Association of Long-Term Air Pollution with Prevalence and Incidence of Distal Sensorimotor Polyneuropathy: KORA F4/FF4 Study

Background: Air pollution contributes to type 2 diabetes and cardiovascular diseases, but its relevance for other complications of diabetes, in particular distal sensorimotor polyneuropathy (DSPN), is unclear. Recent studies have indicated that DSPN is also increasingly prevalent in obesity.Objectives: We aimed to assess associations of air pollutants with prevalent and incident DSPN in a population-based study of older individuals with high rates of type 2 diabetes and obesity.Methods: Cross-sectional analyses on prevalent DSPN were based on 1,075 individuals 62–81 years of age from the German Cooperative Health Research in the Region of Augsburg (KORA) F4 survey (2006–2008). Analyses on incident DSPN included 424 individuals without DSPN at baseline (KORA F4), of whom 188 had developed DSPN by the KORA FF4 survey (2013–2014). Associations of annual average air pollutant concentrations at participants’ residences with prevalent and incident DSPN were estimated using Poisson regression models with a robust error variance adjusting for multiple confounders.Results: Higher particle number concentrations (PNCs) were associated with higher prevalence [risk ratio (RR) per interquartile range (IQR) increase=1.10 (95% CI: 1.01, 1.20)] and incidence [1.11 (95% CI: 0.99, 1.24)] of DSPN. In subgroup analyses, particulate (PNC, PM10, PMcoarse, PM2.5, and PM2.5abs) and gaseous (NOx, NO2) pollutants were positively associated with prevalent DSPN in obese participants, whereas corresponding estimates for nonobese participants were close to the null [e.g., for an IQR increase in PNC, RR=1.17 (95% CI: 1.05, 1.31) vs. 1.06 (95% CI: 0.95, 1.19); pinteraction=0.22]. With the exception of PM2.5abs, corresponding associations with incident DSPN were positive in obese participants but null or inverse for nonobese participants, with pinteraction≤0.13 [e.g., for PNC, RR=1.28 (95% CI: 1.08, 1.51) vs. 1.03 (95% CI: 0.90, 1.18); pinteraction=0.03].Discussion: Both particulate and gaseous air pollutants were positively associated with prevalent and incident DSPN in obese individuals. Obesity and air pollution may have synergistic effects on the development of DSPN. https://doi.org/10.1289/EHP7311     

Inhibition of human CYP19 by azoles used as antifungal agents and aromatase inhibitors, using a new LC-MS/MS method for the analysis of estradiol product formation

Azoles are used as fungicides in agriculture or antifungal drugs in medicine. Their therapeutic activity is based on the inhibition of fungal lanosterol-14alpha-demethylase (CYP51). Azoles are also used for the treatment of estrogen-dependent diseases, e.g. in breast cancer therapy. Inhibition of CYP19 (aromatase) is the working principle for tumor therapy, but is an unwanted side effect of azoles used as fungicides or antifungal drugs. The inhibition of recombinant human CYP19 by 21 azoles in use for the three different purposes was investigated using the natural substrate testosterone. Estradiol product formation was measured by a newly developed and fully validated analytical method based on liquid chromatography-tandem mass spectrometry utilizing photospray ionization (APPI). Potency of enzyme inhibition was expressed in terms of IC50 concentrations. The two cytostatic drugs fadrozole and letrozole were the most potent inhibitors. However, azoles used as fungicides, e.g. prochloraz, or as antifungal drugs, e.g. bifonazole, were almost as potent inhibitors of aromatase as the drugs used in tumor therapy. Comparison of plasma concentrations that may be reached in antifungal therapy do not allow for large safety factors for bifonazole and miconazole. The IC50 values were compared to data obtained with other substrates, such as the pseudo-substrate dibenzylfluorescein (DBF). A high correlation was found, indicating that the fluorescence assay with DBF can well be used for potency ranking and screening of chemicals for aromatase inhibition. The data for antifungal drugs show that side effects on steroid hormone synthesis in humans due to inhibition of aromatase should be considered.     

Tim3 Is Upregulated and Protective in Nephrotoxic Serum Nephritis

T cell immunoglobulin and mucin protein-3 (Tim3) is mainly expressed on the cell surface of T-helper lymphocytes (T_H) that negatively regulates T_H-type 1 (T_H-1) responses. Because blockade of Tim3 aggravates disease activity in T_H-1–dependent diseases, we investigated whether Tim3 is involved in the pathogenesis of the T_H-1–dependent nephrotoxic nephritis (NTS). We first evaluated Tim3 expression in mice after induction of nephrotoxic serum nephritis (NTS) and then studied the effects of anti-Tim3 treatment toward the course of NTS for up to seven days. Whereas Tim3 expression was undetectable in control mice, we found significantly increased Tim3 expression in kidneys, but not in draining lymph nodes, at one, four, and eight weeks after induction of NTS. Tim3-expressing cells that infiltrated kidneys of mice subjected to NTS turned out to be CD4⁺ T cells rather than CD8⁺ cytotoxic T cells and dendritic cells. Administration of a blocking anti-Tim3 antibody aggravated nephritis as shown by significantly increased albuminuria, respective histological changes, and increased expression of the kidney injury molecule lipocalin-2. In parallel, an increase of infiltrating T cells, macrophages, and macrophage pro-inflammatory cytokine formation as well as increased proliferation and apoptosis in kidneys of anti-Tim3–treated mice was detected. Together, we provide the first evidence that Tim3 is up-regulated in kidneys in NTS and that Tim3 exerts protective roles in the course of disease.T-helper (T_H) cells play an essential role for the pathogenesis of various autoimmune diseases. T_H-1 cells, which induce a pro-inflammatory immune response, have been associated with the pathogenesis of rheumatoid arthritis, type I diabetes, or Crohn disease, but more recently T_H-17 cells have also gained interest as important effector cells in these experimental models.^1,2 In contrast, T_H-2 cell activation is essential for the development of allergic asthma and host response toward parasitic infections.^3,4 Whereas several mechanisms in the priming and differentiation of naïve T cells have been elucidated, the pathways determining the functional activity of differentiated effector T cells are largely unknown.The T cell immunoglobulin and mucin domains (Tim) are a group of cell surface receptors differentially expressed on mature T cells and macrophages that can control the functionality of T cell subsets by inducing activating or apoptotic signals after interaction with specific ligands.⁵ Specifically, Tim3 is preferentially expressed on differentiated T_H-1 cells,^6,7 but also on cytotoxic CD8⁺ T cells, T_H-17 cells, CD4⁺CD25⁺ regulatory T cells (Tregs), dendritic cells, and mast cells.^8,9,10,11,12 Thereby, Tim3 acts as a negative regulator of pro-inflammatory immune effector pathways. Accordingly, administration of a blocking anti-Tim3 antibody in a model of experimental allergic encephalomyelitis resulted in activation and expansion of macrophages in the brain and worsening of the disease.⁷ This observation could be traced back to direct cell-to-cell-interaction between differentiated T_H-1 cells and CD11b⁺/F4/80⁺ macrophages,⁷ which was inhibited by Tim3. These findings were confirmed in a mouse model of experimental type I diabetes mellitus.¹¹ In addition, these authors found that anti-Tim3 blockade dampened the antigen-specific immunosuppressive function of Tregs.¹¹Experimental nephrotoxic nephritis (NTS) is an established murine model to study glomerulonephritis.¹³ On the one hand, CD4⁺ T effector cells mediate NTS thereby contributing to albuminuria and kidney damage.¹⁴ Accordingly, the depletion of the master switch gene of T_H-1 cell differentiation, t-bet, attenuated the development of NTS in mice.¹⁵ On the other hand, Tregs, mast cells, and dendritic cells, all of which express Tim3, are also supposed to be centrally involved in the pathogenesis of NTS^14,16,17 as CD4⁺CD25⁺FoxP3⁺ Treg have been shown to be protective in this setting.¹⁴ Because Tregs and mast cells were mainly found in the regional draining lymph nodes, it was concluded that the regulation of the immune response in NTS takes place in secondary lymphoid organs rather than in the kidney.^14,17 However, as Tim3 plays a central role in the functional control of immune cell populations, which are also involved in the pathogenesis of NTS,¹¹ we were interested to evaluate the role of Tim3 in this experimental disease model. We thus studied the expression of Tim3 in this murine NTS model and examined whether modulation of Tim3 functionality would have an impact on the course of disease.     

Erste Erfahrungen und Ergebnisse mit der Einführung eines Patientenüberleitungsbogens

Es wird ein studentisches Forschungsprojekt in Zusammenarbeit zwischen dem Institut für Gesundheits- und Pflegewissenschaft und den BG-Kliniken Bergmannstrost, Halle, Saale, beschrieben, das sich mit der Einführung eines Patientenüberleitungsbogens (PüB) mit dem Ziel der Entwicklung eines Dokumentationsinstruments zur kontinuierlichen Informationsweitergabe an die Pflegenden und andere, an der nachstation?ren Versorgung beteiligten Berufsgruppen unter den Pr?missen eines integrativen, Berufsgruppen übergreifenden Ansatzes befasste. Zugleich sollte mehr Transparenz für Patienten und deren Angeh?rige geschaffen werden. Das methodische Vorgehen war prozessorientiert: in der Identifikationsphase wurden die Ziele des Projekts untersucht, die Konzeptionsphase diente der überprüfung der Praxisrelevanz, des Iststands der Entlassungsmodalit?ten und einer Dokumentenanalyse und daran anschlie?end der Entwicklung eines überleitungsbogens und dessen überarbeitung nach der überprüfung durch Experten. Die Pretestphase beinhaltete 35 unfallchirurgisch versorgten Patienten, die zum Zeitpunkt der Untersuchung ?lter als 64 Jahre waren. Diese wurden telefonisch mittels Interviewleitfaden zur Weitergabe des überleitungsbogens durch die Patienten entsprechend der Zielstellung nachbefragt. Die Ergebnisse beziehen sich neben dem Resultat der Dokumentenanalsye und der Beschreibung der Stichprobe auf die Verwirklichung der definierten Ziele, den integrativen Ansatz, die patientenseitige Akzeptanz im Sinn von Selbstbestimmung, die Qualit?t der Dokumentation und die Einsch?tzung des PüB aus der Sicht der station?r Pflegenden. In dem Patientenüberleitungsbogen ist ein praktikables Instrument zur Informationsweitergabe in der Versorgungskette unter Einbeziehung des Patienten zu sehen; neben der Verbesserung einiger methodischer Aspekte sollten zukünftig Barrieren für die Integration der Berufsgruppen übergreifenden Information analysiert und minimiert werden. Für die spezifischen Vorgaben der gesetzlichen Unfallversicherung in Bezug zu den Behandlungszielen und zur Bemessung des Pflegegelds kann der Bogen nach spezifischer Adaption ein aussagef?higes, spezifisches Dokumentationsinstrument sein.      

Influence of residual alveolar bone height on osseointegration of implants in the maxilla: a pilot study

Aims/Background: For sinus floor augmentation and simultaneous implant placement, a minimum of 5 mm of residual bone height has been recommended empirically. This study was designed to test this assumption in an experimental animal trial. Material and methods: In eight mini pigs, three premolars and two molars were removed on one side of the maxilla. Three months later, the animals were assigned to four groups of two animals each. A cavity was created at the base of the alveolar process so that the residual bone height was reduced to 2, 4, 6 and 8 mm, respectively. Six implants were installed and an inlay augmentation procedure was carried out using a particulated iliac bone graft. Implants were loaded with fixed provisional restorations after a healing period of 6 months. The animals were sacrificed after 6 months of functional loading. Histologic specimens were prepared and histomorphometric analysis was performed [bone‐to‐implant contact (BIC) ratio, interthread bone area, peri‐implant bone area, crestal bone resorption (CBR)]. Results: Two implants were lost during follow‐up and fibrous encapsulation was detected in one additional implant. All failures occurred in one animal with a residual alveolar height of 2 mm. On the buccal aspect, BIC turned out to be significantly higher for 6 mm when compared with 2/4 mm (75.8 ± 26.1 vs. 58 ± 23.2/53.9 ± 22.8; P<0.05), while on the palatal aspect, BIC was significantly higher for 6/8 mm when compared with 2/4 mm (80 ± 17.8/78.9 ± 10.3 vs. 55.8 ± 26.5/55.6 ± 21.3; P<0.05). For an alveolar height of 8 mm, CBR tended to be significantly lower than for bone heights of 2/4 mm (3.8 ± 2.3 vs. 5.3 ± 2.6/5.8 ± 3.9; P<0.05). Correlation analysis revealed a significant association of BIC and interthread bone area as well as a negative association to CBR on the palatal aspect. Conclusion: The results of the present study show that the combination of maxillary inlay grafting and simultaneous implant placement does not hinder osseous integration even though the alveolar crest has been reduced to a residual height of 4 mm and below. However, according to histomorphometry, the highest predictability is gained in sites with residual bone heights of 6 and 8 mm.     

Prognostic Impact of HIF-1α Expression in Patients with Definitive Radiotherapy for Cervical Cancer

PURPOSE: To investigate the relationship between the hypoxia-inducible factor-(HIF-)1alpha expression in tumor tissue, tumor oxygenation and hemoglobin levels in patients with advanced cervical cancers prior to radiotherapy and the effect on clinical outcome. PATIENTS AND METHODS: The investigation included 44 patients who underwent definitive radiotherapy for advanced cervical cancers between May 1995 and March 1999. Tumor biopsies were taken prior to treatment, and HIF-1alpha expression was determined by immunohistochemistry. In the same tumor area, tumor tissue oxygenation (pO2) was measured using the Eppendorf device. RESULTS: The 5-year cancer-specific survival of all patients was 60%. Twelve of 44 tumor specimens were HIF-1alpha-negative with a significantly better 5-year survival (92 +/- 8%) versus 32 patients who were HIF-1alpha-positive (45 +/- 10%; p < 0.02). There was no correlation between HIF-1alpha expression and tumor oxygenation (p = 0.57 both for pO2 median and hypoxic fraction < 5 mmHg vs. HIF-1alpha expression). However, patients with hemoglobin levels < 11 g/dl showed elevated HIF-1alpha expression compared to patients with hemoglobin levels > 12.5 g/dl (p = 0.04). Furthermore, HIF-1alpha correlated with vascular endothelial growth factor expression (p = 0.002). In a multivariate Cox regression model, HIF-1alpha expression (relative risk [RR] = 7.5; p = 0.05) revealed an increased risk of tumor-related death. CONCLUSION: The study indicates, that endogenous tumor markers such as HIF-1alpha may serve as prognostic markers of clinical outcome concerning cervical cancer after primary radiotherapy.