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.

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.

Correction: Nasal Sebaceous Carcinoma-Rare Presentation.

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

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.

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.

[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.

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.

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.

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.

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.

BH3 peptidomimetics potently activate apoptosis and demonstrate single agent efficacy in neuroblastoma.

The major impediment to cure for many malignancies is the development of therapy resistance with resultant tumor progression. Genetic alterations leading to subversion of inherent apoptosis pathways are common themes in therapy resistance. Bcl-2 family proteins play a critical role in regulating mitochondrial apoptosis that governs chemotherapeutic effects, and defective engagement of these pathways contributes to treatment failure. We have studied the efficacy of BH3 peptidomimetics consisting of the minimal death, or BH3, domains of the proapoptotic BH3-only proteins Bid and Bad to induce apoptosis using neuroblastoma (NB) as a model system. We demonstrate that BH3 peptides, modified with an arginine homopolymer for membrane transduction (called r8-BidBH3 and r8-BadBH3, respectively), potently induce apoptosis in NB cells, including those with MYCN amplification. Cell death is caspase 9 dependent, consistent with a requirement for the intrinsic mitochondrial pathway. Substitutions at highly conserved residues within the r8-BidBH3 peptide abolish apoptotic efficacy supporting activity through specific BH domain interactions. Concomitant exposure to r8-BadBH3 and r8-BidBH3 at sublethal monotherapy doses revealed potent synergy consistent with a competitive displacement model, whereby BH3 peptides displace sequestered BH3 proteins to induce cell death. Further, BH3 peptides demonstrate antitumor efficacy in a xenograft model of NB in the absence of additional genotoxic or trophic stressors. These data provide proof of principle that targeted re-engagement of apoptosis pathways may be of therapeutic utility, and BH3-like compounds are attractive lead agents to re-establish therapy-induced apoptosis in refractory malignancies.

Measuring longitudinal white matter changes: comparison of a visual rating scale with a volumetric measurement.

BACKGROUND AND PURPOSE: Detection of longitudinal changes in white matter hyperintensities (WMH) by using visual rating scales is problematic. We compared a widely used visual rating scale with a volumetric method to study longitudinal white matter changes. METHODS: WMH were assessed with the visual Scheltens scale and a volumetric method in 100 elderly subjects aged 70-81 years for whom repetitive MR images were available with an interval of 33 (SD, 1.4) months. Reliability was determined by intraclass correlation coefficients. To examine the sensitivity of both the visual and volumetric method, we calculated Spearman rank correlations of WMH ratings and volume measurements with age. RESULTS: Reliability of the visual rating scale was good, whereas reliability of the volumetric measurement was excellent. For baseline measurements of WMH, we found weaker associations between WMH and age when assessed with the visual scale (r = 0.20, P = .045) than with the volumetric method (r = 0.31, P = .002). Longitudinal evaluation of WMH assessments showed regression in 26% of the subjects when analyzed with the visual rating scale against 12% of the subjects when using volumetric measurements. Compared with the visual rating, the correlation between progression in WMH and age was twice as high when using the volumetric measurement (r = 0.19, P = .062 and r = 0.39, P < .001, respectively). CONCLUSION: Volumetric measurements of WMH offer a more reliable, sensitive, and objective alternative to visual rating scales in studying longitudinal white matter changes.

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.

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.

Lack of effect of pravastatin on cerebral blood flow or parenchymal volume loss in elderly at risk for vascular disease.

BACKGROUND AND PURPOSE: Ageing is associated with a decline in cerebral blood flow. Animal studies have shown that cholesterol-lowering therapy with statins might preserve cerebral blood flow (CBF). We examined the effect of 40 mg pravastatin on the decline in CBF and brain volume in a subset of elderly subjects participating in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial. METHODS: Randomization was not stratified according to whether or not subjects participated in the MRI substudy. In 391 men (n=226) and women (n=165) aged 70 to 82 years (mean+/-SD, 75+/-3.2), we measured total CBF (in mL/min) at baseline and after a mean+/-SD follow-up of 33+/-1.4 months with a gradient-echo phase-contrast MRI technique. Total CBF was defined as the summed flows in both internal carotid and vertebral arteries. Parenchymal volume (whole brain) was segmented with the use of in-house-developed semiautomatic software. RESULTS: Total CBF significantly declined in the placebo-allocated group, from 521+/-83 to 504+/-92 mL/min (P=0.0036) and in the pravastatin-allocated group from 520+/-94 to 506+/-92 mL/min (P=0.018). This decline was not significantly different between treatment groups (P=0.56). There was also a significant reduction in brain volume over time (P<0.001), which was not different between the treatment groups (P=0.47). When expressed per unit of parenchymal volume, the decline in CBF over time was no longer statistically significant. CONCLUSIONS: Elderly people at risk for cerebral vascular disease had a significant decline in CBF with increasing age that was explained by a concomitant reduction in brain volume. Treatment with 40 mg pravastatin daily had no beneficial effect on total CBF.

Effect of oxygen insufflation during endotracheal suctioning on arterial pressure and oxygenation in coronary artery bypass graft patients.

BACKGROUND Numerous studies have demonstrated the need for increased inspired oxygen with endotracheal suctioning to prevent hypoxemia; however, increased arterial pressure has been reported as a consequence of lung hyperinflation/inflation used to deliver hyperoxygenation. OBJECTIVES To compare insufflation during endotracheal suctioning with a standard procedure of hyperoxygenation using a ventilator on arterial pressure, pulmonary artery pressure, heart rate, arterial oxygen saturation, and blood gases in intubated, mechanically ventilated coronary artery bypass graft patients. METHODS A within-subjects, repeated-measures design was used to measure arterial pressure (systolic, diastolic, and mean), pulmonary artery pressure (systolic, diastolic, and mean), airway pressure, heart rate and rhythm, arterial oxygen tension, arterial carbon dioxide tension, pH, and arterial oxygen saturation during an oxygen insufflation protocol and a hyperoxygenation protocol via the ventilator. RESULTS Using analysis of variance for repeated measures, statistically significant time effects were found for all variables. Statistically significant differences between protocols over time were found for arterial pressure, arterial oxygen tension, and arterial oxygen saturation. CONCLUSIONS Oxygen insufflation resulted in less increase in arterial pressure than did the hyperoxygenation protocol. The hyperoxygenation protocol resulted in hyperoxia. Based on this study, oxygen insufflation is a safe alternative for providing oxygen during endotracheal suctioning.

[Role of statins in prevention of stroke and dementia]. / De rol van statinen bij de preventie van beroerte en dementie.

There is accumulating evidence that statins reduce stroke risk, even though total cholesterol is not a risk factor for stroke. The explanation for this discrepancy is subject to discussion. It should be realised that the beneficial effects of statins on stroke risk have only been demonstrated in a select population, i.e. middle-aged men with ischaemic heart disease. Several clinical trials are underway to examine the effects of statins on stroke risk in more characteristic groups of patients who are at increased risk of developing stroke. The results of these studies should be awaited before statins are recommended for the prevention of stroke. Recently it has been reported that statins lower the risk of developing dementia. These conclusions were drawn from two cross-sectional studies. Because of the nature of the studies, only an association between the use of statins and a lower risk of developing dementia was shown, and not a causal relationship. Experimentally-controlled studies have to be designed to investigate the effect of statins on dementia.