Cone cGMP-gated channel mutations and clinical findings in patients with achromatopsia, macular degeneration, and other hereditary cone diseases

Unrelated patients with achromatopsia, macular degeneration with onset under age 50 years, cone degeneration or dysfunction, cone-rod degeneration, or macular malfunction were screened for mutations in the three genes known to be associated with achromatopsia: the GNAT2 gene encoding the alpha subunit of cone transducin and the CNGA3 and CNGB3 genes encoding the alpha and beta subunits of the cone cGMP-gated cation channel. We found no examples of patients with GNAT2 mutations. Out of 36 achromats, 12 (33%) had mutations in CNGA3 (13 different mutations including five novel mutations) and 12 (33%) had mutations in CNGB3 (six different mutations including four novel mutations). All achromats with CNG mutations had residual, presumably cone function as determined by computer-averaged 30-Hz electroretinograms (ERGs). There was considerable variability in acuity and color vision, with most patients having acuities of 20/200-20/400 and complete absence of color perception, and others having acuities of 20/25-20/40 and some color vision. Two pseudodominant achromatopsia cases were uncovered, both with CNGA3 mutations, including one family in which some compound heterozygotes with achromatopsia mutations were clinically unaffected. We found two novel CNGB3 changes in three patients with juvenile macular degeneration, a phenotype not previously associated with mutations in the cone channel subunits. These patients had subnormal acuity (20/30-20/60), normal to subnormal color vision, and normal to subnormal full-field cone ERG amplitudes. Our results indicate that some patients with channel protein mutations retain residual foveal cone function. Based on our findings, CNGB3 should be considered as a candidate gene to be evaluated in patients with forms of cone dysfunction, including macular degeneration.     

Hyperbaric oxygenation mitigates focal cerebral injury and reduces striatal dopamine release in a rat model of transient middle cerebral artery occlusion

The usefulness of the administration of hyperbaric oxygen (HBO) in the treatment of acute focal cerebral ischemia remains debatable. A significant association exists between focal cerebral injury and an excessive release of extracellular dopamine (DA). In vivo microdialysis was used in the present study to examine the effect of HBO on DA release in the striatum during ischemia and reperfusion in rats. The histological changes occurring were also evaluated. Focal cerebral ischemia was induced by occlusion of the middle cerebral artery (MCA) using a surgically placed intraluminal filament. Control rats (n=8) were subjected to 1 h of ischemia, whilst the study rats (n=8) were in addition treated with HBO (2.8 atmospheres of absolute pressure 100% O₂) during ischemia. Both groups were returned to breathing room air at normal pressure during reperfusion. Microdialysis samples were continuously collected at 15 min intervals at 2 μl·min^–1. The [mean (SE)] increase in release of striatal DA attained significance after 30 min of occlusion of MCA [170 (24)%], and continued to increase [268 (26)% at 45 min] reaching a peak level at 60 min [672 (59)%] before returning to the baseline level during the late reperfusion phase. There was no significant change in the level of DA in HBO treated rats during the period of ischemia. A significant reduction in edema and neuronal shrinkage were observed by histological examination in HBO treated rats when compared to the control rats. The results showed that HBO, when administered during ischemia, offered significant neuroprotection in our experimental model of transient focal cerebral ischemia in the rat. The mechanism seems to imply, at least in part, a reduced level of DA. Electronic Publication     

Evaluating mechanism and severity of injuries among trauma patients admitted to Sina Hospital, the National Trauma Registry of Iran

Purpose: Injuries are one of the leading causes of death and lead to a high social and financial burden. Injury patterns can vary significantly among different age groups and body regions. This study aimed to evaluate the relationship between mechanism of injury, patient comorbidities and severity of injuries. Methods: The study included trauma patients from July 2016 to June 2018, who were admitted to Sina Hospital, Tehran, Iran. The inclusion criteria were all injured patients who had at least one of the following: hospital length of stay more than 24 h, death in hospital, and transfer from the intensive care unit of another hospital. Data collection was performed using the National Trauma Registry of Iran minimum dataset. Results: The most common injury mechanism was road traffic injuries (49.0%), followed by falls (25.5%). The mean age of those who fell was significantly higher in comparison with other mechanisms (p < 0.001). Severe extremity injuries occurred more often in the fall group than in the vehicle collision group (69.0% vs. 43.5%, p < 0.001). Moreover, cases of severe multiple trauma were higher amongst vehicle collisions than injuries caused by falls (27.8% vs. 12.9%, p = 0.003). Conclusion: Comparing falls with motor vehicle collisions, patients who fell were older and sustained more extremity injuries. Patients injured by motor vehicle collision were more likely to have sustained multiple trauma than those presenting with falls. Recognition of the relationship between mechanisms and consequences of injuries may lead to more effective interventions.     

Evaluation of the effect of cognitive behavioral therapy on tocophobia: A systematic review and meta-analysis

Non-medical approaches including cognitive behavioral therapy (CBT) have been proposed for the management of tocophobia. A new method of performing CBT is through internet. The aim of this systematic review and meta-analysis was to evaluate the effect of internet-based and traditional CBT on tocophobia. A literature search was conducted on qualitative and quantitative articles from 2000 to 2019 in Pubmed, Scopus, Web of Science and Cochrane databases using search terms referring to tocophobia and CBT. Identified articles were screened in two steps; 1) title and abstract and 2) full text screening. The quality of the quantitative and qualitative studies was assessed using the quality criteria proposed by the Cochrane Collaboration and Jonna Briggs Institute (JBI) checklist respectively. Out of the 382 relevant studies, 9 studies were eligible for the review. A high level of heterogeneity was observed in the studies (I² = 94%, P < 0.001). The meta-analysis showed that both internet-based, and traditional CBT were effective in reducing tocophobia. CBT was more effective in interventions in the Middle Eastern compared to European countries. More than five CBT sessions could significantly reduce tocophobia. Healthcare providers and midwives should have basic knowledge on physiological interventions to reduce tocophobia.     

Clock genes alterations and endocrine disorders

Background

Various endocrine signals oscillate over the 24‐hour period and so does the responsiveness of target tissues. These daily oscillations do not occur solely in response to external stimuli but are also under the control of an intrinsic circadian clock.

Design

We searched the PubMed database to identify studies describing the associations of clock genes with endocrine diseases.

Results

Various human single nucleotide polymorphisms of brain and muscle ARNT‐like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK) genes exhibited significant associations with type 2 diabetes mellitus. ARNTL2 gene expression and upregulation of BMAL1 and PER1 were associated with the development of type 1 diabetes mellitus. Thyroid hormones modulated PER2 expression in a tissue‐specific way, whereas BMAL1 regulated the expression of type 2 iodothyronine deiodinase in specific tissues. Adrenal gland and adrenal adenoma expressed PER1, PER2, CRY2, CLOCK and BMAL1 genes. Adrenal sensitivity to adrenocorticotrophin was also affected by circadian oscillations. A significant correlation between the expression of propio‐melanocorticotrophin and PER 2, as well as between prolactin and CLOCK, was found in corticotroph and lactosomatotroph cells, respectively, in the pituitary. Clock genes and especially BMAL1 showed an important role in fertility, whereas oestradiol and androgens exhibited tissue‐specific effects on clock gene expression. Metabolic disorders were also associated with circadian dysregulation according to studies in shift workers.

Conclusions

Clock genes are associated with various endocrine disorders through complex mechanisms. However, data on humans are scarce. Moreover, clock genes exhibit a tissue‐specific expression representing an additional level of regulation. Their specific role in endocrine disorders and their potential implications remain to be further clarified.     

Age-related alterations in the protein expression profile of C57BL/6J mouse pituitaries

The aim of our study was to monitor the protein expression profile in pituitary glands of healthy C57BL/6J mice during aging. Pituitary glands of 4-week old (immature), 3-month old (mature), and >25-month old mice were analysed by proteomic tools such as two-dimensional electrophoresis and N-terminal micro-sequencing. A change was detected in the expression of growth hormone after sexual maturation. Our particular interest, however, was directed against up-regulated proteins in the old pituitary glands, which are proposed to be involved in the process of neuroendocrine aging.

Among these proteins, the expression of glutathione-S-transferase (GST) and apolipoprotein A-1 were increased in old pituitaries. Furthermore, ubiquitin carboxyl-terminal hydrolase (UCH-L1) was significantly up-regulated in senescent C57BL/6J mouse pituitaries. Since only the rat homologue was known, we isolated and analysed the mouse UCH-L1 sequence. Since GST is involved in antioxidative defence and UCH-L1 is part of the ubiquitin/proteasome system, which is responsible for the removal of damaged proteins, these results suggest increased oxidative burden and an increased activity of the ubiquitin system.     

Effects of Ramelteon on the Prevention of Postoperative Delirium in Older Patients Undergoing Orthopedic Surgery: The RECOVER Randomized Controlled Trial

ObjectivesPostoperative delirium, associated with negative consequences including longer hospital stays and worse cognitive and physical outcomes, is frequently accompanied by sleep-wake disturbance. Our objective was to evaluate the efficacy and short-term safety of ramelteon, a melatonin receptor agonist, for the prevention of postoperative delirium in older patients undergoing orthopedic surgery.DesignA quadruple-masked randomized placebo-controlled trial (Clinical Trials.gov NCT02324153) conducted from March 2017 to June 2019.SettingTertiary academic medical center.ParticipantsPatients aged 65 years or older, undergoing elective primary or revision hip or knee replacement.InterventionRamelteon (8 mg) or placeboMeasurementsEighty participants were randomized to an oral gel cap of ramelteon or placebo for 3 consecutive nights starting the night before surgery. Trained research staff conducted delirium assessments for 3 consecutive days starting on postoperative day (POD) 0, after recovery from anesthesia, and on to POD2. A delirium diagnosis was based upon DSM-5 criteria determined by expert panel consensus.ResultsOf 80 participants, five withdrew consent (one placebo, four ramelteon) and four were excluded (four ramelteon) after randomization. Delirium incidence during the 2 days following surgery was 7% (5 of 71) with no difference between the ramelteon versus placebo: 9% (3 of 33) and 5% (2 of 38), respectively. The adjusted odds ratio for postoperative delirium as a function of assignment to the ramelteon treatment arm was 1.28 (95% confidence interval: 0.21–7.93; z-value 0.27; p-value = 0.79). Adverse events were similar between the two groups.ConclusionIn older patients undergoing elective primary or revision hip or knee replacement, ramelteon was not efficacious in preventing postoperative delirium.     

EFFECT OF PRE-COOLING ON PAIN ASSOCIATED WITH DENTAL INJECTIONS IN CHILDREN: A SYSTEMATIC REVIEW

ObjectivesSeveral methods, including cooling of the injection site, have been proposed for pain control during the dental local anesthetic injection. This systematic review aimed to evaluate the scientific evidence on the precooling of the injection site to reduce pediatric dental injection pain.Data SourcesThe search terms were selected according to the Medical Subject Headings and non-Medical Subject Headings. The main keywords included dental injection, cooling, pain, and children. Potentially eligible studies involved the subjective or objective pain evaluation in children receiving any dental injection. Risk of bias assessment was carried out using the Cochrane risk of bias tool. An electronic search was carried out for published studies in the English language up to March 2020 on Scopus, Cochrane, and PubMed databases. Of 761 articles retrieved initially, 14 were eligible to be included in the systematic review, of which 6 articles were excluded. Regarding the type of intervention, 6 articles used cooling agents in the intervention group, and 2 studies used the Buzzy device (a combination of cold and vibratory stimuli). All studies included in the systematic review except one considered that the use of intra- or extra-oral cooling could reduce pain during anesthesia injections in children significantly.ConclusionOverall, the evidence presented in this review was limited and had low quality. It may be concluded that application of cold agents before dental anesthesia can be more helpful than the traditional dental injection in reducing pain in children. Besides, the use of the Buzzy device showed promising results, as shown by 2 studies.