The risk of Plasmodium vivax parasitaemia after P. falciparum malaria: An individual patient data meta-analysis from the WorldWide Antimalarial Resistance Network.

BACKGROUND: There is a high risk of Plasmodium vivax parasitaemia following treatment of falciparum malaria. Our study aimed to quantify this risk and the associated determinants using an individual patient data meta-analysis in order to identify populations in which a policy of universal radical cure, combining artemisinin-based combination therapy (ACT) with a hypnozoitocidal antimalarial drug, would be beneficial. METHODS AND FINDINGS: A systematic review of Medline, Embase, Web of Science, and the Cochrane Database of Systematic Reviews identified efficacy studies of uncomplicated falciparum malaria treated with ACT that were undertaken in regions coendemic for P. vivax between 1 January 1960 and 5 January 2018. Data from eligible studies were pooled using standardised methodology. The risk of P. vivax parasitaemia at days 42 and 63 and associated risk factors were investigated by multivariable Cox regression analyses. Study quality was assessed using a tool developed by the Joanna Briggs Institute. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42018097400). In total, 42 studies enrolling 15,341 patients were included in the analysis, including 30 randomised controlled trials and 12 cohort studies. Overall, 14,146 (92.2%) patients had P. falciparum monoinfection and 1,195 (7.8%) mixed infection with P. falciparum and P. vivax. The median age was 17.0 years (interquartile range [IQR] = 9.0-29.0 years; range = 0-80 years), with 1,584 (10.3%) patients younger than 5 years. 2,711 (17.7%) patients were treated with artemether-lumefantrine (AL, 13 studies), 651 (4.2%) with artesunate-amodiaquine (AA, 6 studies), 7,340 (47.8%) with artesunate-mefloquine (AM, 25 studies), and 4,639 (30.2%) with dihydroartemisinin-piperaquine (DP, 16 studies). 14,537 patients (94.8%) were enrolled from the Asia-Pacific region, 684 (4.5%) from the Americas, and 120 (0.8%) from Africa. At day 42, the cumulative risk of vivax parasitaemia following treatment of P. falciparum was 31.1% (95% CI 28.9-33.4) after AL, 14.1% (95% CI 10.8-18.3) after AA, 7.4% (95% CI 6.7-8.1) after AM, and 4.5% (95% CI 3.9-5.3) after DP. By day 63, the risks had risen to 39.9% (95% CI 36.6-43.3), 42.4% (95% CI 34.7-51.2), 22.8% (95% CI 21.2-24.4), and 12.8% (95% CI 11.4-14.5), respectively. In multivariable analyses, the highest rate of P. vivax parasitaemia over 42 days of follow-up was in patients residing in areas of short relapse periodicity (adjusted hazard ratio [AHR] = 6.2, 95% CI 2.0-19.5; p = 0.002); patients treated with AL (AHR = 6.2, 95% CI 4.6-8.5; p < 0.001), AA (AHR = 2.3, 95% CI 1.4-3.7; p = 0.001), or AM (AHR = 1.4, 95% CI 1.0-1.9; p = 0.028) compared with DP; and patients who did not clear their initial parasitaemia within 2 days (AHR = 1.8, 95% CI 1.4-2.3; p < 0.001). The analysis was limited by heterogeneity between study populations and lack of data from very low transmission settings. Study quality was high. CONCLUSIONS: In this meta-analysis, we found a high risk of P. vivax parasitaemia after treatment of P. falciparum malaria that varied significantly between studies. These P. vivax infections are likely attributable to relapses that could be prevented with radical cure including a hypnozoitocidal agent; however, the benefits of such a novel strategy will vary considerably between geographical areas.

An optimal control approach for blood pressure regulation during head-up tilt.

This paper presents an optimal control approach to modeling effects of cardiovascular regulation during head-up tilt (HUT). Many patients who suffer from dizziness or light-headedness are administered a head-up tilt test to explore potential deficits within the autonomic control system, which maintains the cardiovascular system at homeostasis. This system is complex and difficult to study in vivo, and thus we propose to use mathematical modeling to achieve a better understanding of cardiovascular regulation during HUT. In particular, we show the feasibility of using optimal control theory to compute physiological control variables, vascular resistance and cardiac contractility, quantities that cannot be measured directly, but which are useful to assess the state of the cardiovascular system. A non-pulsatile lumped parameter model together with pseudo- and clinical data are utilized in the optimal control problem formulation. Results show that the optimal control approach can predict time-varying quantities regulated by the cardiovascular control system. Our results compare favorable to our previous study using a piecewise linear spline approach, less a priori knowledge is needed, and results were obtained at a significantly lower computational cost.

Cardiovascular dynamics during head-up tilt assessed via pulsatile and non-pulsatile models.

This study develops non-pulsatile and pulsatile models for the prediction of blood flow and pressure during head-up tilt. This test is used to diagnose potential pathologies within the autonomic control system, which acts to keep the cardiovascular system at homeostasis. We show that mathematical modeling can be used to predict changes in cardiac contractility, vascular resistance, and arterial compliance, quantities that cannot be measured but are useful to assess the system's state. These quantities are predicted as time-varying parameters modeled using piecewise linear splines. Having models with various levels of complexity formulated with a common set of parameters, allows us to combine long-term non-pulsatile simulations with pulsatile simulations on a shorter time-scale. We illustrate results for a representative subject tilted head-up from a supine position to a [Formula: see text] angle. The tilt is maintained for 5 min before the subject is tilted back down. Results show that if volume data is available for all vascular compartments three parameters can be identified, cardiovascular resistance, vascular compliance, and ventricular contractility, whereas if model predictions are made against arterial pressure and cardiac output data alone, only two parameters can be estimated either resistance and contractility or resistance and compliance.

A physiologically based pharmacokinetic model of vitamin D.

Despite the plethora of studies discussing the benefits of vitamin D on physiological functioning, few mathematical models of vitamin D predict the response of the body on low-concentration supplementation of vitamin D under sunlight-restricted conditions. This study developed a physiologically based pharmacokinetic (PBPK) model utilizing published human data on the metabolic cascade of orally derived, low-concentration (placebo, 5 µg and 10 µg) supplementation of vitamin D over the course of 28 days in the absence of sunlight. Vitamin D and its metabolites are highly lipophilic and binding assays of these compounds in serum may not account for binding by lipids and additional proteins. To compensate for the additional bound amounts, this study allowed the effective adipose-plasma partition coefficient to vary dynamically with the concentration of each compound in serum utilizing the Hill equation for binding. Through incorporating the optimized parameters with the adipose partition coefficient adaptation to the PBPK model, this study was able to fit serum concentration data for circulating vitamin D at all three supplementation concentrations within confidence intervals of the data. Copyright © 2017 John Wiley & Sons, Ltd.

Synthesis of iron oxyhydroxide-coated rice straw (IOC-RS) and its application in arsenic(V) removal from water.

Because of the recognition that arsenic (As) at low concentrations in drinking water causes severe health effects, the technologies of As removal have become increasingly important. In this study, a simplified and effective method was used to immobilize iron oxyhydroxide onto a pretreated naturally occurring rice straw (RS). The modified RS adsorbent was characterized, using scanning electron microscope, Fourier transform infrared spectroscopy, thermogravimetric analyzer, and surface area analyzer. Experimental batch data of As(V) adsorption were modeled by the isotherms and kinetics models. Although all isotherms, the Langmuir model fitted the equilibrium data better than Freundlich and Dubinin-Radushkevich models and confirmed the surface homogeneity of adsorbent. The iron oxyhydroxide-coated rice straw (IOC-RS) was found to be effective for the removal of As(V) with 98.5% sorption efficiency at a concentration of <50 mg/L of As(V) solution, and thus maximum uptake capacity is ∼22 and 20 mg As(V)/g of IOC-RS at pH 4 and 6, respectively. The present study might provide new avenues to achieve the As concentrations required for drinking water recommended by the World Health Organization.

Multiple Complicated Concurrent Hernias in a Single Patient: A Case Report.

Multiple complicated concurrent hernias with obturator hernia and paraesophageal hernia unusually occur in clinical settings. The obturator hernias belong to a rare pelvic hernia that accounts for a minority of all abdominal hernias. Besides, paraesophageal hernias occur commonly in elderly female patients. Clinical manifestations of these hernias are usually unspecific and the diagnosis is based on computed tomography (CT). In this paper, we presented a case of multiple complicated hernias in an 81-year-old woman. She was admitted to our hospital due to intestinal obstruction that was caused by a simultaneous obturator and paraesophageal hernia. She was successfully treated by laparoscopic hernia repair. Postoperative progression was favorable. She was then discharged from the hospital after four hospital days.

Assessment of Health-Related Quality of Life in Patients with Chronic Heart Failure: A Cross-Sectional Study in Vietnam.

Introduction Heart failure is currently a global health issue, imposing a burden on disease prevalence and mortality rates for patients, while simultaneously impacting the quality of life for affected individuals. Data on assessing the health-related quality of life (HRQoL) of patients with chronic heart failure in developing countries, including Vietnam, is still limited. This study was conducted with the aim of describing the quality of life of patients with chronic heart failure in Vietnam. Methods This cross-sectional investigation enrolled 140 chronic heart failure outpatients, utilizing a convenience sample at Hai Duong Province Hospital, Vietnam, spanning from December 2021 to April 2022. Essential patient variables encompassing age, gender, and heart failure duration were gathered. Surveying of patients took place at the outpatient clinic during chronic heart failure follow-up visits using the 36-Item Short Form Health Survey (SF-36) questionnaire. The SF-36 comprises eight dimensions: (1) Physical functioning, (2) Role limitations due to physical health, (3) Bodily pain, (4) General health perceptions, (5) Vitality, (6) Social role functioning, (7) Role limitations due to emotional health, and (8) Mental health. Component analysis of the SF-36 revealed two distinct concepts: a physical component summary (PCS) reflecting the physical aspect and a mental component summary (MCS) reflecting the mental aspect. Results The research involved 140 participants diagnosed with chronic heart failure, having a median age of 59 years (interquartile range (IQR): 52-63). Among them, 61.4% were male, and 50% exhibited reduced left ventricular ejection fraction (LVEF) (≤ 40%). The role limitations due to the physical health domain indicated the lowest score, registering a median value of 0 (IQR 0-25). Domains with median scores below the 25-point threshold encompassed role limitations due to physical health (0 points). Those with scores ranging from 25 to 49 points constituted general health perceptions (25 points), role limitations due to emotional health (33.3 points), vitality (45 points), and mental health (48 points). Bodily pain and social role functioning achieved median scores at a moderate level (50-74 points), scoring 62 and 62.5 points, respectively. The overall HRQoL score on the SF-36 scale was 45.2 (IQR: 32.1-58.7) points. Median scores for the PCS and MCS were 44.3 (IQR: 30.5-52) and 47.0 (IQR: 32.6-65.4), respectively. No statistically significant differences in PCS and MCS scores were observed when subgroup analysis was performed based on variables like age, gender, or LVEF. However, in the vitality domain, female patients exhibited a significantly lower median score than male patients (p-value = 0.046). In the physical functioning domain, individuals aged ≥ 60 had lower median scores than those aged < 60 years (p = 0.022). Additionally, the group with LVEF ≤ 40% had lower median scores compared to the group with LVEF > 40% (p = 0.038) in role limitations due to emotional health domain. Conclusion In Vietnam, the HRQoL in the outpatient population with chronic heart failure was notably low when assessed using the SF-36 questionnaire. Large-scale, multicenter studies are needed to provide stronger, more conclusive evidence.

Controlled cortical impact traumatic brain injury in 3xTg-AD mice causes acute intra-axonal amyloid-ß accumulation and independently accelerates the development of tau abnormalities.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized pathologically by progressive neuronal loss, extracellular plaques containing the amyloid-ß (Aß) peptides, and neurofibrillary tangles composed of hyperphosphorylated tau proteins. Aß is thought to act upstream of tau, affecting its phosphorylation and therefore aggregation state. One of the major risk factors for AD is traumatic brain injury (TBI). Acute intra-axonal Aß and diffuse extracellular plaques occur in ∼30% of human subjects after severe TBI. Intra-axonal accumulations of tau but not tangle-like pathologies have also been found in these patients. Whether and how these acute accumulations contribute to subsequent AD development is not known, and the interaction between Aß and tau in the setting of TBI has not been investigated. Here, we report that controlled cortical impact TBI in 3xTg-AD mice resulted in intra-axonal Aß accumulations and increased phospho-tau immunoreactivity at 24 h and up to 7 d after TBI. Given these findings, we investigated the relationship between Aß and tau pathologies after trauma in this model by systemic treatment of Compound E to inhibit γ-secretase activity, a proteolytic process required for Aß production. Compound E treatment successfully blocked posttraumatic Aß accumulation in these injured mice at both time points. However, tau pathology was not affected. Our data support a causal role for TBI in acceleration of AD-related pathologies and suggest that TBI may independently affect Aß and tau abnormalities. Future studies will be required to assess the behavioral and long-term neurodegenerative consequences of these pathologies.

Single treatment of non-melanoma skin cancers using a pulsed-dye laser with stacked pulses.

BACKGROUND AND OBJECTIVE: Non-melanoma skin cancers are the most common cause of cancer worldwide. Within this grouping, the most common skin cancer is basal cell carcinoma (BCC) followed by squamous cell carcinoma (SCC). Recent evidence has shown that BCCs can be cleared by a pulsed-dye laser after multiple treatments using a single pass setting. Given the necessity for multiple treatments in the prior studies, we sought to determine whether tumor clearance could instead be achieved using a single treatment of the pulsed-dye laser in a stacked pulse setting. STUDY DESIGN/MATERIALS AND METHODS: Twenty patients with 23 biopsy-proven BCCs and SCCIS that measured 0.4-3 cm in size and located on the trunk and extremities were recruited for this study. The lesions were randomized into three study arms: a control group (no treatment), first treatment group (S1), and second treatment group (S2). The S1 group was treated using a 595 nM pulsed-dye laser (PDL) at pulse energy of 15 J/cm(2), 3-millisecond pulse length, with no dynamic cooling, using a 7-mm spot size with 10% overlap of pulses and two passes. The S2 group was treated using the same 595 nM PDL at 7.5 J/cm(2), 3-millisecond pulse length, with no dynamic cooling, using a 10-mm spot size with 10% overlap of pulses and double stacked pulses. All the treated lesions were treated with a 4 mm margin of clinically normal skin. The lesions were subsequently surgically excised and examined by histopathology. RESULTS: There was no significant difference in the dimensions of the tumors between the three study arms, with a mean area of 94 mm(2) [SEM ± 15.2] for the control group, 88 mm(2) [SEM ± 12.1] for the S1 treatment group, and 105 mm(2) [SEM ± 23.6] for the S2 treatment group. In the control group, there were two out seven lesions with no residual tumors, representing a background tumor clearance rate of approximately 28%. The S1 treatment group had two out of eight lesions with no residual lesion representing a clearance rate of 25%, similar to the background clearance rate. The S2 treatment group had a clearance rate of five out seven lesions, representing a clearance rate of 71%. The two lesions with residual tumors were noted to be beyond the central treatment zone by histopathology and if excluded, results in a clearance rate of 100%. By the Fisher's exact test with a Bonferroni correction, there is a trend towards significance between the S2 treatment group and the control group with a P-value of 0.028. CONCLUSIONS: The results of our pilot study suggest that BCCs and SCCIS can be cleared in a single treatment using a pulsed-laser in a stacked pulse setting. However, given the small sample size of this pilot study, further larger scale studies will be needed to determine statistical significance and long-term recurrence rate and to further validate these findings.

Comparison of two dengue NS1 rapid tests for sensitivity, specificity and relationship to viraemia and antibody responses.

BACKGROUND: Dengue is a major public health problem in tropical and subtropical countries. Rapid and easy diagnosis of dengue can assist patient triage and care-management. The detection of DENV NS1 on rapid lateral flow tests offers a fast route to a presumptive dengue diagnosis but careful evaluations are urgently needed as more and more people use them. METHODS: The sensitivity and specificity of the Bio-Rad NS1 Ag Strip and SD Dengue Duo (NS1/IgM/IgG) lateral flow rapid tests were evaluated in a panel of plasma samples from 245 Vietnamese patients with RT-PCR confirmed dengue and 47 with other febrile illnesses. RESULTS: The NS1 rapid tests had similar diagnostic sensitivities (respectively 61.6% and 62.4%) in confirmed dengue cases but were 100% specific. When IgM/IgG results from the SD Dengue Duo were included in the test interpretation, the sensitivity improved significantly from 62.4% with NS1 alone to 75.5% when NS1 and/or IgM was positive and 83.7% when NS1 and/or IgM and/or IgG was positive. Both NS1 assays were significantly more sensitive for primary than secondary dengue. NS1 positivity was associated with the underlying viraemia as NS1-positive samples had a significantly higher viraemia than NS1-negative samples. CONCLUSIONS: These data suggest that the NS1 test component of these assays are highly specific and have similar levels of sensitivity. The IgM parameter in the SD Duo test improved overall test sensitivity without compromising specificity. The SD Dengue Duo lateral flow rapid test deserves further prospective evaluation in dengue endemic settings.

A multicompartment liver-based pharmacokinetic model for benzene and its metabolites in mice.

Benzene is a highly flammable, colorless liquid. Ubiquitous exposures result from its presence in gasoline vapors, cigarette smoke, and industrial processes. After uptake into the body, benzene undergoes a series of metabolic transformations to multiple metabolites that exert toxic effects on the bone marrow. We developed a physiologically based pharmacokinetic model for the uptake and elimination of benzene in mice to relate the concentration of inhaled and orally administered benzene to the tissue doses of benzene and its key metabolites. This model takes into account the zonal distribution of enzymes and metabolism in the liver rather than treating the liver as one homogeneous compartment, and considers metabolism in tissues other than the liver. Analysis was done to examine the existence and uniqueness of solutions of the system. We then formulated an inverse problem to obtain estimates for the unknown parameters; data from multiple laboratories and experiments were used. Despite the sources of variability, the model simulations matched the data reasonably well in most cases. Our study shows that the multicompartment metabolism model does improve predictions over the previous model (Cole et al. in J. Toxicol. Environ. Health, 439-465, 2001) and that in vitro metabolic constants can be successfully extrapolated to predict in vivo data for benzene metabolism and dosimetry.

Amalgam tattoo.

A 53-year-old woman with a history of melanoma status-post excision two years prior presented with a 4-month history of 4, dark-brown macules on the inferior surface of her tongue. A biopsy specimen showed a squamous mucosa with chronic submucosal inflammation and brown pigment. The clinical and histopathologic findings were consistent with a diagnosis of amalgam tattoo. Amalgam tattoos are common, oral pigmented lesions that clinically present as isolated, blue, grey, or black macules on the gingivae, the buccal and alveolar mucosae, the palate, and/or the tongue. They are due to deposition of a mixture of silver, tin, mercury, copper, and zinc, which are components of an amalgam filling, into the oral soft tissues. Amalgam tattoos can either be treated surgically or with a Q-switched ruby laser. In the case of our patient with the history of melanoma, her oral lesions proved not to be the more dire diagnosis of malignant melanoma.

Cutaneous umbilical endometriosis.

A 35-year-old woman presented with a four-month history of a tender umbilical nodule that bleeds during her menstrual period. Physical examination showed a hyperpigmented umbilical nodule. A biopsy specimen showed fibrotic dermis with increased numbers of blood vessels and scattered glandular structures with areas of hemosiderin deposition consistent with a diagnosis of endometriosis. Cutaneous umbilical endometriosis is rare, with an estimated incidence of 0.5 to 1.0 percent. Although anti-gonadotropin medications, such as danazol, have been used for symptomatic control, but surgical excision is the treatment of choice owing to the possibility of malignant degeneration of cutaneous endometriosis.

The effect of chloroquine dose and primaquine on Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient pooled meta-analysis.

BACKGROUND: Chloroquine remains the mainstay of treatment for Plasmodium vivax malaria despite increasing reports of treatment failure. We did a systematic review and meta-analysis to investigate the effect of chloroquine dose and the addition of primaquine on the risk of recurrent vivax malaria across different settings. METHODS: A systematic review done in MEDLINE, Web of Science, Embase, and Cochrane Database of Systematic Reviews identified P vivax clinical trials published between Jan 1, 2000, and March 22, 2017. Principal investigators were invited to share individual patient data, which were pooled using standardised methods. Cox regression analyses with random effects for study site were used to investigate the roles of chloroquine dose and primaquine use on rate of recurrence between day 7 and day 42 (primary outcome). The review protocol is registered in PROSPERO, number CRD42016053310. FINDINGS: Of 134 identified chloroquine studies, 37 studies (from 17 countries) and 5240 patients were included. 2990 patients were treated with chloroquine alone, of whom 1041 (34·8%) received a dose below the target 25 mg/kg. The risk of recurrence was 32·4% (95% CI 29·8-35·1) by day 42. After controlling for confounders, a 5 mg/kg higher chloroquine dose reduced the rate of recurrence overall (adjusted hazard ratio [AHR] 0·82, 95% CI 0·69-0·97; p=0·021) and in children younger than 5 years (0·59, 0·41-0·86; p=0·0058). Adding primaquine reduced the risk of recurrence to 4·9% (95% CI 3·1-7·7) by day 42, which is lower than with chloroquine alone (AHR 0·10, 0·05-0·17; p<0·0001). INTERPRETATION: Chloroquine is commonly under-dosed in the treatment of vivax malaria. Increasing the recommended dose to 30 mg/kg in children younger than 5 years could reduce substantially the risk of early recurrence when primaquine is not given. Radical cure with primaquine was highly effective in preventing early recurrence and may also improve blood schizontocidal efficacy against chloroquine-resistant P vivax. FUNDING: Wellcome Trust, Australian National Health and Medical Research Council, and Bill & Melinda Gates Foundation.

Blood pressure and blood flow variation during postural change from sitting to standing: model development and validation.

Short-term cardiovascular responses to postural change from sitting to standing involve complex interactions between the autonomic nervous system, which regulates blood pressure, and cerebral autoregulation, which maintains cerebral perfusion. We present a mathematical model that can predict dynamic changes in beat-to-beat arterial blood pressure and middle cerebral artery blood flow velocity during postural change from sitting to standing. Our cardiovascular model utilizes 11 compartments to describe blood pressure, blood flow, compliance, and resistance in the heart and systemic circulation. To include dynamics due to the pulsatile nature of blood pressure and blood flow, resistances in the large systemic arteries are modeled using nonlinear functions of pressure. A physiologically based submodel is used to describe effects of gravity on venous blood pooling during postural change. Two types of control mechanisms are included: 1) autonomic regulation mediated by sympathetic and parasympathetic responses, which affect heart rate, cardiac contractility, resistance, and compliance, and 2) autoregulation mediated by responses to local changes in myogenic tone, metabolic demand, and CO(2) concentration, which affect cerebrovascular resistance. Finally, we formulate an inverse least-squares problem to estimate parameters and demonstrate that our mathematical model is in agreement with physiological data from a young subject during postural change from sitting to standing.

Α-synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration.

Accumulation of misfolded alpha-synuclein (α-syn) into Lewy bodies (LBs) and Lewy neurites (LNs) is a major hallmark of Parkinson's disease (PD) and dementia with LBs (DLB). Recent studies showed that synthetic preformed fibrils (pffs) recruit endogenous α-syn and induce LB/LN pathology in vitro and in vivo, thereby implicating propagation and cell-to-cell transmission of pathological α-syn as mechanisms for the progressive spread of LBs/LNs. Here, we demonstrate that α-syn monoclonal antibodies (mAbs) reduce α-syn pff-induced LB/LN formation and rescue synapse/neuron loss in primary neuronal cultures by preventing both pff uptake and subsequent cell-to-cell transmission of pathology. Moreover, intraperitoneal (i.p.) administration of mAb specific for misfolded α-syn into nontransgenic mice injected intrastriatally with α-syn pffs reduces LB/LN pathology, ameliorates substantia nigra dopaminergic neuron loss, and improves motor impairments. We conclude that α-syn antibodies could exert therapeutic effects in PD/DLB by blocking entry of pathological α-syn and/or its propagation in neurons.

Nrf2 regulates haematopoietic stem cell function.

Coordinating the balance between haematopoietic stem cell (HSC) quiescence and self-renewal is crucial for maintaining haematopoiesis lifelong. Equally important for haematopoietic function is modulating HSC localization within the bone marrow niches, as maintenance of HSC function is tightly controlled by a complex network of intrinsic molecular mechanisms and extrinsic signalling interactions with their surrounding microenvironment. In this study we demonstrate that nuclear factor erythroid 2-related factor 2 (Nfe2l2, or Nrf2), well established as a global regulator of the oxidative stress response, plays a regulatory role in several aspects of HSC homeostasis. Nrf2 deficiency results in an expansion of the haematopoietic stem and progenitor cell compartment due to cell-intrinsic hyperproliferation, which was accomplished at the expense of HSC quiescence and self-renewal. We further show that Nrf2 modulates both migration and retention of HSCs in their niche. Moreover, we identify a previously unrecognized link between Nrf2 and CXCR4, contributing, at least partially, to the maintenance of HSC function.

Adverse events associated with mohs micrographic surgery: multicenter prospective cohort study of 20,821 cases at 23 centers.

IMPORTANCE: Detailed information regarding perioperative risk and adverse events associated with Mohs micrographic surgery (MMS) can guide clinical management. Much of the data regarding complications of MMS are anecdotal or report findings from single centers or single events. OBJECTIVES: To quantify adverse events associated with MMS and detect differences relevant to safety. DESIGN, SETTING, AND PARTICIPANTS: Multicenter prospective inception cohort study of 21 private and 2 institutional US ambulatory referral centers for MMS. Participants were a consecutive sample of patients presenting with MMS for 35 weeks at each center, with staggered start times. EXPOSURE: Mohs micrographic surgery. MAIN OUTCOMES AND MEASURES Intraoperative and postoperative minor and serious adverse events. RESULTS: Among 20 821 MMS procedures, 149 adverse events (0.72%), including 4 serious events (0.02%), and no deaths were reported. Common adverse events reported were infections (61.1%), dehiscence and partial or full necrosis (20.1%), and bleeding and hematoma (15.4%). Most bleeding and wound-healing complications occurred in patients receiving anticoagulation therapy. Use of some antiseptics and antibiotics and sterile gloves during MMS were associated with modest reduction of risk for adverse events. CONCLUSIONS AND RELEVANCE: Mohs micrographic surgery is safe, with a very low rate of adverse events, an exceedingly low rate of serious adverse events, and an undetectable mortality rate. Common complications include infections, followed by impaired wound healing and bleeding. Bleeding and wound-healing issues are often associated with preexisting anticoagulation therapy, which is nonetheless managed safely during MMS. We are not certain whether the small effects seen with the use of sterile gloves and antiseptics and antibiotics are clinically significant and whether wide-scale practice changes would be cost-effective given the small risk reductions.

Inhibition of JNK by a peptide inhibitor reduces traumatic brain injury-induced tauopathy in transgenic mice.

Traumatic brain injury (TBI) is a major environmental risk factor for subsequent development of Alzheimer disease (AD). Pathological features that are common to AD and many tauopathies are neurofibrillary tangles (NFTs) and neuropil threads composed of hyperphosphorylated tau. Axonal accumulations of total and phospho-tau have been observed within hours to weeks, and intracytoplasmic NFTs have been documented years after severe TBI in humans. We previously reported that controlled cortical impact TBI accelerated tau pathology in young 3xTg-AD mice. Here, we used this TBI mouse model to investigate mechanisms responsible for increased tau phosphorylation and accumulation after brain trauma. We found that TBI resulted in abnormal axonal accumulation of several kinases that phosphorylate tau. Notably, c-Jun N-terminal kinase (JNK) was markedly activated in injured axons and colocalized with phospho-tau. We found that moderate reduction of JNK activity (40%) by a peptide inhibitor, D-JNKi1, was sufficient to reduce total and phospho-tau accumulations in axons of these mice with TBI. Longer-term studies will be required to determine whether reducing acute tau pathology proves beneficial in brain trauma.

Distinct temporal and anatomical distributions of amyloid-ß and tau abnormalities following controlled cortical impact in transgenic mice.

Traumatic brain injury (TBI) is a major environmental risk factor for Alzheimer's disease. Intracellular accumulations of amyloid-ß and tau proteins have been observed within hours following severe TBI in humans. Similar abnormalities have been recapitulated in young 3xTg-AD mice subjected to the controlled cortical impact model (CCI) of TBI and sacrificed at 24 h and 7 days post injury. This study investigated the temporal and anatomical distributions of amyloid-ß and tau abnormalities from 1 h to 24 h post injury in the same model. Intra-axonal amyloid-ß accumulation in the fimbria was detected as early as 1 hour and increased monotonically over 24 hours following injury. Tau immunoreactivity in the fimbria and amygdala had a biphasic time course with peaks at 1 hour and 24 hours, while tau immunoreactivity in the contralateral CA1 rose in a delayed fashion starting at 12 hours after injury. Furthermore, rapid intra-axonal amyloid-ß accumulation was similarly observed post controlled cortical injury in APP/PS1 mice, another transgenic Alzheimer's disease mouse model. Acute increases in total and phospho-tau immunoreactivity were also evident in single transgenic Tau(P301L) mice subjected to controlled cortical injury. These data provide further evidence for the causal effects of moderately severe contusional TBI on acceleration of acute Alzheimer-related abnormalities and the independent relationship between amyloid-ß and tau in this setting.