Transient Lowering Research Articles

Large variation in carbon dioxide emissions from tropical peat swamp forests due to disturbances

The huge carbon stock of tropical peat swamp forest (PSF) in Southeast Asia has been threatened by environmental disturbances due to quasi-periodic El Niño-Southern Oscillation (ENSO) droughts, biomass and peat burning, smoke haze, drainage, and deforestation. Carbon dioxide (CO2) emissions from such disturbances have not been well quantified because of insufficient field data. Therefore, we quantified the ecosystem-scale CO2 balance and examine the disturbance effects from a long-term field experiment for 12–15 years at three PSF sites with different degrees of degradation in Indonesia. Here, we show a drastic change of an undrained PSF from a CO2 sink to a source owing to the transient groundwater lowering by the droughts, a significant decrease in ecosystem photosynthesis due to the radiation attenuation by smoke haze in drought years, and long-lasting CO2 emissions through enhanced peat decomposition by drainage. The impact on CO2 emissions was greater from drainage than drought-induced disturbances.

Pineal Abnormalities in Psychosis and Mood Disorders: A Systematic Review.

The pineal gland (PG) is a small interhemispheric brain structure that influences human physiology in many ways, most importantly via secretion of the hormone melatonin which is known to regulate sleep and wakefulness. Here, we systematically reviewed existing neuroimaging studies of PG structure, and/or melatonin release (MLT) in psychosis and mood disorders. Medline, PubMed, and Web of Science databases were searched (on 3 February 2023), yielding 36 studies (8 PG volume, 24 MLT). The findings showed smaller-than-normal PG volume in people with schizophrenia, regardless of symptom severity and illness stage; and smaller-than-normal PG volume in major depression, with some indication of this being present only in certain subgroups, or in those with high scores on the 'loss of interest' symptom. There was considerable evidence of lower-than-normal MLT as well as aberrant MLT secretion pattern in schizophrenia. A similar picture, though less consistent than that seen in schizophrenia, emerged in major depression and bipolar disorder, with some evidence of a transient lowering of MLT following the initiation of certain antidepressants in drug-withdrawn patients. Overall, PG and MLT aberrations appear to represent transdiagnostic biomarkers for psychosis and mood disorders, but further work is needed to establish their clinical correlates and treatment implications.

Early tension regulation coupled to surface myomerger is necessary for the primary fusion of C2C12 myoblasts

Here, we study the time-dependent regulation of fluctuation–tension during myogenesis and the role of the fusogen, myomerger. We measure nanometric height fluctuations of the basal membrane of C2C12 cells after triggering differentiation. Fusion of cells increases fluctuation–tension but prefers a transient lowering of tension (at ~2–24 h). Cells fail to fuse if early tension is continuously enhanced by methyl-β-cyclodextrin (MβCD). Perturbing tension regulation also reduces fusion. During this pre-fusion window, cells that finally differentiate usually display lower tension than other non-fusing cells, validating early tension states to be linked to fate decision. Early tension reduction is accompanied by low but gradually increasing level of the surface myomerger. Locally too, regions with higher myomerger intensity display lower tension. However, this negative correlation is lost in the early phase by MβCD-based cholesterol depletion or later as differentiation progresses. We find that with tension and surface-myomerger’s enrichment under these conditions, myomerger clusters become pronouncedly diffused. We, therefore, propose that low tension aided by clustered surface-myomerger at the early phase is crucial for fusion and can be disrupted by cholesterol-reducing molecules, implying the potential to affect muscle health.

Transient and relict landforms in a lithologically heterogeneous post-orogenic landscape in the intertropical belt (Alto Paranaíba region, Brazil)

High elevations and steep slopes are currently observed in ancient mountain ranges despite active tectonics having ceased tens to hundreds of millions of years ago. Explanations for landscape dynamics in these settings generally postulate that post-orogenic relief is either the product of a recent topographic rejuvenation episode (or episodes) or was formed by ancient orogenesis after which the landscape has survived ever since, perhaps in a topographic equilibrium condition where erosion is spatially uniform. Here, we explore the morphology of a tropical wet and dry, high relief post-orogenic landscape in the Brazilian continental interior capped by ferruginous duricrusts and characterised by stark lithological variability. We explore whether a decline in relief has remained constant or increased during its post-orogenic evolution. We show that river knickpoints demarcate regional topographic transitions between 1) flat, relict uplands, 2) a rugged transition zone where channels and adjacent hillslopes are steep, and 3) gentle lowland morphologies in downstream areas. Relict areas are primarily capped by ferruginous duricrusts that are likely Eocene, as suggested by weathering geochronology in surrounding areas. Topography in the study area records at least two regional, transient topographic disequilibrium events, where the oldest drop in relative base level is expressed by knickpoints lying in high elevations fixed within ferruginous duricrusts that slow the propagation of the transient base level lowering signal. This transience is consistent with regional uplift events, likely driven by denudational isostatic rebound or compressional far-field stresses, with local effects superimposed linked with the strike-slip reactivation of old faults and the formation of the Pratinha Pull-Apart Basin. Relief is growing as the topography is slowly decaying, yet the topographic configuration of the area was established before these disequilibrium events. Our study demonstrates that ancient and younger landforms coexist in a post-orogenic setting, implying that the competing hypotheses for post-orogenic development are not mutually exclusive.

Post-hoc analysis of pegloticase pivotal trials in chronic refractory gout: relationship between fluctuations in plasma urate levels and acute flares.

To determine factors associated with gout flares in subjects treated with pegloticase. Gout flares from two randomised controlled trials comparing pegloticase (8 mg every 2 weeks [q2] or monthly [q4]) versus placebo were analysed. Responders had persistent urate lowering (<6mg/dL) whereas, non-responders had transient urate lowering during the 6-month RCTs. Gout flares (self-reported) were defined as acute joint pain and swelling requiring treatment. Gout flare prophylaxis (colchicine, 0.6 mg once or twice daily, or a non-steroidal anti-inflammatory drug) was initiated 1 week before the first infusion and continued throughout the study. Plasma urate at the time of flare and the change in urate preceding a flare were analysed. Mean flare rates increased with pegloticase versus placebo during the first 3 months followed by marked reductions during months 4-6. The increase in flares with pegloticase during the first 3 months was most evident (p=0.0006) and the decrease during the second 3 months was least marked (p=0.0006) in subjects receiving monthly pegloticase. Fluctuation in urate levels was highest in monthly responders (p=0.002) and was associated with flare occurrence. Multivariate linear regression analysis indicated the only variables significantly associated with flares were treatment group and absolute change in plasma urate before flares. Pegloticase treatment increased flares during the first 3 months of treatment in all groups when plasma urate was significantly lowered and was followed by a decline in months 4-6 in patients maintaining a low plasma urate. Flares associated with pegloticase treatment were associated with decreases and fluctuations in plasma urate levels.

Development of a multivariable improvement measure for gout

BackgroundGout is a heterogeneous inflammatory disease with numerous clinical manifestations. A composite means to assess the impact of therapy on numerous aspects of gout could be useful.MethodsResults from patients treated with pegloticase or placebo in two randomized clinical trials and their open-label extension were assessed using a novel evidence-based Gout Multivariable Improvement Measure (GMIM) derived from previously reported criteria for remission and complete response. Improvement was defined as serum urate (sU) < 6 mg/dL and absence of flares during the preceding 3 months plus 20, 50, and 70% improvement in tophus size, patient global assessment, pain, and swollen and tender joints.ResultsPatients treated with pegloticase manifested a significantly greater GMIM20, 50, and 70 response vs those treated with placebo (GMIM20 at 6 months 37.1% vs 0%, respectively). Higher response rates were significantly more frequent in subjects with persistent urate lowering (GMIM 58.1% at 6 months) in response to pegloticase versus those with only transient urate lowering (GMIM 7.1% at 6 months). However, when the requirement for a decrease in sU to < 6 mg/dL was omitted, a substantial percentage of subjects with transient urate lowering met the GMIM clinical criteria. A sensitivity analysis indicated that gout flares contributed minimally to the model. The response measured by GMIM persisted into the open-level extension for as long as 2 years. Finally, subjects who received placebo in the randomized control trials, but pegloticase in the open-label extension, manifested GMIM responses comparable to that noted with pegloticase-treated subjects in the randomized controlled trials.ConclusionsGMIM captures changes in disease activity in response to treatment with pegloticase and may serve as an evidence-based tool for assessment of responses to other urate-lowering therapies in gout patients.

214-OR: Role of Hypothalamic MAPK/ERK Signaling in Diabetes Remission Induced by the Central Action of Fibroblast Growth Factor 1 (FGF1)

The hypothalamic arcuate nucleus-median eminence (ARC-ME) is a target for sustained diabetes remission induced by fibroblast growth factor 1 (FGF1). To identify intracellular signaling cascades underlying this effect, we considered evidence that sustained signal transduction responses engaged by FGF1 are integrin-dependent. To determine if the sustained antidiabetic response of diabetic ob/ob mice to intracerebroventricular (icv) injection of FGF1 is also integrin-dependent, we investigated the response to a mutant FGF1 that is unable to activate integrin receptors (R50E FGF1). We found that although icv injection of R50E FGF1 mimics the transient anorexia, weight loss and blood glucose lowering responses induced by native FGF1 (P&amp;lt;0.001 vs. Veh for each), it fails to elicit sustained diabetes remission. Similarly, MAPK/ERK signaling is induced in the ARC-ME (primarily in tanycytes) for up to 24 h following a single icv FGF1 injection in both wild type and ob/ob mice, but the duration of this response is reduced by∼70% following icv R50E FGF1 injection (P&amp;lt;0.0001 vs. icv FGF1). We therefore hypothesized that owing to its integrin-dependent nature, FGF1-induced remission of diabetic hyperglycemia requires sustained activation of the MAPK/ERK signaling pathway in the ARC-ME. To test this hypothesis, 4 groups of diabetic ob/ob mice were studied. Each group received a single icv injection of either saline vehicle or recombinant FGF1 (3 µg), followed immediately by continuous icv infusion of either the MAPK inhibitor U0126 or its vehicle (DMSO) for 24 h. We report that the duration of the antidiabetic effect induced by icv FGF1 injection is attenuated by pharmacologic blockade of MAPK/ERK signaling. We conclude that the sustained remission of diabetic hyperglycemia induced by the central action of FGF1 depends upon its ability to activate hypothalamic MAPK/ERK signaling in a sustained manner. Disclosure J.M. Brown: None. B.N. Phan: None. H. Wasanwala: None. M.E. Matsen: None. A. Secher: Employee; Spouse/Partner; Gubra. Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. G.J. Morton: Research Support; Self; Novo Nordisk A/S. M.W. Schwartz: Research Support; Self; Novo Nordisk A/S. J. Scarlett: None. Funding National Institutes of Health (K08DK114474, DK101997, DK083042, DK035816, P30DK017047, HL007312); University of Washington

Acute effects of long-distance running on mechanical and morphological properties of the human plantar fascia.

Long‐distance running (LDR) can induce transient lowering of the foot arch, which may be associated with mechanical fatigue of the plantar fascia (PF). However, this has not been experimentally tested in vivo. The purpose of this study was to test our hypothesis that LDR induces transient and site‐specific changes in PF stiffness and morphology and that those changes are related to the lowering of the foot arch. Ten male recreational long‐distance runners and 10 untrained men were requested to run overground for 10 km. Before and after running, shear wave velocity (SWV: an index of soft tissue stiffness) and thickness of PF at three different sites from its proximal to distal end were measured using supersonic shear imaging and B‐mode ultrasonography. Foot dimensions including the navicular height were measured using a three‐dimensional foot scanner. SWV at the proximal site of PF and navicular height was significantly decreased in both groups after running, with a higher degree in untrained men (−21.9% and −14.1%, respectively) than in runners (−4.0% and −6.3%, respectively). The relative change (%Δ) in SWV was positively correlated with %Δnavicular height in both groups (r = .69 and r = .65, respectively). Multiple regression analysis revealed that %ΔSWV at the proximal site solely explained 72.7% of the total variance in %Δnavicular height. It is concluded that LDR induces transient and site‐specific decreases in PF stiffness. These results suggest that the majority of running‐induced lowering of the foot arch is attributable to the reduction of PF stiffness at the proximal site.

Splash zone lowering analysis of a large subsea spool piece

Lifting operation though the wave splash zone is challenging. Careful numerical analysis in the design phase is needed to minimize associated risks. This study addresses numerical modeling and analysis of the splash zone lowering of a large subsea spool. A typical offshore construction vessel is used for the operation. The objective is to compare the effects from different numerical methods and parameters on the allowable sea states and the operability. These methods and parameters include wave short-crestedness, shielding effects from the vessel, wave direction and wave seed number. A coupled numerical model of the spool-vessel system is established in SIMO program, which is a simulation tool for marine operations. Slamming and submergence-dependent loads on the spool during the transient lowering process are calculated. A large number of time-domain simulations has been performed to derive the allowable sea states. The operational criteria for assessment of the sea states include slack sling, snap loads in wires and clearance between spool and the vessel. Operability analysis of the operation at one reference site in the Barent Sea is established using 50-year hindcast data. The influences from different methods on the allowable sea states and the operability are compared and discussed in detail.

1637P - Pneumothorax is a novel sensitivity biomarker for targeting VEGFR2 in lung metastatic sarcoma

Background: The prognosis of metastatic bone and soft-tissue sarcoma remain distal. VEGFR2 inhibitor (VEGFR2i) has been recently found promising but is limited due to the heterogeneous durability of response. Methods: From Jan 2016 to Jun 2018, 44 patients with lung metastatic sarcoma, including 32 osteosarcoma, 4 Ewing sarcoma, 3 leiomyosarcoma, 2 chondrosarcoma and 3 other sarcoma, given apatinib treatment were reviewed. Of these patients, extra-pulmonary lesions were noticed in 14 cases including local recurrence (9), bone (3), lymph node (2) and brain (1). A starting 250∼500 mg per day was chosen, with dose adjustment according to the individual tolerability. Progression-free survival (PFS) was accessed by RECIST 1.1 criteria and used to discover the potential predictor of durability of response. Results: The mean 6 month PFS was 58.9 +/- 8.4%, with the duration of response varying from 1 months to no less than 17 months. 12 of the 44 (27.3%) patients required a long-term dose lowering while the remaining well tolerated or has a dose transient lowering less than 7 days. Adverse effects (AEs) greater than degree 2 was seen in 50.0%, including pneumothorax in 11 cases (25.0%). In 9 of 11 cases with pneumothorax, no or minimal drug discontinuance was conducted, with 5 spontaneous recoveries, 3 recoveries with tube drainage, and 1 thoracic empyema with video-assisted thoracoscopic debridement. Multivariate analysis showed that AEs (HR = 0.29 p = 0.008) and sarcoma type (osteosarcoma vs other, HR = 0.17, p = 0.001) were the independent predictors for PFS with VEGFR2i therapy. Surprisingly, pneumothorax was found to be the strongest predictor among all AEs based on the effect size (HR = 0.29, p = 0.036), indicating that the susceptibility of pneumothorax to VEGFR2i might be a new mechanism-based toxicity biomarker for lung metastatic osteosarcoma. Conclusions: Our result suggested that pneumothorax is a favorable biomarker for targeting VEGFR2 in lung metastatic sarcoma and we encourage no or minimal drug discontinuation in this circumstance. Legal entity responsible for the study: Ruijin Hospital, Oncological Orthopaedic Department. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Clinical significance of 'cardiometabolic memory': a systematic review of randomized controlled trials.

'Cardiometabolic memory' has been proposed based on clinical evidence to explain how, even after the cessation of a clinical trial, the superiority of one treatment over the outcome persists. To understand the cardiometabolic memory phenomenon, we performed a systematic review of randomized controlled trials (RCTs) using PubMed in August 2016. The search terms 'randomized controlled trial', 'post-trial follow-up' and 'diabetes, hypertension or dyslipidemia' were used, and articles published after the year 2000 were searched. We judged the memory phenomenon to be positive when the cardiovascular outcome at the end of the post-trial follow-up period in the intervention group was significantly superior even though the favorable control of a risk factor (blood glucose, blood pressure or lipid level) during the trial period was lost after the cessation of the intervention. Among 907 articles retrieved in the initial screening, 21 articles were judged as describing a positive memory phenomenon. Eight, six and seven of the articles concerned diabetes, hypertension and dyslipidemia, respectively. Transient intensive glucose lowering rather easily induced memory for the suppression of diabetic microangiopathies, while memory for the suppression of macroangiopathies tended to be first evident in the post-trial follow-up period. Transient intensive blood pressure lowering was generally effective in the formation of memory for the suppression of cardiovascular events and had an especially strong impact on risk reduction of chronic heart failure. Transient intensive LDL cholesterol lowering clearly had a long-term beneficial effect on risk reduction of cardiovascular events. Our systematic review revealed the clinical relevance of cardiometabolic memory.

Safety, Tolerability, and Pharmacokinetics of Fosphenytoin Loading in Patients With Subarachnoid Hemorrhage.

Fosphenytoin is frequently used for the rapid delivery of phenytoin in subarachnoid hemorrhage (SAH) patients. The present study was performed to investigate the safety, tolerability, and pharmacokinetic profiles of rapid intravenous loading of fosphenytoin in SAH patients. Fosphenytoin was administered intravenously as a single loading dose of 20 mg phenytoin-equivalent/kg at an infusion rate of 150 mg PE/min to 30 adult patients with SAH, who experienced seizures or had a clinical suspicion of nonconvulsive seizures. Serum concentrations of free phenytoin were determined, and adverse events were assessed at 0, 10, 20 minutes, and 24 hours after the infusion of fosphenytoin. Four patients experienced transient lowering of blood pressure, but other adverse events were not observed. All patients achieved the therapeutic level of free phenytoin (1-2 mg/L) at the end of infusion, but most patients (28/30) entered the markedly supratherapeutic range and the mean serum concentration was 17.7 ± 8.13 mg/L; higher serum concentration was maintained up to 20 minutes after infusion (mean concentration; 3.46 ± 3.75 mg/L). At 24 hours after loading, a majority of the patients (25/30) maintained their levels within the therapeutic range of free phenytoin. Rapid intravenous loading of fosphenytoin was well tolerated and effective in promptly achieving the therapeutic level of free phenytoin, but most patients experienced overshoot of free phenytoin at the end of infusion. Because increased serum concentrations may increase the risk of cardiovascular complications, additional studies are needed to determine the optimal dose and infusion rate of fosphenytoin in SAH patients.

Sediment processes and flow reversal in the undular tidal bore of the Garonne River (France)

A tidal bore is a series of waves propagating upstream as the tidal flow turns to rising, and the bore front corresponds to the leading edge of the tidal wave in a funnel shaped estuarine zone with macro-tidal conditions. Some field observations were conducted in the tidal bore of the Garonne River on 7 June 2012 in the Arcins channel, a few weeks after a major flood. The tidal bore was a flat undular bore with a Froude number close to unity: Fr1 = 1.02 and 1.19 (morning and afternoon respectively). A key feature of the study was the simultaneous recording of the water elevation, instantaneous velocity components and suspended sediment concentration (SSC) estimates, together with a detailed characterisation of the sediment bed materials. The sediment was some silty material (d50 ≈ 13 μm) which exhibited some non-Newtonion thixotropic behaviour. The velocity and SSC estimate were recorded simultaneously at high frequency, enabling a quantitative estimate of the suspended sediment flux at the end of the ebb tide and during the early flood tide. The net sediment flux per unit area was directed upstream after the bore, and its magnitude was much larger than that at end of ebb tide. The field observations highlighted a number of unusual features on the morning of 7 June 2012. These included (a) a slight rise in water elevation starting about 70 s prior to the front, (b) a delayed flow reversal about 50 s after the bore front, (c) some large fluctuations in suspended sediment concentration (SSC) about 100 s after the bore front and (d) a transient water elevation lowering about 10 min after the bore front passage. The measurements of water temperature and salinity showed nearly identical results before and after the tidal bore, with no evidence of saline and thermal front during the study.

Nematic order and phase transition dynamics under intense electric fields

Electrically induced order variations, occurring in the microseconds timescale, in nematic liquid crystals are framed within the Landau-de Gennes Q -tensor theory. We provide a numerical model implemented with a moving mesh finite element method and describe the order dynamics in a symmetric π-cell subjected to very strong electric fields. Our simulations put in evidence bulk order reconstruction delocalisation and transient order lowering phenomena induced by intense applied electric fields, as well as first and second order characteristics of the splay – bend transition.

Prepubertal Testicular Tumors in Korea: A Single Surgeon's Experience of More Than 20 Years

PurposeTo present clinical and histological features of prepubertal testicular tumors through the analysis of the long-term experiences of a single surgeon.Materials and MethodsThe charts of 48 children treated for testicular tumors from 1986 to 2010 were retrospectively reviewed. All patients underwent radical orchiectomy. The patients' ages, clinical presentations, histopathological findings, kinetics of tumor markers, and outcomes were recorded.ResultsThe patients' median age at the initial diagnosis was 19.5 months (range, 3 to 84 months). All patients presented with either a palpable mass (76%) or scrotal size discrepancy (24%). Compared with a palpable mass, scrotal size discrepancy led to delay in diagnosis by 5 months. Regarding histology, yolk sac tumors and teratomas accounted for 53% and 36% of the tumors, respectively. The mean preoperative alpha-fetoprotein (AFP) level was significantly higher in patients with yolk sac tumors than in those with teratomas (4,600 ng/mL vs. 6.3 ng/mL), and only one patient with a teratoma had a preoperative AFP value higher than 20 ng/mL. Following radical orchiectomy, 72%, 8%, and 16% of patients with a yolk sac tumor showed normalization, persistent elevation, and relapse after transient lowering of AFP, respectively. Preoperative AFP was greater in patients with non-normalization than in those with normalization. Five of six patients with non-normalization showed evidence of either vascular invasion or endolymphatic tumor emboli.ConclusionsWe found a higher number of yolk sac tumors than teratomas in patients with prepubertal testicular tumors. AFP was the most useful marker in the diagnosis and follow-up of childhood yolk sac tumors. Relapsed yolk sac tumors often showed pathological evidence of aggressiveness.

Gastric Bypass Surgery Is Followed by Lowered Blood Pressure and Increased Diuresis - Long Term Results from the Swedish Obese Subjects (SOS) Study

ObjectiveTo compare two bariatric surgical principles with regard to effects on blood pressure and salt intake.BackgroundIn most patients bariatric surgery induces a sustained weight loss and a reduced cardiovascular risk profile but the long-term effect on blood pressure is uncertain.MethodsCohort study with data from the prospective, controlled Swedish Obese Subjects (SOS) study involving 480 primary health care centres and 25 surgical departments in Sweden. Obese patients treated with non-surgical methods (Controls, n = 1636 and n = 1132 at 2 y and 10 y follow up, respectively) were compared to patients treated with gastric bypass (GBP, n = 245 and n = 277, respectively) or purely restrictive procedures (vertical banded gastroplasty or gastric banding; VBG/B, n = 1534 and n = 1064, respectively).ResultsAt long-term follow-up (median 10 y) GBP was associated with lowered systolic (mean: −5.1 mm Hg) and diastolic pressure (−5.6 mmHg) differing significantly from both VBG/B (−1.5 and −2.1 mmHg, respectively; p<0.001) and Controls (+1.2 and −3.8 mmHg, respectively; p<0.01). Diurnal urinary output was +100 ml (P<0.05) and +170 ml (P<0.001) higher in GBP subjects than in weight-loss matched VBG/B subjects at the 2 y and 10 y follow-ups, respectively. Urinary output was linearly associated with blood pressure only after GBP and these patients consumed approximately 1 g salt per day more at the follow-ups than did VBG/B (P<0.01).ConclusionsThe purely restrictive techniques VBG/B exerted a transient blood pressure lowering effect, whereas gastric bypass was associated with a sustained blood pressure reduction and an increased diuresis. The daily salt consumption was higher after gastric bypass than after restrictive bariatric surgery.

A Rare Cause of Cardiac Tamponade: Hypereosinophilic Syndrome

We describe a male adult patient who presented with chest discomfort and shortness of breath. A diagnosis of cardiac tamponade was made by transthoracic echocardiogram. Urgent pericardiocentesis was performed and analysis of pericardial fluid showed presence of eosinophil. Complete blood picture showed peripheral eosinphilia as well. Subsequent work up for eosinophilia showed ova of Clonorchis sinesis from the stool thus a course of praziquantel was given. Transient clinical improvement and lowering of eosinophil count were observed but two weeks later he developed acute coronary syndrome. Urgent coronary angiogram showed coronary vasospasm. Endomyocardial biopsy was performed afterwards which showed marked eosinophilic infiltrate. Bone marrow biopsy and skin biopsy showed marked marrow eosinophilia and leucocytoclastic vasculitis with abundant eosinophils, respectively. A diagnosis of hypereosinophilic syndrome was made after exclusion of secondary and clonal eosinophilia. After oral steroid was given, his condition was stabilized and the eosinophil count was normalized.

Intrapancreatic delivery of human umbilical cord blood aldehyde dehydrogenase-producing cells promotes islet regeneration

We sought to investigate the stimulation of islet regeneration by transplanted human umbilical cord blood (UCB) cells purified according to high aldehyde dehydrogenase (ALDH) activity (ALDH(hi)), a conserved characteristic of multiple progenitor lineages. We hypothesised that direct intrapancreatic (iPan) delivery of ALDH(hi) progenitors would augment islet regeneration via timely and localised exposure to islet-regenerative stimuli. Cells were purified from UCB based on flow cytometry for low ALDH activity (ALDH(lo)) vs ALDH(hi). UCB ALDH(lo) or ALDH(hi) cells were compared for surface marker expression, as well as haematopoietic, endothelial and multipotent stromal progenitor content in vitro. UCB ALDH(lo) or ALDH(hi) cells were i.v. or iPan injected into streptozotocin-treated non-obese diabetic/severe combined immune-deficient mice temporally monitored for blood glucose, serum insulin and glucose tolerance. Human cell recruitment and survival in the pancreas, insulin content, islet-associated cell proliferation and islet vascularisation were documented in situ. UCB-derived ALDH(hi) cells were highly enriched for haematopoietic and endothelial progenitor frequency, and showed increased expression of progenitor and myeloid cell surface markers. Although i.v. transplantation of ALDH(hi) cells demonstrated low pancreas engraftment and only transient blood glucose lowering capacity, iPan injected ALDH(hi) cells reversed established hyperglycaemia, increased serum insulin and improved the response to a glucose challenge. iPan injected ALDH(hi) cells surrounded damaged islets at early time points and increased islet-associated cell proliferation, resulting in the recovery of beta cell mass. iPan delivery of UCB ALDH(hi) cells potentiated islet-associated cell proliferation, insulin production and islet revascularisation, resulting in the recovery of host islet function. Elucidation of the progenitor-specific pathways stimulated during islet regeneration may provide new approaches to promote islet expansion during diabetes.

Transient pharmacologic lowering of Aβ production prior to deposition results in sustained reduction of amyloid plaque pathology

BackgroundAlzheimer’s disease (AD) is the leading cause of dementia among the elderly. Disease modifying therapies targeting Aβ that are in development have been proposed to be more effective if treatment was initiated prior to significant accumulation of Aβ in the brain, but optimal timing of treatment initiation has not been clearly established in the clinic. We compared the efficacy of transient pharmacologic reduction of brain Aβ with a γ-secretase inhibitor (GSI ) for 1–3 months (M) treatment windows in APP Tg2576 mice and subsequent aging of the mice to either 15M or 18M.ResultsThese data show that reducing Aβ production in a 2-3M windows both initiated and discontinued before detectable Aβ deposition has the most significant impact on Aβ loads up to 11M after treatment discontinuation. In contrast, initiation of treatment for 3M windows from 7-10M or 12-15M shows progressively decreasing efficacy.ConclusionsThese data have major implications for clinical testing of therapeutics aimed at lowering Aβ production, indicating that; i) these therapies may have little efficacy unless tested as prophylactics or in the earliest preclinical stage of AD where there is no or minimal Aβ accumulation and ii) lowering Aβ production transiently during a critical pre-deposition window potentially provides long-lasting efficacy after discontinuation of the treatment.

Transient Lowering of the Viral Set Point After Temporary Antiretroviral Therapy of Primary HIV Type 1 Infection

Whether temporary antiretroviral treatment during primary HIV infection (PHI) lowers the viral set point or affects the subsequent CD4 count decline remains unclear. The objectives of this study were to analyze the clinical, viral, and immunological effects of temporary early HAART during PHI. This is a cohort study of patients with laboratory evidence of PHI. Independent predictors of early HAART and the viral set point were analyzed using multiple regression analysis. Plasma HIV-1 RNA (pVL) and CD4 trajectories were analyzed using linear mixed models. A total of 332 patients were included in the analysis. Sixty-four patients started HAART within 180 days of seroconversion. A higher baseline pVL was independently predictive of the start of early HAART (OR: 2.69/log10pVL, p = 0.001). Thirty-two patients who interrupted early HAART were compared with 250 patients who remained untreated for more than 180 days after seroconversion. Temporary early HAART was not significantly associated with a longer AIDS-free survival but did result in an initial, but transient lowering of the viral set point. The viral set point was initially 0.6 log copies/ml lower after interruption of early HAART (p < 0.001) and remained lower during 83 weeks of follow-up. No significant difference in the slopes of CD4 decline was detected between the groups. Temporary HAART in PHI is started more frequently in patients with a higher pVL and can transiently lower the viral set point compared to never treated patients.