Enduring inequality: educational disparities in health among the oldest old in Sweden 1992–2011

Objectives

Although the past two decades have involved changes in the living conditions of the oldest old in Sweden, little is known about how health inequalities have developed in this group during the period. This study explores the educational disparities in a wide range of health outcomes among the oldest old in Sweden between 1992 and 2011.

Methods

The study uses the repeated cross-sectional design of the SWEOLD survey, a nationally representative survey of the oldest old in Sweden with comparable data from 1992, 2002, and 2011. The development of educational disparities in health was tracked across the three waves.

Results

The results show that although the prevalence of most health problems increased during the period, the prevalence of disability in activities of daily living decreased. Despite these changes, educational disparities in health remained largely unaffected.

Conclusions

The results of the study suggest that the association between education and health is remarkably robust. It prevailed into the oldest age groups, was consistently found for a wide range of health problems, and tended to be stable over extended periods of time.

     

Estimation of drug receptor occupancy when non-displaceable binding differs between brain regions – extending the simplified reference tissue model

AimThe simplified reference tissue model (SRTM) is used for estimation of receptor occupancy assuming that the non-displaceable binding in the reference region is identical to the brain regions of interest. The aim of this work was to extend the SRTM to also account for inter-regional differences in non-displaceable concentrations, and to investigate if this model allowed estimation of receptor occupancy using white matter as reference. It was also investigated if an apparent higher affinity in caudate compared with other brain regions, could be better explained by a difference in the extent of non-displaceable binding.MethodsThe analysis was based on a PET study in six healthy volunteers using the 5-HT_1B receptor radioligand [¹¹C]-AZ10419369. The radioligand was given intravenously as a tracer dose alone and following different oral doses of the 5-HT_1B receptor antagonist AZD3783. Non-linear mixed effects models were developed where differences between regions in non-specific concentrations were accounted for. The properties of the models were also evaluated by means of simulation studies.ResultsThe estimate (95% CI) of Ki_PL was 10.2 ng ml⁻¹ (5.4, 15) and 10.4 ng ml⁻¹ (8.1, 13.6) based on the extended SRTM with white matter as reference and based on the SRTM using cerebellum as reference, respectively. The estimate (95% CI) of Ki_PL for caudate relative to other brain regions was 55% (48, 62%).ConclusionsThe extended SRTM allows consideration of white matter as reference region when no suitable grey matter region exists. AZD3783 affinity appears to be higher in the caudate compared with other brain regions.     

Somatostatin receptor 1–5; expression profiles during rat development

Background

Somatostatin acts through five receptor subtypes (SSTRs 1–5). We aimed to investigate SSTRs mRNA expression and protein distribution in whole rat embryos, with special emphasis on the pancreas.

Material and methods

Rat embryos were collected on embryonal days 10, 11, 12, 14, 15, 17, 19, 21, and at birth. Presence of SSTRs was investigated with RT-PCR techniques and immunohistochemistry.

Results

There was no SSTR5 mRNA expression in the whole rat embryos. All SSTR1–5 proteins were observed at embryonal day 10, but the localization varied between the different subtypes. From day 11 to birth SSTRs protein presence increased with time in major structures such as skin and cartilage. It remained similar over time in the heart and liver. In the fetal pancreas mRNA expression of SSTR2 and 4 was detected at day 14, and there was an increase up to birth. Only SSTR1 protein co-localized to a higher extent with the islet hormones studied. SSTR2 was present in all islet endocrine cells except for β-cells. In contrast, the immunostaining for SSTR3–4 was co-localized with insulin and PP, and, finally, SSTR5 with glucagon and pancreatic polypeptide. In mRNA isolated from whole rat embryos SSTR1-2 and SSTR4 expression showed a peak at day 14, while SSTR3 mRNA was not present until day 15.

Conclusion

The present data suggest a role for SSTRs during the development of the rat embryo. Subsequent functional studies may elucidate regulatory roles of specific SSTRs for the growth and differentiation of the pancreas as well as other organs.     

Repeated Moderate Noise Exposure in the Rat—an Early Adulthood Noise Exposure Model

In this study, we investigated the effects of varying intensity levels of repeated moderate noise exposures on hearing. The aim was to define an appropriate intensity level that could be repeated several times without giving rise to a permanent hearing loss, and thus establish a model for early adulthood moderate noise exposure in rats. Female Sprague-Dawley rats were exposed to broadband noise for 90 min, with a 50 % duty cycle at levels of 101, 104, 107, or 110 dB sound pressure level (SPL), and compared to a control group of non-exposed animals. Exposure was repeated every 6 weeks for a maximum of six repetitions or until a permanent hearing loss was observed. Hearing was assessed by the auditory brainstem response (ABR). Rats exposed to the higher intensities of 107 and 110 dB SPL showed permanent threshold shifts following the first exposure, while rats exposed to 101 and 104 dB SPL could be exposed at least six times without a sustained change in hearing thresholds. ABR amplitudes decreased over time for all groups, including the non-exposed control group, while the latencies were unaffected. A possible change in noise susceptibility following the repeated moderate noise exposures was tested by subjecting the animals to high-intensity noise exposure of 110 dB for 4 h. Rats previously exposed repeatedly to 104 dB SPL were slightly more resistant to high-intensity noise exposure than non-exposed rats or rats exposed to 101 dB SPL. Repeated moderate exposure to 104 dB SPL broadband noise is a viable model for early adulthood noise exposure in rats and may be useful for the study of noise exposure on age-related hearing loss.     

Advancing Paternal Age and Schizophrenia: The Impact of Delayed Fatherhood

Objective: It is well known that advancing paternal age is associated with an increased risk of schizophrenia in offspring, but the mechanism behind this association remains unknown. This study investigates if delayed fatherhood rather than advancing paternal age per se might explain the increased risk of schizophrenia in offspring associated with advancing paternal age. Methods: This is a register-based study of the Swedish population looking at people born 1955–1985 who have 1 or 2 siblings (n = 2 589 502). The main analysis investigated whether the association between advancing paternal age and schizophrenia was explained by delayed fatherhood. Possible confounding factors were taken into account. Cox regression was used throughout. Results: In the main analysis the association between advancing paternal age and increased risk of schizophrenia in offspring disappeared after controlling for delayed fatherhood (hazard ratio [HR] = 0.93, 95% CI = 0.72–1.21 comparing 45+ years old fathers to those 25–29), whereas delayed fatherhood showed an association with increased risk of schizophrenia in offspring comparing 35–39 and 40–44 years old fathers to 25–29 year olds (HR = 1.37, 95% CI = 1.18–1.58; HR = 1.81, 95% CI = 1.44–2.28, respectively). The results remained when controlling for possible confounders. Conclusions: This study suggests that the association between paternal age and schizophrenia is not due to paternal age per se, but rather to an unknown factor associated with both delayed fatherhood and schizophrenia.Key words: risk factors, psychotic disorders, epidemiology, parents, registries     

Therapy response monitoring of the early effects of a new BRAF inhibitor on melanoma xenograft in mice: evaluation of 18F‐FDG‐PET and 18F‐FLT‐PET

Inhibition of the V600E mutated BRAF kinase gene (BRAF^V600E) is an important and effective approach to treating melanomas. A new specific small molecule inhibitor of BRAF^V600E, PLX3603, showed potent melanoma growth‐inhibiting characteristics in preclinical studies and is currently under clinical investigation. In this study we investigated the feasibility of ¹⁸F‐FDG and ¹⁸F‐FLT‐PET to monitor the early effects of the BRAF^V600E inhibitor in mice with melanoma xenografts. SCID/beige mice with subcutaneous (s.c.) A375 melanoma xenografts, expressing BRAF^V600E, received the BRAF^V600E inhibitor twice daily orally (0, 25, 50 and 75 mg/kg). At 1, 3 and 7 days after start of therapy, the uptake of ¹⁸F‐FDG and ¹⁸F‐FLT in the tumor and normal tissues was determined in ex vivo tissue samples. Serial ¹⁸F‐FDG and ¹⁸F‐FLT‐PET scans were acquired of animals at 1 day before and 1, 3 and 7 days after start of treatment with 75 mg/kg BRAF^V600E inhibitor. A dose‐dependent decrease in ¹⁸F‐FDG uptake in the A375 tumors was observed by ex vivo biodistribution analysis. Administration of 75 mg/kg BRAF inhibitor for 1, 3 and 7 days resulted in a significantly decreased ¹⁸F‐FDG uptake in A375 tumors (41, 35 and 51%, respectively). ¹⁸F‐FLT uptake in the A375 tumors was low at baseline and no significant changes in ¹⁸F‐FLT uptake were observed at any of the doses administered. These effects were corroborated by serial in vivo ¹⁸F‐FDG and ¹⁸F‐FLT‐PET imaging. These data demonstrate that ¹⁸F‐FDG‐PET can be used as an imaging biomarker to noninvasively evaluate the early effects of PLX3603. Copyright © 2014 John Wiley & Sons, Ltd.     

Lentiviral Gene Therapy Using Cellular Promoters Cures Type 1 Gaucher Disease in Mice

Gaucher disease is caused by an inherited deficiency of the enzyme glucosylceramidase. Due to the lack of a fully functional enzyme, there is progressive build-up of the lipid component glucosylceramide. Insufficient glucosylceramidase activity results in hepatosplenomegaly, cytopenias, and bone disease in patients. Gene therapy represents a future therapeutic option for patients unresponsive to enzyme replacement therapy and lacking a suitable bone marrow donor. By proof-of-principle experiments, we have previously demonstrated a reversal of symptoms in a murine disease model of type 1 Gaucher disease, using gammaretroviral vectors harboring strong viral promoters to drive glucosidase β-acid (GBA) gene expression. To investigate whether safer vectors can correct the enzyme deficiency, we utilized self-inactivating lentiviral vectors (SIN LVs) with the GBA gene under the control of human phosphoglycerate kinase (PGK) and CD68 promoter, respectively. Here, we report prevention of, as well as reversal of, manifest disease symptoms after lentiviral gene transfer. Glucosylceramidase activity above levels required for clearance of glucosylceramide from tissues resulted in reversal of splenomegaly, reduced Gaucher cell infiltration and a restoration of hematological parameters. These findings support the use of SIN-LVs with cellular promoters in future clinical gene therapy protocols for type 1 Gaucher disease.     

Diet-Induced Weight Loss Alters Functional Brain Responses during an Episodic Memory Task

ObjectiveIt has been suggested that overweight is negatively associated with cognitive functions. The aim of this study was to investigate whether a reduction in body weight by dietary interventions could improve episodic memory performance and alter associated functional brain responses in overweight and obese women.Methods20 overweight postmenopausal women were randomized to either a modified paleolithic diet or a standard diet adhering to the Nordic Nutrition Recommendations for 6 months. We used functional magnetic resonance imaging to examine brain function during an episodic memory task as well as anthropometric and biochemical data before and after the interventions.ResultsEpisodic memory performance improved significantly (p = 0.010) after the dietary interventions. Concomitantly, brain activity increased in the anterior part of the right hippocampus during memory encoding, without differences between diets. This was associated with decreased levels of plasma free fatty acids (FFA). Brain activity increased in pre-frontal cortex and superior/middle temporal gyri. The magnitude of increase correlated with waist circumference reduction. During episodic retrieval, brain activity decreased in inferior and middle frontal gyri, and increased in middle/superior temporal gyri.ConclusionsDiet-induced weight loss, associated with decreased levels of plasma FFA, improves episodic memory linked to increased hippocampal activity.Key Words: Functional magnetic resonance imaging, Episodic memory, Obesity, Diet interventions, Hippocampus     

Human papillomavirus prevalence and type‐distribution in cervical glandular neoplasias: Results from a European multinational epidemiological study

Cervical glandular neoplasias (CGN) present a challenge for cervical cancer prevention due to their complex histopathology and difficulties in detecting preinvasive stages with current screening practices. Reports of human papillomavirus (HPV) prevalence and type‐distribution in CGN vary, providing uncertain evidence to support prophylactic vaccination and HPV screening. This study [108288/108290] assessed HPV prevalence and type‐distribution in women diagnosed with cervical adenocarcinoma in situ (AIS, N = 49), adenosquamous carcinoma (ASC, N = 104), and various adenocarcinoma subtypes (ADC, N = 461) from 17 European countries, using centralised pathology review and sensitive HPV testing. The highest HPV‐positivity rates were observed in AIS (93.9%), ASC (85.6%), and usual‐type ADC (90.4%), with much lower rates in rarer ADC subtypes (clear‐cell: 27.6%; serous: 30.4%; endometrioid: 12.9%; gastric‐type: 0%). The most common HPV types were restricted to HPV16/18/45, accounting for 98.3% of all HPV‐positive ADC. There were variations in HPV prevalence and ADC type‐distribution by country. Age at diagnosis differed by ADC subtype, with usual‐type diagnosed in younger women (median: 43 years) compared to rarer subtypes (medians between 57 and 66 years). Moreover, HPV‐positive ADC cases were younger than HPV‐negative ADC. The six years difference in median age for women with AIS compared to those with usual‐type ADC suggests that cytological screening for AIS may be suboptimal. Since the great majority of CGN are HPV16/18/45‐positive, the incorporation of prophylactic vaccination and HPV testing in cervical cancer screening are important prevention strategies. Our results suggest that special attention should be given to certain rarer ADC subtypes as most appear to be unrelated to HPV.