the carotid bulb. Three diastolic images (ECG R-wave) from the left and three images from the right common carotid arteries were analysed using GE and Artery Measurement System (AMS) semi-automated softwares. Mean systolic and diastolic blood pressures were 120 ± 13 and 76 ± 8 mmHg, respectively. The cIMTmean (left + right)/2 by GE and cIMTmean (left + right)/2 AMS were highly correlated (r = 0·92, P<0·001). Higher values were measured by GE (0·72 ± 0·12 mm) compared with AMS (0·69 ± 0·12 mm), and this was significant (P<0·001). The coefficients of variation for the intra-observer variability of cIMTmean (left + right)/2 were 1·0% (GE) and 2·2% (AMS). cIMTmean measured by GE's semi-automated edge-detection method correlated well with that measured by AMS. However, there were small but significant systematic differences between the cIMTmean values measured by the two techniques. Thus, the use of only one type of measurement program seems favourable in follow-up studies and when evaluating treatment effects.

Non invasive assessment of the human tear film dynamics.

Dry eye disease, or keratoconjunctivitis sicca, is a multifactorial syndrome with altered tear film homeostasis leading to ocular irritations. These alterations cause discomfort and stress for the patient, but only a few objective parameters allow for proper differential diagnosis into different subtypes of this condition. The mostly invasively performed standard assessment procedures for tear film diagnosis are manifold, but often correlate quite poorly with the subjectively reported symptoms. Due to the inherent limitations, e.g. the subjectivity of the commonly performed invasive tests, a number of devices have been developed to assess the human tear film non-invasively. Since the production, delivery, distribution and drainage of the tear film is a dynamic process, we have focused our review on non-invasive methods which are capable of continuous or repetitive observations of the tear film during an inter-blink interval. These dynamic methods include (1) Interferometry, (2) Pattern Projection, (3) Aberrometry, (4) Thermography; and (5) Evaporimetry. These techniques are discussed with respect to their diagnostic value, both for screening and differential diagnostic of Dry Eye Disease. Many of the parameters obtained from these tests have been shown to have the potential to reliably discriminate patients from healthy subjects, especially when the tests are performed automatically and objectively. The differentiation into subtypes based solely on a single, dynamic parameter may not be feasible, but the combination of non-invasively performed procedures may provide good discrimination results.

Effect of alveolar bone support on zygomatic implants in an extra-sinus position--a finite element analysis study.

The objective was to investigate the influence of maxillary alveolar bone on the stress distribution of zygomatic implants in an extra-sinus position. A three-dimensional finite element model was created based on a computed tomography scan of an edentulous female patient. Two zygomatic implants were modelled and placed in the skull in an extra-sinus position. These were supported by the zygomatic bone and the maxillary alveolar bone and were connected by a fixed bridge. This model was duplicated, and the area of the maxillary alveolar bone supporting the implants was removed. Occlusal and lateral forces were applied to both models and the maximum von Mises stresses were recorded. Higher maximum stresses were noted in the model with no alveolar support. Occlusal stresses were higher than lateral stresses in the model with no alveolar support, while occlusal stresses were lower than lateral stresses in the model with alveolar support. Low stresses were noted in the zygomatic bone in both models. Maxillary alveolar bone support is beneficial in the distribution of forces for zygomatic implants placed in an extra-sinus position.

Effect of alveolar bone support on zygomatic implants: a finite element analysis study.

The objective of this study was to investigate the influence of maxillary alveolar bone on the stress distribution of zygomatic implants. A three-dimensional finite element model was created of half of a skull. Two zygomatic implants were modelled, placed in the skull supported by the zygomatic bone and the maxillary alveolar bone and connected by a fixed bridge. This model was duplicated, and the area of the maxillary alveolar bone supporting the implants was removed. Occlusal and lateral forces were applied to both models and the maximum von Mises stresses were recorded. Higher maximum stresses were noted in the model with no alveolar support. Occlusal stresses were higher than lateral stresses in the model with no alveolar support. Low stresses were noted in the zygomatic bone in both models. In conclusion, maxillary alveolar bone support is beneficial in the distribution of forces for zygomatic implants.

Cinacalcet improves bone density in post-kidney transplant hyperparathyroidism.

The recent availability of cinacalcet has provided a possible alternative to parathyroidectomy in kidney transplant patients with persistent hyperparathyroidism, but its effect on bone mass density (BMD) is unknown. From our database containing 163 kidney transplants performed at our center from 1999 to 2007, we compared recipients who received cinacalcet for persistent hypercalcemia and hyperparathyroidism following renal transplantation (n = 8) with up to two other posttransplant patients matched for age, sex, race, and graft function (n = 15). The outcome of the study was BMD changes from baseline to 12, 24, and 36 months post-renal transplantation. Repeated-measures mixed model was used to assess the difference of BMD change between two groups. Cinacalcet therapy was started at a median of 9 (range = 1 to 24) months posttransplant with a mean dose 56 ± 29 mg/d (mean duration = 1.6; range = 1 to 2.1 years). Cinacalcet therapy was associated with significant reduction of serum calcium compared to control. Cinacalcet therapy was associated with greater BMD increase at the hip over the 36-month posttransplant period. Cinacalcet was well tolerated. Our results suggest that cinacalcet may have a small but favorable effect on bone density following kidney transplantation.

Cardiac function in mild primary hyperparathyroidism and the outcome after parathyroidectomy.

OBJECTIVE: Primary hyperparathyroidism (PHPT) is associated with cardiovascular morbidity. The extent of cardiovascular abnormalities in patients with mild-asymptomatic disease is unclear. Using sensitive echocardiographic methods, we compared cardiac structure and function in patients with mild PHPT and in healthy controls, and evaluated the changes after parathyroidectomy (PTX). METHODS: In a prospective case-control design, we studied 51 PHPT patients without any cardiovascular risk factors/diseases and 51 healthy matched controls. Cardiac structure, and systolic and diastolic function were evaluated by echocardiography and Doppler tissue imaging (DTI). Blood pressure (BP) and heart rate were measured. RESULTS: We observed no differences in systolic or diastolic function or in cardiac morphology between the PHPT patients and the age-matched healthy controls. The regional peak systolic myocardial velocities (S') measured with DTI decreased at all sites (P<0.05) after PTX (tricuspid annulus 14.23+/-1.85 to 13.48+/-1.79, septal 8.48+/-0.96 to 7.97+/-0.85, and lateral 9.61+/-2.05 to 8.87+/-1.63 cm/s, part of the mitral annulus). At baseline, systolic BP was higher in patients compared to controls (127.6+/-17.1 vs 119.6+/-12.6 mmHg, P<0.05). After PTX, both systolic (127.6+/-17.1 vs 124.6+/-16.6 mmHg, P<0.05) and diastolic (80.3+/-9.6 vs 78.4+/-8.6 mmHg, P<0.05) BP decreased. CONCLUSIONS: Our results indicate that patients with PHPT without cardiovascular risk factors have a normal global systolic and diastolic function and cardiac morphology. BP and the systolic velocities were marginally reduced after PTX, but reflected the values of the control group. Our findings warrant further investigation of the clinical and prognostic significance of these possibly disease-related inotropic effects.

Mortality in primary open-angle glaucoma: 'two cupped discs and a funeral'.

PURPOSE: The aim of this study was to investigate the causes of mortality in individuals with open-angle glaucoma (OAG). METHODS: All-cause mortality data from the Registry of Births, Deaths and Marriages for the Australian state of Tasmania, for all people who were at least 40 years of age at the time of death, were classified using International Classification of Diseases-10 guidelines. This information was cross-referenced to identify participants in the Glaucoma Inheritance Study in Tasmania (GIST) who had died. Contingency tables were used for crude analysis and then models were constructed, adjusting for age at death as well as gender. RESULTS: Between 1996 and 2005, a total of 33 879 deaths were recorded. Data were unavailable for 4868 (14.4%) people. The mean age at death for the study sample was 78.4+/-11.5 (range 41-109) years. Of those cases known to have OAG by their participation in GIST (n=2409), full mortality data were available for 741 (92.0%). Following adjustment for the age at death and male gender, the odds ratio for death due to ischaemic heart disease in people with OAG compared to the general population not known to have OAG was significant (OR=1.30, 95% CI: 1.08-1.56; P=0.006). Crude analysis revealed that there were significantly fewer people with OAG who died due to metastatic cancer (P<0.001); however, this did not remain significant following adjustment for age and gender. CONCLUSION: The pathoaetiological relationship between OAG and ischaemic heart disease is unclear and requires further investigation. Increased awareness of the association between cardiovascular disease and OAG is warranted.

Suicide trends diverge by method: Swiss suicide rates 1969-2005.

We examined the change in Swiss suicide rates since 1969, breaking down the rates according to the method used. The descriptive analyses of the main suicide methods are presented. The suicide rates reached a peak in the late 1970s/early 1980s and declined in more recent years. Firearm suicides and suicides by falls were the exception and sustained their upwards trend until the 1990s. Suicide by vehicle exhaust asphyxiation showed a rapid decline following the introduction of catalytic converters in motor vehicles. No substantial method substitution was observed. Suicide by poisoning declined in the 1990s but rose again following an increase in assisted suicide in somatically incurable patients. Suicide is too often regarded as a homogeneous phenomenon. With regard to the method they choose, suicide victims are a heterogeneous population and it is evident that different suicide methods are chosen by different people. A better understanding of the varying patterns of change over time in the different suicide methods used may lead to differentiated preventive strategies.

miR-29b expression is associated with disease-free survival in patients with ovarian serous carcinoma.

Micro-RNAs are a group of small noncoding RNAs approximately 22 nucleotides in length. Recent work has shown differential expression of mature micro-RNAs in human cancers. We characterized the alteration in expression of miR-29b in ovarian serous carcinoma. miR-29b expression was analyzed using quantitative stem-loop reverse transcriptase polymerase chain reaction on a set of 50 formalin-fixed, paraffin-embedded ovarian serous carcinoma samples. Protein expression of p53, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, Ki-67, and insulinlike growth factor 1 was quantified in the corresponding tissue microarray. The expression profile of miR-29b was correlated with clinicopathological and patient survival data. We provide definitive evidence that miR-29b is down-regulated in a significant proportion of ovarian serous carcinomas and is associated with specific clinicopathological features, most notably high miR-29b expression being associated with reduced disease-free survival.

Suicide after bereavement: an overlooked problem.

BACKGROUND: To examine the effect of time on suicide after bereavement among widowed persons. METHOD: The data were extracted from Swiss mortality statistics for the period 1987-2005. The time between bereavement and subsequent death, specifically by suicide, was determined by linkage of individual records of married persons. The suicide rates and the standardized mortality ratios in the first week/month/year of widowhood were calculated based on person-year calculations. RESULTS: The annualized suicide rates in widowed persons were highest in the first week after bereavement: 941 males and 207 females per 100,000. The corresponding standardized mortality ratios were approximately 34 and 19 respectively. In the first month(s) after bereavement, the rates and the ratios decreased, first rapidly, then gradually. Except in older widows, they did not reach the baseline levels during the first year after bereavement. CONCLUSIONS: The suicide risk of widowed persons is increased in the days, weeks and months after bereavement. Widowed persons are a clear-cut risk group under the aegis of undertakers, priests and general practitioners.

Dissociation of depletional induction and posttransplant lymphoproliferative disease in kidney recipients treated with alemtuzumab.

Transplant patients are at the risk for posttransplant lymphoproliferative disease (PTLD), a virally-driven malignancy. Induction with the depleting antibody preparations Thymoglobulin and OKT3 is associated with PTLD suggesting that the T-cell depletion increases PTLD risk. We therefore studied 59 560 kidney recipients from the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) database for a relationship between induction agent use and PTLD. Two agents with comparable T-cell depletional effects, alemtuzumab and Thymoglobulin, were compared to nondepletional induction agents or no induction. The overall incidence of PTLD was 0.46% and differed significantly by induction strategy (p < 0.01): without induction (0.43%), basiliximab (0.38%), daclizumab (0.33%), Thymoglobulin (0.67%) and alemtuzumab (0.37%). Thymoglobulin was associated with significantly increased PTLD risk (p = 0.0025), but alemtuzumab (p = 0.74), basiliximab (p = 0.33) and daclizumab, which trended toward a protective effect (p = 0.06), were not. Alemtuzumab and Thymoglobulin treated patients did not differ in any established parameter affecting PTLD risk although alemtuzumab is known to have a more pronounced B-cell depleting effect. Interestingly, maintenance therapy with an mTOR inhibitor was strongly associated with PTLD (0.71%, p < 0.0001). Thus, depletional induction is not an independent risk factor for PTLD. Rather, maintenance drug selection or perhaps the balance between B- and T-cell depletion may be more relevant determinants of PTLD risk.

Topoisomerase II-alpha expression increases with increasing Gleason score and with hormone insensitivity in prostate carcinoma.

AIM: To investigate and compare topoisomerase II-alpha expression in benign prostatic hyperplasia (BPH), prostate cancer of varying Gleason scores and hormone-insensitive prostate cancer. METHODS: The immunohistochemical expression of topoisomerase II-alpha antibody in the above-mentioned diagnostic categories was investigated and compared. RESULTS: Increased expression of topoisomerase II-alpha was seen in the prostate cancers of Gleason scores 7 and 8-10 (p = 0.000) compared with prostate cancers of Gleason score 6 and BPH (p = 0.245). Statistically significant differences were found in the topoisomerase II-alpha gene expression between prostate cancers categorised by Gleason Score. Also, increased expression of topoisomerase II-alpha was seen in the known hormone-resistant prostate carcinomas compared with prostate cancers with no hormone treatment in the subgroup with Gleason scores 8-10, which approached statistical significance (p = 0.081). No statistically significant difference was observed in topoisomerase II-alpha expression between the groups with BPH and prostate carcinoma of Gleason score 6 (p = 0.245). CONCLUSION: Topoisomerase II-alpha expression was found to increase with the known prognostic marker Gleason score and with hormone insensitivity. Objective evidence is provided for clinical trials with drugs targeting topoisomerase II-alpha to be targeted to patients with prostate cancers of Gleason Score >6 and, in particular, prostate cancers of Gleason Scores 8-10.

Dynamics of Campylobacter spp. spread investigated in 14 broiler flocks in Switzerland.

Ten conventional and four extensive outdoor broiler flocks, distributed over nine farms, were investigated twice per week during a 35-58-day rearing period to observe the dynamics of Campylobacter spp. spread within these flocks. Strains isolated during this period were genotyped by restriction fragment length polymorphism analysis of the flaA gene and macrorestriction profiling with pulsed field gel electrophoresis. A total of 4112 samples were collected; 157 (3.8%) of these samples were Campylobacter positive, with all C. jejuni. The positive samples were distributed over three conventional and two extensive outdoor flocks on five farms. These five positive flocks were colonized from the fifth to the seventh week of age and remained colonized until slaughter. Each of the flocks showed a flock-specific genotype of Campylobacter that predominated until slaughter. Presuming different ways of entry, a combination of this fact and the observed dynamics of C. jejuni spread within the flocks indicates that a single source from the environment may have been responsible for the colonization of each flock. These conclusions may serve to further develop combat strategies at farm level.

p16INK4A, CDC6, and MCM5: predictive biomarkers in cervical preinvasive neoplasia and cervical cancer.

AIM: To analyse and compare expression patterns of three potential biomarkers-p16(INK4A), CDC6, and MCM5-and evaluate their use as predictive biomarkers in squamous and glandular cervical preinvasive neoplasia. METHODS: Immunocytochemical analysis of p16(INK4A), MCM5, and CDC6 expression was performed on 20 normal, 38 cervical intraepithelial neoplasia 1 (CIN1), 33 CIN2, 46 CIN3, 10 squamous cell carcinoma, 19 cervical glandular intraepithelial neoplasia (cGIN), and 10 adenocarcinoma samples. Staining intensity was assessed using a 0-3 scoring system. p16(INK4A), MCM5, and CDC6 expression was also examined in ThinPrep slides exhibiting mild, moderate, and severe dyskaryosis. Human papillomavirus (HPV) was detected using a modified SYBR green assay. Fluorogenic polymerase chain reaction (PCR) and solution phase PCR were used for specific HPV typing. RESULTS: All three markers showed a linear correlation between expression and grade of dysplasia. p16(INK4A) and MCM5 protein expression was upregulated in all grades of squamous and glandular dysplasia. CDC6 protein was preferentially expressed in high grade lesions and in invasive squamous cell carcinoma. CONCLUSION: p16(INK4A) expression was closely associated with high risk HPV infection-all grades of squamous and glandular cervical lesions were immunohistochemically positive. MCM5 staining intensity was independent of high risk HPV infection, highlighting its potential as a biomarker in both HPV dependent and independent cervical dysplasia. CDC6 may be a biomarker of high grade and invasive lesions of the cervix, with limited use in low grade dysplasia. p16(INK4A) was the most reliable marker of cervical dysplasia. Combinations of dysplastic biomarkers may be useful in difficult diagnostic cases.

p16INK4A positivity in benign, premalignant and malignant cervical glandular lesions: a potential diagnostic problem.

A wide array of immunohistochemical markers have been evaluated with respect to their specificity in staining dysplastic cervical cells in cervical biopsies and cervical cytological smears. However, there is still a significant demand for better biomarkers to identify neoplastic cervical glandular and squamous epithelial cells precisely. The CDKN2A gene, located on chromosome 9p21, encodes the tumour suppressor protein, p16INK4A, which decelerates the cell cycle by inactivating CDK4 and CDK6. The aim of this study was to compare and contrast the expression pattern of p16INK4A in benign and neoplastic glandular lesions and tubo-endometrioid metaplasia. All cases in each category displayed some p16INK4A expression. Adenocarcinoma and in situ cases showed a combination of intense nuclear and cytoplasmic staining. It was observed that all cases of tubo-endometrioid metaplasia showed occasional nuclear positivity and definite cytoplasmic staining. These findings may have important implications for the potential utility of p16INK4A as a biomarker for glandular dysplastic lesions. While p16INK4A has been demonstrated to be an excellent marker of cervical dysplasia in squamous neoplastic lesions of the cervix, it has potential pitfalls in cervical glandular lesions that may limit the utility of this biomarker in resolving the nature of suspicious glandular lesions, particularly in cytopathology.

p16INK4A as a marker for cervical dyskaryosis: CIN and cGIN in cervical biopsies and ThinPrep smears.

AIM: To examine the potential of p16(INK4A) as a biomarker for dysplastic squamous and glandular cells of the cervix in tissue sections and ThinPrep smears. METHODS: Immunocytochemical analysis of p16(INK4A) expression was performed on 22 normal cervical tissue samples, five cervical glandular intraepithelial neoplasia (cGIN), 38 cervical intraepithelial neoplasia 1 (CIN1), 33 CIN2, 46 CIN3, and 10 invasive cancer cases (eight squamous and two adenocarcinomas). All samples were formalin fixed and paraffin wax embedded, and immunohistochemical analysis was carried out using a mouse monoclonal anti-p16(INK4A) antibody after antigen unmasking. The staining intensity was assessed using a 0 to 3 scoring system. In addition, the expression status of p16(INK4A) was examined in 12 normal ThinPrep smears, one smear exhibiting cGIN, and a total of 20 smears exhibiting mild, moderate, and severe dyskaryosis. Human papillomavirus (HPV) detection was carried out using a modified SYBR green assay system. Fluorogenic polymerase chain reaction (PCR) and solution phase PCR were used for specific HPV typing. RESULTS: p16(INK4A) immunoreactivity was absent in all normal cervical tissues examined. Dysplastic squamous and glandular cells were positive for p16(INK4A) expression in all cases included in this study, except for one CIN3 case. p16(INK4A) expression was mainly nuclear in CIN1 cases, and both nuclear and cytoplasmic in CIN2, CIN3, cGIN, and invasive cases. All cases positive for HPV expressed the p16(INK4A) protein, although not all cases found positive for p16(INK4A) were HPV positive. In general, the p16(INK4A) staining intensity was lower in cases negative for HPV or those containing a low risk HPV type. CONCLUSION: This pattern of overexpression demonstrates the potential use of p16(INK4A) as a diagnostic marker for cervical squamous and also glandular neoplastic lesions. In addition, the technique can be used to identify individual dyskaryotic cells in ThinPrep smears. Thus, p16(INK4A) is a useful marker of cervical dyskaryosis.

Evaluation of liquid-based cytology in cervical screening of high-risk populations: a split study of colposcopy and genito-urinary medicine populations.

A split study evaluated the ThinPrep(R) PapTesttrade mark (TP; Cytyc Corp., Boxborough, MA) compared with current methodologies of cervical cytology in two high-risk cohorts. One thousand, three hundred cases from a colposcopy clinic and a genito-urinary medicine outpatient clinic were examined. The TP reported increased detection of all grades of dyskaryosis (mild, moderate and severe; + 4.5%) and a decrease in borderline and unsuitable cases (- 4.9%). Four cases of high-grade dyskaryosis (moderate or severe) were detected only using the TP, while an additional four cases classified as high-grade dyskaryosis with the TP were reported as borderline by our conventional methods. The split-study finding of increased sensitivity with the TP provides for improved clinical management of patients in our high-risk cohorts.