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Experimental Eye Research Jun 2024Aging changes the responsiveness of our immune defense, and this decline in immune reactivity plays an important role in the increased susceptibility to infections that...
Aging changes the responsiveness of our immune defense, and this decline in immune reactivity plays an important role in the increased susceptibility to infections that marks progressing age. Aging is also the most pronounced risk factor for development of age-related macular degeneration (AMD), a disease that is characterized by dysfunctional retinal pigment epithelial (RPE) cells and loss of central vision. We have previously shown that acute systemic viral infection has a large impact on the retina in young mice, leading to upregulation of chemokines in the RPE/choroid (RPE/c) and influx of CD8 T cells in the neuroretina. In this study, we sought to investigate the impact of systemic infection on the RPE/c in aged mice to evaluate whether infection in old age could play a role in the pathogenesis of AMD. We found that systemic infection in mice led to upregulation of genes from the crystallin family in the RPE/c from aged mice, but not in the RPE/c from young mice. Crystallin alpha A (CRYAA) was the most upregulated gene, and increased amounts of CRYAA protein were also detected in the aged RPE/c. Increased CRYAA gene and protein expression has previously been found in drusen and choroid from AMD patients, and this protein has also been linked to neovascularization. Since both drusen and neovascularization are important hallmarks of advanced AMD, it is interesting to speculate if upregulation of crystallins in response to infection in old age could be relevant for the pathogenesis of AMD.
PubMed: 38945517
DOI: 10.1016/j.exer.2024.109984 -
The Journal of Biological Chemistry Jun 2024Acute respiratory distress syndrome (ARDS) is a deadly clinical presentation in sepsis, COVID, and other lung disorders where vascular fluid leakage is a severe problem....
Acute respiratory distress syndrome (ARDS) is a deadly clinical presentation in sepsis, COVID, and other lung disorders where vascular fluid leakage is a severe problem. Recent findings by Shadab et al in the JBC show that a well-known player in immune function, Syk, also regulates vascular leakage in response to sepsis. An existing FDA-approved inhibitor of Syk, fostamatinib, prevents the vascular leakage and improves survival in a mouse sepsis model, providing promise for ARDS treatment in the clinic.
PubMed: 38945448
DOI: 10.1016/j.jbc.2024.107517 -
International Journal of Infectious... Jun 2024Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory infection (ALRI) in young children. With substantial advances in RSV research, we aimed...
OBJECTIVES
Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory infection (ALRI) in young children. With substantial advances in RSV research, we aimed to conduct an updated systematic review of risk factors for RSV-ALRI in children under five years.
METHODS
We updated our previously published literature search to November 2022 among three English databases and additionally searched three Chinese databases (from January 1995) to identify all relevant publications. We performed random-effects meta-analyses to estimate the pooled odds ratio and 95% confidence interval (CI) for each risk factor and each outcome (RSV-ALRI in the community and RSV-ALRI hospitalisation).
RESULTS
A total of 47 studies were included (26 from the updated search). Indoor air pollution was identified as a possible risk factor for RSV-ALRI in the community (OR 1.45, 95% CI: 1.10-1.90). The identified risk factors for RSV-ALRI hospitalisation fall into four categories: demographic (male sex, Māori and Pacific ethnicities vs European or other ethnicities), pre- and post- neonatal (prematurity, low birth weight, small for gestational age, maternal smoking during pregnancy or lactation, maternal age <30 years vs 30-34 years, multiparity, caesarean section vs vaginal), household and environmental (having siblings, passive smoking, maternal asthma, daycare centre attendance), and health and medical conditions (any chronic diseases, bronchopulmonary dysplasia, HIV infections, congenital heart disease, Down syndrome, cystic fibrosis, previous asthma). The pooled ORs ranged from 1.14 to 4.55.
CONCLUSIONS
Our findings on the risk factors for RSV-ALRI help identify RSV high-risk groups, which has important implications for RSV prevention at both individual and population levels.
PubMed: 38945430
DOI: 10.1016/j.ijid.2024.107125 -
Journal of Stroke and Cerebrovascular... Jun 2024Cerebral Vasomotor Reactivity (VMR) is a property of cerebral hemodynamics that protects from cerebrovascular disease. We aimed to explore the VMR longitudinal changes...
BACKGROUND AND AIM
Cerebral Vasomotor Reactivity (VMR) is a property of cerebral hemodynamics that protects from cerebrovascular disease. We aimed to explore the VMR longitudinal changes in patients with acute non-disabling stroke/Transient Ischemic Attack (TIA) to understand its implication in stroke ethiopatogenesis.
METHODS
VMR by Transcranial Doppler Breath Holding test was performed at 48-72 h from stroke onset (T1) and after 6 months (T2) on MCA of the non-affected hemisphere and PCA of the affected hemisphere.
RESULTS
We consecutively enrolled 124 patients with a median age of 66.0 (IQR 54.75-74.25) years with a median NIHSS 2 (IQR 1-3). Both MCA (1.38 %/s SD 0.58) and PCA (1.35 %/s SD 0.75) BHI at T1 did not differ among different stroke subtypes (p=0.067 and p=0.350; N=124). MCA and PCA BHI decreased from T1 to T2 (respectively 1.39 %/s SD 0.56 vs 1.18%/s SD 0.44 and 1.30 %/s SD 0.69 vs 1.20 %/s SD 0.51; N=109) regardless of ethiopatogenesis (respectively p<0.0001 and p=0.111).
CONCLUSION
the VMR is higher in acute phase than at 6 months in patients with non-disabling stroke/TIA, regardless of etiopathogenesis. The higher VMR in acute phase could be sustained by an increased Cerebral Blood Flow due to collateral circulation activation supporting the ischemic zone.
PubMed: 38945417
DOI: 10.1016/j.jstrokecerebrovasdis.2024.107841 -
Neuroscience Letters Jun 2024There are currently no FDA-approved treatments for cocaine use disorder. Recent preclinical and clinical studies showed that deep brain stimulation (DBS) in limbic...
There are currently no FDA-approved treatments for cocaine use disorder. Recent preclinical and clinical studies showed that deep brain stimulation (DBS) in limbic regions reduced drug seeking behavior. Our previous work indicated that DBS of the nucleus accumbens shell attenuated reinstatement of cocaine seeking, a model of relapse, in male rats. The current experiments were designed to evaluate the effect of electrical DBS on cocaine reinstatement in female rats across the estrous cycle. Rats were allowed to self-administer cocaine and lever responding was subsequently extinguished. Cocaine seeking was reinstated by an acute injection of experimenter-delivered cocaine. The effect of nucleus accumbens shell DBS vs. sham stimulation on cocaine-primed reinstatement was evaluated in female and male rats using a within-subjects counterbalanced design. Consistent with previous work, accumbens shell DBS suppressed cocaine seeking in male rats. In sharp contrast, accumbens shell DBS had no effect on cocaine reinstatement in female rats evaluated in either the estrus or non-estrus phases. These results suggest that changes across the estrous cycle are not responsible for the differences in the effect of DBS on cocaine reinstatement between female and male rats.
PubMed: 38945352
DOI: 10.1016/j.neulet.2024.137888 -
Translational Research : the Journal of... Jun 2024Renal aging and the subsequent rise in kidney-related diseases are attributed to senescence in renal tubular epithelial cells (RTECs). Our study revealed that the...
Renal aging and the subsequent rise in kidney-related diseases are attributed to senescence in renal tubular epithelial cells (RTECs). Our study revealed that the abnormal expression of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), a reader of RNA N6-methyladenosine, is critically involved in cisplatin-induced renal tubular senescence. In cisplatin-induced senescence of RTECs, the promoter activity and transcription of IGF2BP3 is markedly suppressed. It was due to the down regulation of MYC proto-oncogene (MYC), which regulates IGF2BP3 transcription by binding to the putative site at 1852 to 1863 of the IGF2BP3 promoter. Overexpression of IGF2BP3 ameliorated cisplatin-induced renal tubular senescence in vitro. Mechanistic studies revealed that IGF2BP3 inhibits cellular senescence in RTECs by enhancing cyclin-dependent kinase 6 (CDK6) mRNA stability and increasing its expression. The inhibition effect of IGF2BP3 on tubular senescence is partially reversed by the knockdown of CDK6. Further, IGF2BP3 recruits nuclear cap binding protein subunit 1 (NCBP1) and inhibits CDK6 mRNA decay, by recognizing mA modification. Specifically, IGF2BP3 recognizes mA motif "GGACU" at nucleotides 110-114 in the 5' untranslated region (UTR) field of CDK6 mRNA. The involvement of IGF2BP3/CDK6 in alleviating tubular senescence was confirmed in a cisplatin-induced acute kidney injury (AKI)-to-chronic kidney disease (CKD) model. Clinical data also suggests an age-related decrease in IGF2BP3 and CDK6 levels in renal tissue or serum samples from patients. These findings suggest that IGF2BP3/CDK6 may be a promising target in cisplatin-induced tubular senescence and renal failure.
PubMed: 38945255
DOI: 10.1016/j.trsl.2024.06.004 -
The Lancet. Neurology Jun 2024The accuracy of prognostication in patients with cervical spinal cord injury (SCI) needs to be improved. We aimed to explore the prognostic value of preserved spinal...
BACKGROUND
The accuracy of prognostication in patients with cervical spinal cord injury (SCI) needs to be improved. We aimed to explore the prognostic value of preserved spinal tissue bridges-injury-spared neural tissue adjacent to the lesion-for prediction of sensorimotor recovery in a large, multicentre cohort of people with SCI.
METHODS
For this longitudinal study, we included patients with acute cervical SCI (vertebrae C1-C7) admitted to one of three trauma or rehabilitation centres: Murnau, Germany (March 18, 2010-March 1, 2021); Zurich, Switzerland (May 12, 2002-March 2, 2019); and Denver, CO, USA (Jan 12, 2010-Feb 16, 2017). Patients were clinically assessed at admission (baseline), at discharge (3 months), and at 12 months post SCI. Midsagittal tissue bridges were quantified from T2-weighted images assessed at 3-4 weeks post SCI. Fractional regression and unbiased recursive partitioning models, adjusted for age, sex, centre, and neurological level of injury, were used to assess associations between tissue bridge width and baseline-adjusted total motor score, pinprick score, and light touch scores at 3 months and 12 months. Patients were stratified into subgroups according to whether they showed better or worse predicted recovery.
FINDINGS
The cohort included 227 patients: 93 patients from Murnau (22 [24%] female); 43 patients from Zurich (four [9%] female); and 91 patients from Denver (14 [15%] female). 136 of these participants (from Murnau and Zurich) were followed up for up to 12 months. At 3 months, per preserved 1 mm of tissue bridge at baseline, patients recovered a mean of 9·3% (SD 0·9) of maximal total motor score (95% CI 7·5-11.2), 8·6% (0·8) of maximal pinprick score (7·0-10·1), and 10·9% (0·8) of maximal light touch score (9·4-12·5). At 12 months post SCI, per preserved 1 mm of tissue bridge at baseline, patients recovered a mean of 10·9% (1·3) of maximal total motor score (8·4-13·4), 5·7% (1·3) of maximal pinprick score (3·3-8·2), and 6·9% (1·4) of maximal light touch score (4·1-9·7). Partitioning models identified a tissue bridge cutoff width of 2·0 mm to be indicative of higher or lower 3-month total motor, pinprick, and light touch scores, and a cutoff of 4·0 mm to be indicative of higher and lower 12-month scores. Compared with models that contained clinical predictors only, models additionally including tissue bridges had significantly improved prediction accuracy across all three centres.
INTERPRETATION
Tissue bridges, measured in the first few weeks after SCI, are associated with short-term and long-term clinical improvement. Thus, tissue bridges could potentially be used to guide rehabilitation decision making and to stratify patients into more homogeneous subgroups of recovery in regenerative and neuroprotective clinical trials.
FUNDING
Wings for Life, International Foundation for Research in Paraplegia, EU project Horizon 2020 (NISCI grant), and ERA-NET NEURON.
PubMed: 38945142
DOI: 10.1016/S1474-4422(24)00173-X -
Psychiatry Research Jun 2024In October 2023, Israel sustained a massive terror attack, with 1,300 people murdered, over 240 kidnapped, and millions exposed to the horrors. This study's aim is to...
In October 2023, Israel sustained a massive terror attack, with 1,300 people murdered, over 240 kidnapped, and millions exposed to the horrors. This study's aim is to examine the profile of patients arriving to the emergency department (ED) for psychiatric services during the month following the attack, compared to a similar period the year prior. In this cohort study, we compared patients arriving to the ED of a large general hospital in the center of Tel Aviv for psychiatric services during the month post-attack with the previous year using t-tests and chi-square exams. In 2023, 256 patients arrived in the ED for psychiatric evaluation and/or treatment, 46 % more than in 2022. Of these, 64 % were examined due to symptoms related to the terror attack. In 2023, significantly fewer patients had a prior psychiatric diagnosis (68% vs. 89 %). Significantly more patients were diagnosed with acute stress reaction or acute stress disorder in the ED, compared to almost no such diagnoses in 2022 (14 % and 43% vs. 0 % and 1 %). Major terror incidents profoundly influence psychiatric ED visits. Planning efforts for major emergencies should be adapted accordingly.
PubMed: 38945102
DOI: 10.1016/j.psychres.2024.116059 -
Journal of Anxiety Disorders Jun 2024This review evaluates randomized controlled trials (RCTs) intervening on adult state anxiety (fear and emotional distress during dental treatment), chronic dental... (Review)
Review
This review evaluates randomized controlled trials (RCTs) intervening on adult state anxiety (fear and emotional distress during dental treatment), chronic dental (trait) anxiety or dental phobia (disproportionately high trait anxiety; meeting diagnostic criteria for specific phobia). Seven online databases were systematically searched. 173 RCTs met inclusion criteria, of which 67 qualified for 14 pooled analyses. To alleviate state anxiety during oral surgery, moderate-certainty evidence supports employing hypnosis (SMD=-0.31, 95 %CI[-0.56,-0.05]), and low-certainty evidence supports prescribing benzodiazepines (SMD=-0.43, [-0.74,-0.12]). Evidence for reducing state anxiety is inconclusive regarding psychotherapy, and does not support virtual reality exposure therapy (VRET), virtual reality distraction, music, aromatherapy, video information and acupuncture. To reduce trait anxiety, moderate-certainty evidence supports using Cognitive Behavioral Therapy (CBT; SMD=-0.65, [-1.06, -0.24]). Regarding dental phobia, evidence with low-to-moderate certainty supports employing psychotherapy (SMD=-0.48, [-0.72,-0.24]), and CBT specifically (SMD=-0.43, [-0.68,-0.17]), but not VRET. These results show that dental anxieties are manageable and treatable. Clinicians should ensure that interventions match their purpose-managing acute emotions during treatment, or alleviating chronic anxiety and avoidance tendencies. Existing research gaps underscore the necessity for future trials to minimize bias and follow CONSORT reporting guidelines.
PubMed: 38945067
DOI: 10.1016/j.janxdis.2024.102891 -
Translational Oncology Jun 2024Adjuvant radiotherapy after mastectomy or breast conserving surgery (BCS) is the standard of care for majority of patients with breast cancer. This is however associated...
BACKGROUND
Adjuvant radiotherapy after mastectomy or breast conserving surgery (BCS) is the standard of care for majority of patients with breast cancer. This is however associated with mucosal and epidermal toxicity of organs at risk (OARs). Breast cancer patients are exposed to a plethora of wrong perceptions, misinformation and myths concerning the usefulness and adverse effects of radiotherapy. There is paucity of literature on the incidence and severity of radiation-induced acute toxicities experienced by patients with breast cancer in Ghana.
AIM
To assess the occurrence and severity of four main acute radiation-induced toxicities among female breast cancer patients treated with external beam radiotherapy at a major cancer treatment centre in Ghana.
METHODS
Data on the occurrence of acute toxicities among patients was collected from patients' medical records, through a semi-structured questionnaire and via weekly clinical assessments. The Common Terminology Criteria for Adverse Events (CTCAE) grading scale (version 4.0) was used to grade the severity of these toxicities. Descriptive and inferential statistics using an independent two-sampled t-test (two-tailed), one-way analysis of variance (ANOVA), Pearson's Chi-square and Fisher's exact tests were performed.
RESULTS
Dermatitis, fatigue, pharyngitis, and breast (chest) pain were the radiation toxicities found among the breast cancer patients undergoing treatment on the two machines. The mean predominant radiation doses associated with the onset of dermatitis, fatigue, pharyngitis, and chest pain in the breast cancer patients were 22.32 Gy, 22.48 Gy, 13.59 Gy, and 19.27 Gy respectively for treatment with a statistically significant (p = 0.0173). Radiation dermatitis was the most dominant acute radiation toxicity recorded, and its incidence and severity. The range of Fisher's p-values (0.689-0.999) between the acute radiation toxicities with both machines revealed no statistical significance.
CONCLUSION
Radiation dermatitis was the dominant acute toxicity, both in incidence and severity for patients treated. There was no statistical significance in the incidence and severity of acute radiation side effects.
PubMed: 38945020
DOI: 10.1016/j.tranon.2024.102032