Restoring aged stem cell functionality: Current progress and future directions.

Stem cell dysfunction is a hallmark of aging, associated with the decline of physical and cognitive abilities of humans and other mammals [Cell 2013;153:1194]. Therefore, it has become an active area of research within the aging and stem cell fields, and various techniques have been employed to mitigate the decline of stem cell function both in vitro and in vivo. While some techniques developed in model organisms are not directly translatable to humans, others show promise in becoming clinically relevant to delay or even mitigate negative phenotypes associated with aging. This review focuses on diet, treatment, and small molecule interventions that provide evidence of functional improvement in at least one type of aged adult stem cell.

Incidence and predictors of iron deficiency anaemia in parturients undergoing elective caesarean section at a tertiary hospital in New Zealand: a retrospective, observational cohort study.

BACKGROUND: Worldwide, iron deficiency anaemia in pregnancy is a significant problem which can be especially problematic when delivery is by caesarean section, a procedure associated with significant blood loss. Optimising iron stores pre-delivery remains an overarching goal. We aim to measure the incidence of iron deficiency anaemia in patients undergoing elective caesarean section at our institution and determine any associated predictors, as well as adverse outcomes. METHODS: A retrospective, observational cohort study of patients presenting for elective caesarean section over a two-year period. Patient data was collected from hospital electronic records. Iron deficiency anaemia was defined a haemoglobin < 110 g/L and a ferritin < 30 µg/L in the three-month period prior to delivery. The primary aim was to establish the incidence of iron deficiency anaemia at the time of delivery and any associated predictors. Secondary outcomes included any association between the primary outcome and complications defined by the hospital discharge complication coding system, as well as an evaluation of the number of blood tests carried out antenatally per trimester. RESULTS: One thousand and ninety-three women underwent caesarean section over the study period and 16.2% had iron deficiency anaemia. Patients with iron deficiency anaemia were more likely to be of Maori and Pacific Island ethnicity, have a greater booking body mass index, be younger and have a greater parity. Pre-operative anaemia was associated with a greater likelihood of post-operative blood transfusion. CONCLUSIONS: There remains potential for optimisation of iron deficiency anaemia in our local population undergoing elective caesarean section.

Rapid Loss and Recovery of Vision Following Steroid Treatment in Orbital Myositis: A Case Report.

A 65-year-old African American man initially presented to the emergency department complaining of headaches, retro-orbital pressure, decreased vision, white flashes and floaters, and palinopsia of both eyes. After complete evaluation, he was diagnosed with migraine with aura and discharged to home with an ophthalmology follow-up. Upon follow-up with the ophthalmology team, he had developed severe periorbital inflammation, proptosis, chemosis, and vision loss that was greatest on the left side. The patient was immediately hospitalized for further evaluation and steroid treatment. His vision, ocular symptoms, and physical findings dramatically and rapidly improved with a 3-day course of high-dose intravenous steroids. Existing literature is sparse on rapid loss and recovery of vision following steroid treatment for orbital myositis. The exact mechanism of vision loss in orbital myositis is not understood and merits further investigation. Orbital myositis is a subset of nonspecific orbital inflammatory syndrome. It remains a poorly understood condition that mimics other, more common conditions such as thyroid eye disease and orbital cellulitis. If left untreated, orbital myositis could progress to the point of continued inflammation, enlargement of ocular tissues, ocular ischemia, and optic neuritis. To reverse these symptoms and prevent further progression, a quick diagnosis followed by steroid treatment is imperative.

Scalable, cell type-selective, AAV-based in vivo CRISPR screening in the mouse brain.

CRISPR-based genetic screening directly in mammalian tissues in vivo is challenging due to the need for scalable, cell-type selective delivery and recovery of guide RNA libraries. We developed an in vivo adeno-associated virus-based and Cre recombinase-dependent workflow for cell type-selective CRISPR interference screening in mouse tissues. We demonstrate the power of this approach by identifying neuron-essential genes in the mouse brain using a library targeting over 2000 genes.

Early diagnosis of surgically curable lung cancer is commonly serendipitous.

AIMS: Lung cancer is the largest cause of cancer death in New Zealand, accounting for 18.3% of cancer-related deaths.[[1,2]] There is limited literature on how patients with lung cancer clinically present in New Zealand. The aim of this cohort study was to identify the rate of incidentally diagnosed lung cancer in the Midland Region, the common symptomatology and route of diagnosis. METHODS: This retrospective cohort study included patients with lung cancer who underwent potentially curative thoracic surgery between January 2011 to June 2018 at Waikato Hospital, New Zealand. Symptoms or signs recorded were cough, dyspnoea, haemoptysis, lymphadenopathy, chest pain, hoarseness, fatigue, weight loss and finger clubbing. The lung cancer cases were grouped into incidental finding, symptomatic general practitioner, symptomatic emergency department and surveillance. RESULTS: Three hundred and ten patients with lung cancer had thoracic surgery with curative intent at Waikato Hospital. Two hundred and fourteen (69%) patients had symptoms which prompted presentation to a treating physician and 96 (31%) patients were asymptomatic. Incidental diagnosis was demonstrated in 121 (39.4%) patients. Of the patients diagnosed incidentally, 36.4% (n=44) had symptoms of lung cancer with the main symptoms including 45% with cough (n=20), 28% with dyspnoea (n=12) and 28% chest pain (n=12). CONCLUSIONS: In New Zealand, a large amount of lung cancer is still diagnosed incidentally with symptoms of cough, dyspnoea and chest pain. Further research into the development of a lung cancer screening program in New Zealand for a high-risk population is warranted.

Transforaminal Endoscopic Discectomy Under General and Local Anesthesia: A Single-Center Study.

Percutaneous spinal endoscopy is used for the treatment of disorders of the lumbar spine, as it has several advantages over traditional surgical methods. The performance of percutaneous spinal endoscopy is not possible without applying anesthesia methods. Two types (local and general) of anesthesia are used for percutaneous spinal endoscopy. Both, local and general anesthesia approaches contribute to safety in surgical procedures. Although it is believed that the method of local anesthesia has more benefits over general anesthesia, such as lowering the risk of postoperative neurological complications in a patient, the literature on the topic is inconclusive. The study aims to perform a comparative analysis of the two anesthesia methods using a prospective case-control design. Patients were divided into two groups: those who received local anesthesia (LA) (20 patients), and those who underwent general anesthesia (GA) (20 patients). As a result of the study, 40% of the patients experienced moderate pain and 5% of the patients experienced excruciating pain intraoperatively in the LA group. Although Visual Analog Scale and Oswestry Disability Index scores improved more rapidly in LA group, at the 12-month check-up point there was no significant difference between cases and controls. Nevertheless, there were postoperative complications such as nerve root injury in 10% of the patients; nausea, vomiting, dizziness, drowsiness in 15% of the patients in the GA group, and an insignificant or no such complications in patients of the LA group. The present study demonstrates that LA contributes to more positive short-term outcomes for patients as it facilitates nerve root damage prevention, and has no postoperative side effects on patients' well being.

A Comparison of the Assay Sensitivity of Average and Worst Pain Intensity in Pharmacologic Trials: An ACTTION Systematic Review and Meta-Analysis.

Identifying methods to improve assay sensitivity in randomized clinical trials (RCTs) may facilitate the discovery of efficacious pain treatments. RCTs evaluating pain treatments typically use average pain intensity (API) or worst pain intensity (WPI) as the primary efficacy outcome. However, little evidence is available comparing the assay sensitivity of these 2 measures. In this systematic review and meta-analysis, we comprehensively reviewed all low back pain, osteoarthritis pain, fibromyalgia, diabetic peripheral neuropathy pain, and postherpetic neuralgia RCTs that used a parallel group design. Eligibility required: 1) primary RCT report published between 1980 and 2016, 2) comparing 1 or more active, efficacious pharmacologic pain treatment(s) with placebo, and 3) providing data on the standardized effect size (SES) for API as well as WPI for all treatment arms. Twenty-seven active versus placebo comparisons were identified in 23 eligible articles. Using a random-effects meta-analysis, API SES and WPI SES did not differ significantly (difference = -.021, 95% confidence interval = -.047 to .004, P = .12). The findings indicate that, depending on the objectives of the study, either API or WPI could be used as a primary outcome measure in clinical trials for the chronic pain conditions included in this analysis. PERSPECTIVE: Understanding the comparative assay sensitivity of API and WPI may advance pain treatment research. A meta-analysis of trials of efficacious pharmacologic treatments in 5 pain conditions did not show a statistically significant difference between the assay sensitivity of API and WPI.

Functional magnetic resonance imaging in adult craniopagus for presurgical evaluation.

Cranially conjoined twins are rare and pose unique challenges in the preoperative evaluation of cerebral language function. The authors report on their experience in the functional magnetic resonance (fMR) imaging evaluation of adult craniopagus (temporoparietooccipital fusion) to evaluate hemispheric language dominance and the eloquent language areas in the preoperative planning stages. Conventional clinical imaging hardware originally designed for individuals was adapted and tailored for use in the twins. They were assigned a selection of language tasks while undergoing fMR imaging. Significant blood oxygen level-dependent activations were detected in the main language regions in each twin, that is, the inferior frontal gyrus (around the Broca area), the middle and superior temporal lobes (around the Wernicke area) together with the inferior parietal lobe, and the middle and superior frontal gyri. Overall, the right-handed twin was strongly left lateralized for language, whereas the left-handed twin showed more bilateral activation during language tasks. Noninvasive language mapping with the aid of fMR imaging has been demonstrated for the first time in total craniopagus.

Disruption of insulin signaling in Myf5-expressing progenitors leads to marked paucity of brown fat but normal muscle development.

Insulin exerts pleiotropic effects on cell growth, survival, and metabolism, and its role in multiple tissues has been dissected using conditional knockout mice; however, its role in development has not been studied. Lineage tracing experiments have demonstrated that interscapular brown adipose tissue (BAT) arises from a Myf5-positive lineage shared with skeletal muscle and distinct from the majority of white adipose tissue (WAT) precursors. In this study, we sought to investigate the effects of impaired insulin signaling in the Myf5-expressing precursor cells by deleting the insulin receptor gene. Mice lacking insulin receptor in the Myf5 lineage (Myf5IRKO) have a decrease of interscapular BAT mass; however, muscle development appeared normal. Histologically, the residual BAT had decreased cell size but appeared mature and potentially functional. Expression of adipogenic inhibitors preadipocyte factor-1, Necdin, and wingless-type MMTV integration site member 10a in the residual BAT tissue was nonetheless increased compared with controls, and there was an enrichment of progenitor cells with impaired adipogenic differentiation capacity, suggesting a suppression of adipogenesis in BAT. Surprisingly, when cold challenged, Myf5IRKO mice did not show impaired thermogenesis. This resistance to cold could be attributed to an increased presence of uncoupling protein 1-positive brown adipocytes in sc WAT as well as increased expression of lipolytic activity in BAT. These data suggest a critical role of insulin signaling in the development of interscapular BAT from Myf5-positive progenitor cells, but it appears to be dispensable for muscle development. They also underscore the importance of compensatory browning of sc WAT in the absence of BAT for thermoregulation.

Mucormycosis in a patient with AIDS receiving systemic steroids.

Mucormycosis is an opportunistic fungal infection with a high mortality rate. Although mucormycosis is relatively rare, recent studies suggest that the incidence is on the rise as a result of increased use of chemotherapy and steroids. The authors present an unusual case of invasive mucormycosis in a hospitalized patient with AIDS who was receiving short-term, high-dose steroids and who had associated steroid-induced diabetes. The patient was otherwise healthy, with no underlying risk factors such as neutropenia or intravenous drug use. The patient developed acute onset of proptosis, vision loss, and invasive Mucor in the left maxillary sinus that extended along the optic nerve intracranially. Despite aggressive treatment, the patient died. Physicians should be aware of steroid-induced diabetes as a risk factor for invasive fungal infections such as mucormycosis.

Acute abdominal pain secondary to chilaiditi syndrome.

Chilaiditi syndrome is a rare condition occurring in 0.025% to 0.28% of the population. In these patients, the colon is displaced and caught between the liver and the right hemidiaphragm. Patients' symptoms can range from asymptomatic to acute intermittent bowel obstruction. Diagnosis is best achieved with CT imaging. Identification of Chilaiditi syndrome is clinically significant as it can lead to many significant complications such as volvulus, perforation, and bowel obstruction. If the patient is symptomatic, treatment is usually conservative. Surgery is rarely indicated with indications including ischemia and failure of resolution with conservative management.

Difficulties in diagnosing an intermittent mesenteroaxial gastric volvulus.

Mesenteroaxial volvulus is a form of gastric volvulus that rotates around the short axis of the stomach. Mesenteroaxial volvulus typically presents secondary to an anatomical defect with symptoms that include epigastric pain, retching, dysphagia and early satiety. Our patient presented with episodic abdominal pain, nausea and vomiting for 2 years. Previous imaging was unremarkable but an esophagogastroduodenoscopy done when the patient most recently presented with abdominal pain revealed a mesenteroaxial volvulus. He underwent a laparoscopic gastrostomy-tube gastropexy and has not had any recurrence of his symptoms to date. This case illustrates the difficulties in diagnosing an intermittent volvulus as untimely imaging of a temporarily unfolded volvulus can delay diagnosis and treatment.

Valproate-induced Parkinsonism in epilepsy patients.

We systematically examined 226 epilepsy patients in a tertiary-referral center and found 6 (5.04%) to have valproate-induced Parkinsonism. There was a significantly higher prevalence of patients with Parkinsonism in the group of patients treated with valproate compared to those who were on other antiepileptic drugs (6 [5.04%] of 119 vs. 0 [0%] of 107; chi2 = 5.54; P = 0.025). These six patients had been on valproate for more than 3 years (mean, 75.67 +/- 25.32 months) at an average dose of 750 +/- 273.86 mg/day. The valproate doses were decreased or discontinued with supplementation from another antiepileptic medication. The mean UPDRS motor score significantly improved from 10.67 +/- 5.1 to 4.75 +/- 2.75 (P < 0.05). There was no relapse of seizures. Clinicians working in tertiary-referral centers should have a high index of suspicion for valproate-induced Parkinsonism. Early recognition and switching into another antiepileptic medication may help reduce unnecessary suffering in these patients.

Knowledge, attitudes, and perceptions of epilepsy in Asia: toward a uniform study protocol.

PURPOSE: Knowledge, attitudes, and perceptions of epilepsy (KAPE) among the public play a major role in determining the extent to which people with epilepsy can be integrated into their society. KAPE SURVEYS IN ASIA: Surveys conducted among Chinese in China, Taiwan, Malaysia, Singapore, and Hong Kong demonstrated similarities as well as differences in certain aspects of KAPE. These suggest that KAPE might not be uniform among other racial groups in the same or different regions of Asia. For KAPE to have usefulness to a country or community, it has to be location specific. TOWARD A UNIFORM STUDY PROTOCOL: There are several advantages of using a uniform study protocol. Collection of KAPE data could be faster for any country or community that chooses to use any existing study protocol. Intraregional, interregional, intercontinental, interethnic, intercommunity, and longitudinal comparison within any subgroup could be carried out. Sharing of common information would enhance the regional effort in improving the quality of life of people affected by epilepsy. However, survey methods need not be uniform. Regional adaptation and flexibility of a unified protocol should be encouraged. After the study, concerted local and regional efforts in epilepsy education must be carried out systematically for the general public as well as for strategic groups. CONCLUSIONS: Determination of the KAPE in different parts of Asia would help to define the magnitude of and be the first step toward alleviating social discrimination against people with epilepsy in Asia.

Severity of histopathologic abnormalities and in vivo epileptogenicity in the in utero radiation model of rats is dose dependent.

PURPOSE: Malformations of cortical development (MCDs) are a frequent cause of refractory epilepsy in humans. The in utero radiation model in rats shares many clinical and histopathologic characteristics with human MCDs. Previous studies reported the presence of clinical seizures in radiated rats, but also suggested a dose-dependent differential effect. METHODS: Time-pregnant Sprague-Dawley rats were irradiated on embryonic day E17 with 100 cGy (low dose), 145 cGy (medium dose), 175 cGy (high dose), or were left untreated. Their adult litters were implanted with bifrontal epidural and hippocampal depth electrodes and underwent long-term video-EEG monitoring. After 2 weeks of monitoring, the animals were killed and their brains processed for histological studies. RESULTS: Spikes were most frequently found in the rats that were subjected to low- and medium-dose radiation at E17 and were less frequently seen in the animals that were subjected to high-dose radiation. No interictal spikes were found in any of the control animals. Seizures were recorded in three of five animals of the medium-dose group. Histological studies showed a dose-dependent decrease in cortical thickness as well as an increase of cortical and hippocampal disorganization. CONCLUSIONS: In vivo epileptogenicity in radiated animals was present only in mild or moderate MCD. No in vivo epileptogenicity was seen in severe radiation-induced MCD.

Benign focal epileptiform discharges of childhood and hippocampal sclerosis.

PURPOSE: Benign focal epileptiform discharges of childhood (BFEDCs) are common EEG findings between ages 4 and 14 years. This epoch of maturational development overlaps with the age at presentation of temporal lobe epilepsy (TLE) due to hippocampal sclerosis (HS) in children. METHODS: From our series of 17 preadolescent children who eventually underwent anteromesial temporal resection for medically refractory TLE due to HS, we identified two children, plus one thereafter, who were initially dismissed as candidates for epilepsy surgery because of abundant extratemporal sharp waves, which were bilateral in two cases. The sharp waves had the distinctive morphology, distribution, and sleep activation suggestive of BFEDCs, but the medical intractability and seizure symptoms were unusual for benign focal epilepsy of childhood. RESULTS: In each case, surgical candidacy was clarified when magnetic resonance imaging (MRI) showed unilateral HS and video-EEG demonstrated seizure onset in the ipsilateral anteromesial temporal region. The postoperative freedom from seizures in each case (follow-up, 2 to 4 years) confirmed that HS was the primary epileptogenic process, and that the BFEDCs were incidental or an atypical secondary manifestation. CONCLUSIONS: These cases illustrate the need for more extensive study of children with BFEDCs when medical intractability and seizure symptoms speak against a simple diagnosis of benign focal epilepsy of childhood. In addition, we observed that the BFEDCs in two of our children had an unusual bilateral occipitofrontal distribution, and we speculate that the coexistence of the BFEDCs in children with HS may not be an incidental finding.