No association between peripheral serotonin-gene-related DNA methylation and brain serotonin neurotransmission in the healthy and depressed state.

BACKGROUND: Methylation of serotonin-related genes has been proposed as a plausible gene-by-environment link which may mediate environmental stress, depressive and anxiety symptoms. DNA methylation is often measured in blood cells, but little is known about the association between this peripheral epigenetic modification and brain serotonergic architecture. Here, we evaluated the association between whole-blood-derived methylation of four CpG sites in the serotonin transporter (SLC6A4) and six CpG sites of the tryptophan hydroxylase 2 (TPH2) gene and in-vivo brain levels of serotonin transporter (5-HTT) and serotonin 4 receptor (5-HT4) in a cohort of healthy individuals (N = 254) and, for 5-HT4, in a cohort of unmedicated patients with depression (N = 90). To do so, we quantified SLC6A4/TPH2 methylation using bisulfite pyrosequencing and estimated brain 5-HT4 and 5-HTT levels using positron emission tomography. In addition, we explored the association between SLC6A4 and TPH2 methylation and measures of early life and recent stress, depressive and anxiety symptoms on 297 healthy individuals. RESULTS: We found no statistically significant association between peripheral DNA methylation and brain markers of serotonergic neurotransmission in patients with depression or in healthy individuals. In addition, although SLC6A4 CpG2 (chr17:30,236,083) methylation was marginally associated with the parental bonding inventory overprotection score in the healthy cohort, statistical significance did not remain after accounting for blood cell heterogeneity. CONCLUSIONS: We suggest that findings on peripheral DNA methylation in the context of brain serotonin-related features should be interpreted with caution. More studies are needed to rule out a role of SLC6A4 and TPH2 methylation as biomarkers for environmental stress, depressive or anxiety symptoms.

Nasal Sebaceous Carcinoma - A Rare Presentation.

Sebaceous carcinoma (SC) is a slow-growing but aggressive malignant skin tumour derived from sebaceous glands. SC most commonly occurs in the periocular region, whereas extraocular sites are rare. SC of the nasal dorsum is a rare pathology, and only a few cases are reported worldwide. Here, we report a case of an 80-year-old man who presented with a mass over the nasal dorsum, diagnosed morphologically and immunohistochemically as sebaceous carcinoma.

Correction: Nasal Sebaceous Carcinoma-Rare Presentation.

[This corrects the article DOI: 10.1007/s12070-023-04439-0.].

Progressive Worsening of Snoring as a Rare Presentation of HPV-Positive Oropharyngeal Squamous Cell Carcinoma.

The incidence of oropharyngeal squamous cell carcinoma (OPSCC) especially human papillomavirus (HPV) associated type is increasing in trend despite reducing in other head and neck squamous cell carcinoma. Muffled voice, dysphagia, neck mass and pain over the throat are among the common presentations; however, health care professional should be aware of unusual presentation to avoid delay in management. We present a case of HPV-positive OPSCC with a rare presentation; progressive worsening of snoring for 6 months duration. Patient sougth medical attention at the some of private clinics for the past 2 months, however, was told to have a normal tonsillar enlargement. Subsequently, patient was referred to our center with impression of obstructive sleep apnea. We highlight the important of early referral to appropriate center and otorhinolaryngology for assessment in cases presented with worsening snoring.

Advanced Nasopharyngeal Carcinoma with Generalized Lymphadenopathy Masquerade as Lymphoma.

Introduction: Nasopharyngeal carcinoma (NPC) is a nasopharyngeal epithelial neoplasm that has distinct aetiological, epidemiological and biological characteristics compared to other head and neck malignancies. Patients usually present late due to non-specific symptoms and deep location of the tumour in the nasopharynx. Case Report: We would like to highlight a case of advanced NPC presenting with generalised lymphadenopathy, without the presence of an obvious nasopharyngeal mass that masqueraded as lymphoma in the initial stage. Conclusions: NPC may share clinical features with other sinonasal pathologies or other malignant lymphoproliferative disorders that lead to a delay in diagnosis. NPC should be one of the differential diagnoses for any cases presenting with cervical lymphadenopathy, especially in adult male patients originating from East or Southeast Asia. Early diagnosis and treatment are crucial because early-stage NPC has an excellent chemoradiotherapy response and high survival rate.

A Missed Diagnosis of Laryngotracheal Injury Secondary to Emergency Intubation: Lessons Learned.

Iatrogenic laryngotracheal trauma is a potentially fatal complication of endotracheal intubation, especially in an emergency setting. Symptoms are almost always related to speech, breathing, and swallowing. Hoarseness being the commonest symptom, while shortness of breath and stridor always signify more devastating injury. We present a case of iatrogenic subglottic and tracheal stenosis, which was misdiagnosed in the emergency department during the first visit. This case report highlights the importance of salient history and thorough examination with a high index of suspicion in a stridorous case with a recent history of intubation. Early detection and management are vital to avoid a life-threatening event.

Hot and cold cognitive disturbances in antidepressant-free patients with major depressive disorder: a NeuroPharm study.

BACKGROUND: Cognitive disturbances are common and disabling features of major depressive disorder (MDD). Previous studies provide limited insight into the co-occurrence of hot (emotion-dependent) and cold (emotion-independent) cognitive disturbances in MDD. Therefore, we here map both hot and cold cognition in depressed patients compared to healthy individuals. METHODS: We collected neuropsychological data from 92 antidepressant-free MDD patients and 103 healthy controls. All participants completed a comprehensive neuropsychological test battery assessing hot cognition including emotion processing, affective verbal memory and social cognition as well as cold cognition including verbal and working memory and reaction time. RESULTS: The depressed patients showed small to moderate negative affective biases on emotion processing outcomes, moderate increases in ratings of guilt and shame and moderate deficits in verbal and working memory as well as moderately slowed reaction time compared to healthy controls. We observed no correlations between individual cognitive tasks and depression severity in the depressed patients. Lastly, an exploratory cluster analysis suggested the presence of three cognitive profiles in MDD: one characterised predominantly by disturbed hot cognitive functions, one characterised predominantly by disturbed cold cognitive functions and one characterised by global impairment across all cognitive domains. Notably, the three cognitive profiles differed in depression severity. CONCLUSION: We identified a pattern of small to moderate disturbances in both hot and cold cognition in MDD. While none of the individual cognitive outcomes mapped onto depression severity, cognitive profile clusters did. Overall cognition-based stratification tools may be useful in precision medicine approaches to MDD.

Oral contraceptives and the serotonin 4 receptor: a molecular brain imaging study in healthy women.

OBJECTIVE: Sex steroid hormones potently shape brain functions, including those critical to maintain mental health such as serotonin signaling. Use of oral contraceptives (OCs) profoundly changes endogenous sex steroid hormone levels and dynamics. Recent register-based studies show that starting an OC is associated with increased risk of developing depression. Here, we investigate whether use of OCs in healthy women is associated with a marker of the serotonin system in terms of serotonin 4 receptor (5-HT4R) brain imaging. METHODS: [11C]SB207145-PET imaging data on 53 healthy women, of whom 16 used OCs, were available from the Cimbi database. We evaluated global effects of OC use on 5-HT4R binding in a latent variable model based on 5-HT4R binding across cortical and subcortical regions. RESULTS: We demonstrate that OC users have 9-12% lower global brain 5-HT4R binding potential compared to non-users. Univariate region-based analyses (pallidostriatum, caudate, hippocampus, amygdala, anterior cingulate cortex, and neocortex) supported the global effect of OC use with the largest difference present in the hippocampus (-12.8% (95% CI [-21.0; -3.9], Pcorrected = 0.03). CONCLUSION: We show that women who use OCs have markedly lower brain 5-HT4R binding relative to non-users, which constitutes a plausible molecular link between OC use and increased risk of depressive episodes. We propose that this reflects a reduced 5-HT4R gene expression, possibly related to a blunted ovarian hormone state among OC users.

Kimura Disease with Parotid Swelling and Cervical Lymphadenopathy: A Case Report and Literature Review.

Kimura disease (KD) is a rare chronic benign inflammatory disorder of unknown etiology that is prevalent in Asian males. The head and neck region, especially the parotid glands and cervical lymph nodes, are most commonly affected. Diagnosis is based on clinicopathological features, while radiology findings are nonspecific. Although various treatment strategies have been proposed, there is a high recurrence rate. Combination therapy has been found to produce better results than monotherapy. We present a case of KD with huge parotid and cervical lymph node involvement that was treated with a combination of surgery and corticosteroids administered perioperatively.

Vasomotor menopausal symptoms and cardiovascular disease risk in midlife: A longitudinal study.

OBJECTIVE: To ascertain the association between vasomotor menopausal symptoms (VSM), hot flushes and night sweats, and cardiovascular disease, coronary heart disease and cerebrovascular disease. STUDY DESIGN: The study sample comprised 8881 women (aged 45-50 years) with available hospital separation data from the 1946-51 cohort (1996-2016) of the ongoing Australian Longitudinal Study on Women's Health, a national prospective cohort study. MAIN OUTCOME MEASURES: First fatal or non-fatal cardiovascular disease, coronary heart disease, and cerebrovascular disease events were obtained through linkage with hospital admission data, the National Death Index, and Medicare Benefits Schedule. Hot flushes and night sweats were assessed via questionnaires at each main survey. Additionally, we calculated the duration of symptoms based on whether or not women reported vasomotor menopausal symptoms in each survey. RESULTS: There were 925 cardiovascular disease, 484 coronary heart disease and 154 cerebrovascular disease events. There was no consistent evidence of any association with vasomotor menopausal symptoms, hot flushes and night sweats. We did find marginally statistically significant associations between presence of night sweats and cardiovascular disease (Hazard Ratio = 1.18, 95 % Confidence Interval: 1.01-1.38), and between the duration of vasomotor menopausal symptoms [years] and coronary heart disease (Hazard Ratioper year = 1.03, 95 % Confidence Interval: 1.00-1.05). However, given the number of associations tested, these findings could very well have arisen by chance. CONCLUSION: In this large longitudinal study with 20 years of follow-up and clinical outcomes we did not find a convincing association between vasomotor menopausal symptoms, hot flushes, night sweats and cardiovascular disease, coronary heart disease and cerebrovascular disease.

Unraveling the associations of age and menopause with cardiovascular risk factors in a large population-based study.

BACKGROUND: Although the association between menopause and cardiovascular disease (CVD) risk has been studied extensively, the simultaneous role of chronological aging herein remains underexposed. This study aims to disentangle the relationships of menopausal status and chronological aging with CVD risk factors in the largest study population to date. METHODS: In this cross-sectional study, CVD risk factors were compared between women with a different menopausal status within the same yearly age strata. The study population comprised female participants of the baseline visit of the population-based LifeLines Cohort Study. A total of 63,466 women, aged between 18 and 65 years, was included. Of them, 39,379 women were considered to be premenopausal, 8669 were perimenopausal, 14,514 were naturally postmenopausal, and 904 were surgically postmenopausal. RESULTS: Compared to postmenopausal women aged 45 years, average total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c) were 0.5 and 0.4 mmol/L higher, respectively, in postmenopausal women aged 50. Systolic and diastolic blood pressure levels were 4 and 1 mmHg higher, respectively. At all ages between 46 and 55 years, and after adjustment for confounders, naturally postmenopausal women had 0.2 to 0.4 mmol/L higher TC and 0.1 to 0.3 mmol/L higher LDL-c levels compared to premenopausal women in the same age range. Systolic blood pressure levels were up to 4 mmHg lower in naturally post- compared to premenopausal women at all ages between 29 and 52 years. Body mass index levels were up to 3.2 kg/m2 higher in women with surgical menopause compared to all other women between the ages 32 and 52 years. All aforementioned results were statistically significant. CONCLUSIONS: Chronological age and menopausal status are both independently associated with CVD risk factors. Based on the comparatively smaller observed differences associated with menopausal status than with chronological aging, the significance of a more unfavorable lipid profile in a later reproductive stage may be less obvious than previously thought.

Neoadjuvant endocrine treatment in early breast cancer: An overlooked alternative?

During the last decade neoadjuvant endocrine therapy (NET) has moved from being reserved for elderly and frail non-chemotherapy candidates to a primary systemic modality in selected patients with hormone sensitive breast cancer. Neoadjuvant hormonal treatment in patients with hormone receptor positive, HER-2 negative early breast cancer is proven to be an effective and safe option; it is associated with a higher rate of breast conserving surgery (BCS), may reduce the need for adjuvant chemotherapy and enables a delay of surgery for medical or practical reasons. Clinical responses range from 13% to 100% with at least 3 months of NET. Methods of assessing response should include MRI of the breast, particularly in lobular tumours. In studies comparing tamoxifen with aromatase inhibitors (AI), AI proved to be superior in terms of tumour response and rates of BCS. Change in Ki67 is accepted as a validated endpoint for comparing endocrine neoadjuvant agents. Levels of Ki67 during treatment are more closely related to long-term prognosis than pretreatment Ki67. Neoadjuvant endocrine therapy provides a unique opportunity for studies of endocrine responsiveness and the development of new experimental drugs combined with systemic hormonal treatment.

From neutrophils to macrophages: differences in regional adipose tissue depots.

Currently, we do not fully understand the underlying mechanisms of how regional adiposity promotes metabolic dysregulation. As adipose tissue expands, there is an increase in chronic systemic low-grade inflammation due to greater infiltration of immune cells and production of cytokines. This chronic inflammation is thought to play a major role in the development of metabolic complications and disease such as insulin resistance and diabetes. We know that different adipose tissue depots contribute differently to the risk of metabolic disease. People who have an upper body fat distribution around the abdomen are at greater risk of disease than those who tend to store fat in their lower body around the hips and thighs. Thus, it is conceivable that adipose tissue depots contribute differently to the inflammatory milieu as a result of varied infiltration of immune cell types. In this review, we describe the role and function of major resident immune cells in the development of adipose tissue inflammation and discuss their regional differences in the context of metabolic disease risk. We find that although initial studies have found regional differences, a more comprehensive understanding of how immune cells interrupt adipose tissue homeostasis is needed.

Associations between Frailty, Complex Care Needs and Quality of Life in Multi-Morbid Older People.

BACKGROUND: Little is known regarding the complex care needs, level of frailty or quality of life of multi-morbid older patients. OBJECTIVES: The objective of this study was to determine the relationship between frailty, complexity of care and quality of life in multi-morbid older people. DESIGN: Cross-sectional study. SETTING: Thirteen primary care practices in the Netherlands. PARTICIPANTS: 1,150 multi-morbid older people living in the community. MEASUREMENTS: The level of frailty was assessed with the Groningen Frailty Indicator. Complexity of care needs was measured with the Intermed for the Elderly Self-Assessment. Quality of life (QoL) was measured with two items of the RAND-36. RESULTS: In total, 758 out of 1,150 (65.9%) patients were frail, 8.3% had complex care needs, and the mean QoL score was 7.1 (standard deviation 1.2). Correlations between frailty and complexity, frailty and QoL, and complexity of care and QoL were 0.67, -0.51 and -0.52 (all p<0.001) respectively. All patients with complex care needs were frail, but, only 12.5% of the frail patients had complex care needs. Problems at climbing up stairs was associated with higher levels of frailty and complexity of care but with a lower QoL. CONCLUSIONS: Higher levels of frailty and complexity of care are associated with a lower QoL in multi-morbid older people. The results of this study contribute to a better understanding these concepts and are valuable for the development of tailored interventions for older persons in the future.

[Proactive and structured care for the elderly in primary care]. / Proactieve en gestructureerde zorg voor kwetsbare oudere patiënten in de eerstelijn: Achtergrond, opzet en uitvoering van een screenings- en zorgprogramma.

BACKGROUND: Currently, primary care for the older, vulnerable patient is reactive, fragmented and does not meet patients needs. Given the expected increase of home-dwelling frail elderly people a transition is needed to proactive and integrated care. METHODS: In the described study, we explore two innovative interventions in primary care. First we describe a newly developed screening and monitoring program for frail elderly patients based on routine care information in general practice. Second, we describe a multidisciplinary intervention program by trained nurses for frail elderly patients in general practice. The effectiveness of the interventions is examined in a three-armed, cluster randomized trial, taking place in 58 primary care practices in Utrecht, the Bilt and Maarsenbroek. RESULTS: Three thousand eight patients are included. Primary outcome measure is the impact of the interventions on the daily activities, measured with the Katz questionnaire. Secondary outcomes measures are the quality of life, mortality, recording in a care or nursing home, visit to an emergency room or outpatient unit, recording in the hospital and volunteer caregivers tax.

Patients' perceptions of doctors' clothing: should we really be 'bare below the elbow'?

INTRODUCTION: In September 2007, the Department of Health published Uniforms and Workwear: an Evidence Base for Guiding Local Policy. Following this, most National Health Service trusts imposed a 'bare below the elbow' dress code policy, with clinical staff asked to remove ties, wristwatches and hand jewellery and to wear short-sleeved tops. There is currently no evidence linking dress code to the transmission of hospital-acquired infection. We designed the current survey to assess patients' perceptions of doctors' appearance, with specific reference to the 'bare below the elbow' policy. MATERIALS AND METHODS: A questionnaire showing photographs of a doctor in three different types of attire ('scrubs', formal attire and 'bare below the elbow') were used to gather responses from 80 in-patients and 80 out-patients in the ENT department. Patients were asked which outfit they felt was the most hygienic, the most professional and the easiest identification of the person as a doctor. They were also asked to indicate their overall preference. RESULTS AND ANALYSIS: Formal attire was considered most professional and the easiest identification that the person was a doctor. Scrubs were considered most hygienic. Respondents' overall preference was divided between scrubs and formal clothes. 'Bare below the elbow' attire received the lowest votes in all categories. DISCUSSION: This finding raises significant questions about the Department of Health policy in question. The authors suggest that an alternative policy should be considered, with scrubs worn for in-patient situations and formal attire during out-patient encounters.

Associations between total cerebral blood flow and age related changes of the brain.

BACKGROUND AND PURPOSE: Although total cerebral blood flow (tCBF) is known to be related to age, less is known regarding the associations between tCBF and the morphologic changes of the brain accompanying cerebral aging. The purpose of this study was to investigate whether total cerebral blood flow (tCBF) is related to white matter hyperintensity (WMH) volume and/or cerebral atrophy. Furthermore, we investigate whether tCBF should be expressed in mL/min, as was done in all previous MR studies, or in mL/100 mL/min, which yielded good results in precious SPECT, PET and perfusion MRI studies investigating regional cerebral blood flow. MATERIALS AND METHODS: Patients were included from the nested MRI sub-study of the PROSPER study. Dual fast spin echo and FLAIR images were obtained in all patients. In addition, single slice phase contrast MR angiography was used for flow measurements in the internal carotids and vertebral arteries. tCBF was expressed in both mL/min and mL/100 mL/min. RESULTS: We found a significant correlation between tCBF in mL/min and both age (r = -.124; p = p

Deregulated Wnt/beta-catenin program in high-risk neuroblastomas without MYCN amplification.

Neuroblastoma (NB) is a frequently lethal tumor of childhood. MYCN amplification accounts for the aggressive phenotype in a subset while the majority have no consistently identified molecular aberration but frequently express MYC at high levels. We hypothesized that activated Wnt/beta-catenin (CTNNB1) signaling might account for this as MYC is a beta-catenin transcriptional target and multiple embryonal and neural crest malignancies have oncogenic alterations in this pathway. NB cell lines without MYCN amplification express higher levels of MYC and beta-catenin (with aberrant nuclear localization) than MYCN-amplified cell lines. Evidence for aberrant beta-catenin-TCF transcriptional activity was demonstrated using expression profiles from 73 primary NBs. Findings included increased WNT ligands (WNT1, WNT6, WNT7A, WNT10B), DVL1 and TCF7 expression in high-risk NBs without MYCN amplification, consistent with canonical beta-catenin signaling. More directly, Patterns of Gene Expression and Gene Set Enrichment Analyses demonstrated beta-catenin target genes (for example, MYC, PPARD, NRCAM, CD44, TCF7) as coordinately upregulated in high-risk NBs without MYCN amplification in comparison to high-risk MYCN-amplified or intermediate-risk NBs, supporting pathway activation in this subset. Thus, high-risk NBs without MYCN amplification may deregulate MYC and other oncogenic genes via altered beta-catenin signaling providing a potential candidate pathway for therapeutic inhibition.

Redox cycling with facing interdigitated array electrodes as a method for selective detection of redox species.

A pair of interdigitated ultramicroelectrodes (UMEs) is used to electrochemically detect a weak reductor (dopamine) in the presence of a stronger one (K(4)[Fe(CN)(6)]). In the mixture of both reductors, one of the two interdigitated electrodes (the generator electrode) is used to oxidize both species at 700 mV vs. Ag/AgCl, followed by subsequent (selective) reduction of the oxidized dopamine at 400 mV. A regenerated dopamine molecule can thus be oxidized several times (redox cycling) and enable selective detection even in the presence of the stronger reductor. In order to obtain high redox cycling efficiency, we designed and realized platinum electrodes with widths of 2 and 4 microm and spacing of 2 microm, which gave redox cycling efficiencies of 9 and 4 respectively. Using this electrode design, a dopamine/K(4)[Fe(CN)(6)] selectivity of 2 could be obtained.