From 1901 to 2022, how far are we from truly understanding the pathogenesis of age-related dementia?

GeroScience - From the first described AD case in 1901 to the current year 2022, understanding the pathogenesis of Alzheimer’s disease (AD) and dementia has undergone a long and tortuous...     

High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation as a treatment option in multiple sclerosis

High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic stem cell transplantation (auto-HSCT) is a new and promising approach to the treatment of multiple sclerosis (MS) patients because currently there are no effective treatment methods for this disease. In this article, we present results of a prospective clinical study of efficacy of HDIT + auto-HSCT in MS patients. The following treatment strategies were employed in the study: "early," "conventional," and "salvage/late" transplantation. Fifty patients with various types of MS were included in this study. No toxic deaths were reported among 50 MS patients; transplantation procedure was well-tolerated by the patients. The efficacy analysis was performed in 45 patients. Twenty-eight patients achieved an objective improvement of neurological symptoms, defined as at least 0.5-point decrease in the Expanded Disability Status Scale (EDSS) score as compared to the baseline and confirmed during 6 months, and 17 patients had disease stabilization (steady EDSS level as compared to the baseline and confirmed during 6 months). The progression-free survival at 6 years after HDIT + auto-HSCT was 72%. Magnetic resonance imaging data were available in 37 patients before transplantation showing disease activity in 43.3%. No active, new, or enlarging lesions were registered in patients without disease progression. In conclusion, HDIT + auto-HSCT suggests positive results in management of patients with different types of MS. Identification of treatment strategies based on the level of disability, namely "early," "conventional," and "salvage/late" transplantation, appears to be feasible to improve treatment outcomes.     

Implementing Adolescent Screening,Brief Intervention,and Referral to Treatment (SBIRT) Education in a Pediatric Residency Curriculum

Background: Screening, brief intervention, and referral to treatment (SBIRT) is recommended as part of routine health care for adolescents as well as adults. In an effort to promote universal SBIRT, the Substance Abuse and Mental Health Services Administration awarded funding to residency programs to develop and implement SBIRT education and training. Our project focused on creating scientifically based, developmentally appropriate strategies and teaching materials for the adolescent age range. This paper describes curriculum development and implementation and presents evaluation data. Methods: Pediatric and child psychiatry residents were trained. The training consisted of 4 activities: (1) case-based teaching modules, (2) role-play of motivational interviewing and brief interventions, (3) mock interviews with trained adolescents, and (4) supervised “hands-on” screening and brief interventions. Main outcome measures included trainee satisfaction, and SBIRT knowledge, perceived self-efficacy, and self- and observer report of use of the SBIRT algorithm. Results: Among 150 total participants completing the SBIRT training modules, nearly all (92.3%) were satisfied/very satisfied with the training modules. Knowledge accuracy immediately post training was high, but declined significantly by the end of the first residency year, with little change across subsequent years of residency. Confidence ratings also declined over time. Use of the SBIRT algorithm during the Adolescent Medicine rotation was high according to trainee self- and faculty observer report. Conclusions: We found evidence of training satisfaction, increased confidence in talking to adolescents about substance use, and widespread use of recommended practices immediately following training. Use of a highly structured algorithm to guide practice, and simple, highly structured brief interventions was a successful training approach, as residents self-reported accurate use of the SBIRT algorithm immediately after training. Knowledge and self-confidence declined over time. It is possible that “booster” sessions and ongoing opportunities to review materials could help residents retain knowledge and skills.     

Spontaneous daily variability of atrial sensitivity. A study with an implanted DDD pacemaker

BACKGROUND: Spontaneous variations in the chronic stimulation threshold were widely investigated in the last few years and formed the basis of the safety margin concept of stimulation energy. The dynamic variability of sensitivity, particularly in the atrium, is less studied and, in the literature, contrasting data are present about the actual entity of these variations. A 2:1 safety margin is still recommended by many authors, although some papers reported that this value was inadequate to guarantee a correct sensing function. AIM OF THE STUDY: We evaluated daily variability of atrial sensitivity (AS) in patients implanted with the Cosmos 3 DDD cardiac pacemaker, with a special algorithm that continuously measures the minimum-maximum sensitivity values in atrium or in the ventricle during a 12-h sampling period. MATERIALS AND METHODS: 34 patients, 20 males and 14 females, with a mean age of 72+/-5 years, were implanted with a Cosmos 3 DDD pacemaker (PM). The indication to implant a PM was sick sinus syndrome in 21 patients and a high degree of AV block in 13 patients. Atrial bipolar leads were always employed. At 1, 2, 3 and 6 months after the implant, we analyzed the minimum-maximum values of atrial sensitivity for the last 12-h. This analysis was performed in the late afternoon. RESULTS: The mean AS varied more than threefold, from a mean minimum of 0.68 to a mean maximum value of 2.19 mV at 1 month, from 0.68 to 2.21 mV at 2 months, from 0.69 to 2.19 mV at 3 months and from 0.67 to 2.17 mV at 6 months, without significant differences among the four follow-up controls. In seven patients, there was a fourfold variation, while the variation was fivefold in five patients. CONCLUSION: In conclusion, from our data, we can confirm that atrial sensitivity may vary widely during the day and, consequently, we recommend that a 3:1 safety margin should be programmed and the recommended 2:1 ratio should be abandoned. Moreover, at implant, particular attention should be paid to obtaining the best atrial signal amplitude, at least threefold higher than the highest sensitivity value available in the implanted PM. To achieve this goal and to obviate to the oversensing phenomena, bipolar leads are preferable to unipolar leads.     

Comparative assessment of the inhibition of recombinant human CYP19 (aromatase) by azoles used in agriculture and as drugs for humans

Azoles (imidazoles and triazoles) are used as antifungal agents in agriculture and in medicine, and also for antiestrogen therapy, e.g., for breast cancer treatment. Antifungal activity is based on inhibition of fungal CYP51 (lanosterol 14alpha-demethylase), and estrogen biosynthesis reduction is due to azole inhibition of CYP19 (aromatase). Inhibition of aromatase by antifungal agents is usually an unwanted side effect and may cause endocrine disruption. A fluorimetric assay based on human recombinant CYP19 enzyme with dibenzylfluorescein as a substrate was used to compare the inhibitory potency of 22 azole compounds. Dose responses were established and duplicate datasets were analyzed with a nonlinear mixed-effects model with cumulative normal distribution for the logarithm of concentration. IC50 values (50% inhibitory concentration) of 13 fungicides used in agriculture ranged more than 700-fold, starting from 0.047 microM. The potency of seven human drugs spanned more than 7000-fold, starting from 0.019 microM. Most potent fungicides included prochloraz, flusilazole, and imazalil, and most potent medicinal antifungals were bifonazole, miconazole, and clotrimazole. These in vitro data indicate that the top-ranking azoles used as antifungal agents or drugs are as potent inhibitors of aromatase as are antiestrogen therapeutics used to treat breast cancer. These putative effects of azole agents and drugs on steroid biosynthesis and sex hormone balance should be considered when used in human subjects and also in wildlife exposed to azole fungicides used in agriculture.     

The role of diabetes mellitus on the formation of severe odontogenic abscesses—a retrospective study

Objectives

To analyze the correlation of diabetes mellitus and hyperglycemia with severe odontogenic abscesses.

Materials and methods

Records of all patients in the Department of Oral and Maxillofacial Surgery of the Medical Center of the Johannes Gutenberg-University who underwent inpatient treatment for severe odontogenic abscesses between 2010 and 2016 were evaluated retrospectively regarding diabetes anamnesis, maximum and fasting blood sugar count, and duration until discharge. In order to compare the numbers to a general maxillofacial group, all patients who received inpatient treatment in 2013 for any diagnosis other than an abscess of the head and neck region were analyzed as well, and the numbers were correlated.

Results

In total, 977 abscess patients were found in the analyzed period. 7.0% of the patients had a known diagnosis of diabetes mellitus type II and 0.6% of type I. Correlation with the general group showed that abscesses were significantly more likely in diabetics as well as patients with abnormal maximum and fasting blood sugar counts. These patients also needed significantly longer inpatient treatment.

Conclusions

Diabetics and patients with abnormal glucose tolerance show significantly higher numbers of severe odontogenic abscesses and might therefore benefit from earlier escalation of antibiotic medication.

Clinical relevance

Severe odontogenic abscesses are one of the most frequent diagnoses in maxillofacial practice. Adjusting the therapeutic approach for diabetics or patients with abnormal blood sugar counts might help to prevent the development of abscesses.

     

Place of death in haematological malignancy: variations by disease sub-type and time from diagnosis to death

Background

The reasons patients with haematological malignancies die in hospital more often than those with other cancers is the subject of much speculation. We examined variations in place of death by disease sub-type and time from diagnosis to death, to identify groups of ‘at-risk’ patients.

Methods

The study is based in the United Kingdom within the infrastructure of the Haematological Malignancy Research Network (HMRN), a large on-going population-based cohort including all patients newly diagnosed with haematological malignancies in the north of England. Diagnostic, demographic, prognostic, treatment and outcome data are collected for each patient and individuals are ‘flagged’ for death. This study includes all adults (≥18 years) diagnosed 1st September 2004 to 31st August 2010 (n?=?10,325), focussing on those who died on/before 31st August 2012 (n?=?4829).

Results

Most deaths occurred in hospital (65.9%), followed by home (15.6%), nursing home (11%) and hospice (7.5%) and there was little variation by diagnostic sub-type overall. Differences in place of death were, however, observed by time from diagnosis to death, and this was closely related to sub-type; 87.7% of deaths within a month of diagnosis happened in hospital and these largely occurred in patients with acute myeloid leukaemia, diffuse large B-cell lymphoma and myeloma. Patients surviving longer, and particularly beyond 1 year, were less likely to die in hospital and this corresponded with an increase in the proportion of home deaths.

Conclusions

Time from diagnosis to death was clearly a major determinant of place of death and many patients that died within three months of diagnosis did so in hospital. This was closely related to disease sub-type, with early deaths occurring most notable in the more aggressive diseases. This is likely to be due to a combination of factors including acute presentation, rapid disease progression without transition to a palliative approach to care and complications of treatment. Nonetheless, hospital deaths also occurred frequently in indolent diseases, suggesting that other factors were likely to contribute to the large proportion of hospital deaths overall. More evidence is needed to fully understand these complex cancers.

     

Enzymatic synthesis and electrochemical characterization of sodium 1,2-naphthoquinone-4-sulfonate-doped PEDOT/MWCNT composite

The development of novel materials with improved functional characteristics for supercapacitor electrodes is of current concern and calls for elaboration of innovative approaches. We report on an eco-friendly enzymatic synthesis of a composite based on poly(3,4-ethylenedioxythiophene) (PEDOT) and multi-walled carbon nanotubes (MWCNTs). The redox active compound, sodium 1,2-naphthoquinone-4-sulfonate (NQS), was used as a dopant for the backbone of the polymer. Oxidative polymerization of 3,4-ethylenedioxythiophene (EDOT) was catalyzed by a high redox potential laccase from the fungus Trametes hirsuta. Atmospheric oxygen served as an oxidant. A uniform thin layer of NQS-doped PEDOT formed on the surface of MWCNTs as a result of the enzymatic polymerization. The PEDOT–NQS/MWCNT composite showed a high specific capacitance of ca. 575 F g⁻¹ at a potential scan rate of 5 mV s⁻¹ and an excellent cycling stability within a potential window between −0.5 and 1.0 V, which makes it a promising electrode material for high-performance supercapacitors.

The use of redox active NSQ as a dopant of PEDOT dramatically increases the specific capacitance and cyclic stability of enzymatically synthesized PEDOT–NSQ/MWCNT composite.