Long-term results of deep sclerectomy with collagen implant.

PURPOSE: To study prospectively the success rate and complications of deep sclerectomy with collagen implant (DSCI). SETTING: Glaucoma Unit, Department of Ophthalmology, Hôpital Ophtalmique Jules Gonin, University of Lausanne, Lausanne, Switzerland. METHODS: This nonrandomized prospective trial comprised 105 eyes of 105 patients with medically uncontrolled primary and secondary open-angle glaucoma. Visual acuity, intraocular pressure (IOP), and slitlamp examinations were performed before surgery and after surgery at 1 and 7 days, and 1, 3, 6, 9, 12, 18, 24, 30, 36, 48, 54, 60, 66, 72, 78, 84, 90, and 96 months. Visual field examinations were repeated every 6 months. RESULTS: Mean follow-up period was 64 months +/- 26.6 (SD). Mean preoperative IOP was 26.8 +/- 7.7 mm Hg, and mean postoperative IOP was 5.2 +/- 3.35 mm Hg at day 1 and 12 +/- 3 mm Hg at month 78. At 96 months, the qualified success rate (ie, patients who achieved IOP <21 mm Hg with and without medication) was 91%, and the complete success rate (ie, IOP <21 mm Hg without medication) was 57%. At 96 months, 34% of patients had an IOP <21 mm Hg with medication. Fifty-one patients (49%) achieved an IOP < or =15 mm Hg without medication. Neodymium:YAG goniopuncture was performed in 54 patients (51%); mean time of goniopuncture performance was 21 months, and mean IOP before goniopuncture was 20 mm Hg, dropping to 11 mm Hg after goniopuncture. No shallow or flat anterior chamber, endophthalmitis, or surgery-induced cataract was observed. However, 26 patients (25%) showed a progression of preexisting senile cataract (mean time 26 months; range 18 to 37 months). Injections of 5-fluorouracil were administered to 25 patients (23%) who underwent DSCI to salvage encysted blebs. Mean number of medications per patient was reduced from 2.3 +/- 0.7 to 0.5 +/- 0.7 (signed rank P<.0001). CONCLUSION: Deep sclerectomy with collagen implant appears to provide stable and reasonable control of IOP at long-term follow-up with few immediate postoperative complications.

Long diagnostic delay in Crohn's disease is associated with complicated disease course and increased operation rate

Background: We have recently shown that the median diagnostic delay to establish Crohn's disease (CD) diagnosis in the Swiss IBD Cohort (SIBDC) was 9 months. Seventy five percent of all CD patients were diagnosed within 24 months. The clinical impact of a long diagnostic delay on the natural history of CD is unknown. Aim: To compare the frequency and type of CD-related complications in the patient groups with long diagnostic delay (>24 months) vs. the ones diagnosed within 24 months. Methods: Retrospective analysis of data from the SIBDCS, comprising a large sample of CD patients followed in hospitals and private practices across Switzerland. Results: Two hundred CD patients (121 female, mean age 44.9 ± 15.0 years, 38% smokers, 71% ever treated with immunomodulators and 35% with anti-TNF) with long diagnostic delay were compared to 697 CD patients (358 female, mean age 39.1 ± 14.9 years, 33% smokers, 74% ever treated with immunomodulators and 33% with anti-TNF) diagnosed within 24 months. No differences in the outcomes were observed between the two patient groups within year one after CD diagnosis. Among those diagnosed 2-5 years ago, CD patients with long diagnostic delay (n = 45) presented more frequently with internal fistulas (11.1% vs. 3.1%, p = 0.03) and bowel stenoses (28.9% vs. 15.7%, p = 0.05), and they more frequently underwent CD-related operations (15.6% vs. 5.0%, p = 0.02) compared to the patients diagnosed within 24 months (n = 159). Among those diagnosed 6-10 years ago, CD patients with long diagnostic delay (n = 48) presented more frequently with extraintestinal manifestations (60.4% vs. 34.6%, p = 0.001) than those diagnosed within 24 months (n = 182). For the patients diagnosed 11-15 years ago, no differences in outcomes were found between the long diagnostic delay group (n = 106) and the one diagnosed within 24 months (n = 32). Among those diagnosed >= 16 years ago, the group with long diagnostic delay (n = 71) more frequently underwent CD-related operations (63.4% vs. 46.5%, p = 0.01) compared to the group diagnosed with CD within 24 months (n = 241). Conclusions: A long diagnostic delay in CD patients is associated with a more complicated disease course and higher number of CD-related operations in the years following the diagnosis. Our results indicate that efforts should be undertaken to shorten the diagnostic delay in CD patients in order to reduce the risk for progression towards a complicated disease phenotype.

Long-term changes in synaptic transmission of the lateral amygdala induced by strong "in vitro" activation

Résumé : L'amygdale latérale (AL) joue un .rôle essentiel dans la plasticité synaptique à la base du conditionnement de la peur. Malgré le faite que la majorité des cellules de l'AL reçoivent les afférentes nécessaires, une potentialisation dans seulement une partie d'entre elles est obligatoire afin que l'apprentissage de la peur ait lieu. Il a été montré que ces cellules expriment la forme active de CREB, et celui-ci a été associé aux cellules dites de type 'nonaccomrnodating' (nAC). Très récemment, une étude a impliqué les circuits récurrents de l'AL dans le conditionnement de la peur. Un lien entre ces deux observations n'a toutefois jamais été établi. t Nous avons utilisé un protocole in vitro de forte activation de l'AL, résultant dans l'induction de 'bursts' provenant de l'hippocampe et se propageant jusqu'à l'AL. Dans l'AL ces 'bursts' atteignent toutes les cellules et se propagent à travers plusieurs chemins. Utilisant ce protocole, nous avons, pour la première fois pu associer dans l'AL, des cellules connectées de manière récurrente avec des cellules de type nAC. Aussi bien dans ces dernières que dans les cellules de type 'accommodating' (AC), une diminution dans la transmission inhibitrice, à la fois exprimée de manière pré synaptique mais également indépendant de la synthèse de protéine a pu être observé. Au contraire, une potentialisation induite et exprimée au niveau pré synaptique ainsi que dépendante de la synthèse de protéine a pu être trouvé uniquement dans les cellules de type nAC. De plus, une hyperexcitabilité, dépendante des récepteurs NMDA a pu être observé, avec une sélection préférentielle des cellules du type nAC dans la génération de bursts. Nous avons également pu démontrer que la transformation d'un certain nombre de cellules de type AC en cellules dites nAC accompagnait cette augmentation générale de l'excitabilité de l'AL. Du faite da la grande quantité d'indices suggérant une connexion entre le système noradrénergique et les états de peur/d'anxiété, les effets d'une forte activation de l'AL sur ce dernier ont été investigués et ont révélés une perte de sa capacité de modulation du 'spiking pattern'. Finalement, des changements au niveau de l'expression d'un certain nombre de gènes, incluant celui codant pour le BDNF, a pu être trouvé à la suite d'une forte activation de l'AL. En raison du lien récemment décrit entre l'expression de la forme active de CREB et des cellules de type nAC ainsi que celui de l'implication des cellules de l'AL connectés de manière récurrente dans l'apprentissage de la peur, nos résultats nous permettent de suggérer un modèle expliquant comment la potentialisation des connections récurrentes entre cellules de type nAC pourrait être à la base de leur recrutement sélectif pendant le conditionnement de la peur. De plus, ils peuvent offrir des indices par rapport aux mécanismes à travers lesquels une sous population de neurones peut être réactivée par une stimulation externe précédemment inefficace, et induire ainsi un signal suffisamment fort pour qu'il soit transmit aux structures efférentes de l'AL. Abstract : The lateral nucleus of the amygdala (LA) is critically involved in the plasticity underlying fear-conditioned learning (Sah et al., 2008). Even though the majority of cells in the LA receive the necessary sensory inputs, potentiation in only a subset is required for fear learning to occur (Repa et al., 2001; Rumpel et al., 2005). These cells express active CREB (CAMP-responsive element-binding protein) (Han et al., 200, and this was related to the non-accommodating (nAC) spiking phenotype (Viosca et al., 2009; Zhou et al., 2009). In addition, a very recent study implicated recurrently connected cells of the LA in fear conditioned learning (Johnson et al., 2008). A link between the two observations has however never been made. In rats, we used an in vitro protocol of strong activation of the LA, resulting in bursting activity, which spread from the hippocampus to the LA. Within the LA, this activity reached all cells and spread via a multitude of pathways. Using this model, we were able to link, for the first time, recurrently connected cells in the LA with cells of the nAC phenotype. While we found a presynaptically expressed, protein synthesis independent decrease in inhibitory synaptic transmission in both nAC and accommodating (AC) cells, only nAC cells underwent a presynaptically induced and expressed, protein synthesis dependent potentiation. Moreover we observed an NMDA dependent hyperexcitability of the LA, with a preferential selection of nAC cells into burst generation. The transformation of a subset of AC cells into nAC cells accompanied this general increase in LA excitability. Given the considerable evidence suggesting a relationship between the central noradrenergic (NA) system and fear/anxiety states (Itoi, 2008), the effects of strong activation of the LA on the noradrenergic system were investigated, which revealed a loss of its modulatory actions on cell spiking patterns. Finally, we found changes in the expression levels of a number of genes; among which the one coding for $DNF, to be induced by strong activation of the LA. In view of the recently described link between nAC cells and expression of pCREB (phosphorylated cAMP-responsive element-binding protein) as well as the involvement of recurrently connected cells of the LA in fear-conditioned learning, our findings may provide a model of how potentiation of recurrent connections between nAC neurons underlies their recruitment into the fear memory trace. Additionally, they may offer clues as to the mechanisms through which a selected subset of neurons can be reactivated by smaller, previously ineffective external stimulations to respond with a sufficiently strong signal, which can be transmitted to downstream targets of the LA.

Inappropriate antidiuretic hormone secretion: long-term successful urea treatment.

Hyponatremia is the main complication of inappropriate antidiuretic hormone secretion (SIADH), sometimes fatal. Treatment strategy depends on the cause and the severity of the hyponatremia. Recent studies have shown the efficacy of urea in treating acute hyponatremia secondary to SIADH, by inducing an osmotic water drive. We describe an infant with chronic hyponatremia secondary to SIADH in which the long-term oral treatment with urea was successful and well tolerated. The aim of this paper is to highlight the potential benefits of urea treatment in case of chronic hyponatremia secondary to SIADH. CONCLUSION: Chronic oral urea treatment in children with SIADH allows an easy and safe water and sodium control and may permit a decrease in fluid restriction in this situation.

The long non-coding RNA NEAT1 is increased in IUGR placentas, leading to potential new hypotheses of IUGR origin/development.

INTRODUCTION: Intrauterine Growth Restriction (IUGR) is a multifactorial disease defined by an inability of the fetus to reach its growth potential. IUGR not only increases the risk of neonatal mortality/morbidity, but also the risk of metabolic syndrome during adulthood. Certain placental proteins have been shown to be implicated in IUGR development, such as proteins from the GH/IGF axis and angiogenesis/apoptosis processes. METHODS: Twelve patients with term IUGR pregnancy (birth weight < 10th percentile) and 12 CTRLs were included. mRNA was extracted from the fetal part of the placenta and submitted to a subtraction method (Clontech PCR-Select cDNA Subtraction). RESULTS: One candidate gene identified was the long non-coding RNA NEAT1 (nuclear paraspeckle assembly transcript 1). NEAT1 is the core component of a subnuclear structure called paraspeckle. This structure is responsible for the retention of hyperedited mRNAs in the nucleus. Overall, NEAT1 mRNA expression was 4.14 (±1.16)-fold increased in IUGR vs. CTRL placentas (P = 0.009). NEAT1 was exclusively localized in the nuclei of the villous trophoblasts and was expressed in more nuclei and with greater intensity in IUGR placentas than in CTRLs. PSPC1, one of the three main proteins of the paraspeckle, co-localized with NEAT1 in the villous trophoblasts. The expression of NEAT1_2 mRNA, the long isoform of NEAT1, was only modestly increased in IUGR vs. CTRL placentas. DISCUSSION/CONCLUSION: The increase in NEAT1 and its co-localization with PSPC1 suggests an increase in paraspeckles in IUGR villous trophoblasts. This could lead to an increased retention of important mRNAs in villous trophoblasts nuclei. Given that the villous trophoblasts are crucial for the barrier function of the placenta, this could in part explain placental dysfunction in idiopathic IUGR fetuses.

CD1d-antibody fusion proteins target iNKT cells to the tumor and trigger long-term therapeutic responses.

Despite the well-established antitumor activity of CD1d-restricted invariant natural killer T lymphocytes (iNKT), their use for cancer therapy has remained challenging. This appears to be due to their strong but short-lived activation followed by long-term anergy after a single administration of the CD1d agonist ligand alpha-galactosylceramide (αGC). As a promising alternative, we obtained sustained mouse iNKT cell responses associated with prolonged antitumor effects through repeated administrations of tumor-targeted recombinant sCD1d-antitumor scFv fusion proteins loaded with αGC. Here, we demonstrate that CD1d fusion proteins bound to tumor cells via the antibody fragment specific for a tumor-associated antigen, efficiently activate human iNKT cell lines leading to potent tumor cell lysis. The importance of CD1d tumor targeting was confirmed in tumor-bearing mice in which only the specific tumor-targeted CD1d fusion protein resulted in tumor inhibition of well-established aggressive tumor grafts. The therapeutic efficacy correlated with the repeated activation of iNKT and natural killer cells marked by their release of TH1 cytokines, despite the up-regulation of the co-inhibitory receptor PD-1. Our results demonstrate the superiority of providing the superagonist αGC loaded on recombinant CD1d proteins and support the use of αGC/sCD1d-antitumor fusion proteins to secure a sustained human and mouse iNKT cell activation, while targeting their cytotoxic activity and cytokine release to the tumor site.

Long-term close follow-up of chorioretinal lesions in presumed ocular tuberculosis.

PURPOSE: To evaluate the long-term outcome (up to 7 years) of presumed ocular tuberculosis (TB) when the therapeutic decision was based on WHO guidelines. METHODS: Twelve out of 654 new uveitic patients (1998-2004) presented with choroiditis and positive tuberculosis skin test (TST) (skin lesion diameter >15 mm). Therapy was administered according to WHO recommendations after ophthalmic and systemic investigation. The area size of ocular lesions at presentation and after therapy, measured on fluorescein and indocyanine green angiographies, was considered the primary outcome. Relapse of choroiditis was considered a secondary outcome. The T-SPOT TB test was performed when it became available. RESULTS: Visual acuity significantly improved after therapy (p=0.0357). The mean total surface of fluorescein lesions at entry was 44.8 ± 20.9 (arbitrary units) and decreased to 32.5 ± 16.9 after therapy (p=0.0165). The mean total surface of indocyanine green lesions at entry was 24.5 ± 13.3 and decreased to 10.8 ± 5.4 after therapy (p=0.0631). The T-SPOT TB revealed 2 false TST-positive results. The mean follow-up was 4.5 ± 1.5 years. Two relapses out of 10 confirmed ocular TB was observed after complete lesion healing, 2.5 years and 4.5 years after therapy, respectively. CONCLUSIONS: A decrease of ocular lesion mean size and a mean improvement of VA were observed after antituberculous therapy. Our long-term follow-up of chorioretinal lesions demonstrated relapse of ocular tuberculosis in 10% of patients with confirmed ocular TB, despite complete initial retinal scarring.

Preoperative upper gastrointestinal testing can help predicting long-term outcome after gastric banding for morbid obesity.

BACKGROUND: Gastric banding (GB) is one of the most popular bariatric procedures for morbid obesity. Apart from causing weight loss by alimentary restriction, it can interfere with functions of the esophagus and upper stomach. The aim of this study was to evaluate if the results of extensive preoperative upper GI testing were correlated with long-term outcome and complications after GB. METHODS: Using a prospectively maintained computerized database including all the patients undergoing bariatric operations in both our hospitals, we performed a retrospective analysis of the patients who underwent complete upper gastrointestinal (GI) testing (endoscopy, pH monitoring, and manometry) before GB. RESULTS: One hundred thirty-four patients underwent complete testing before GB. Abnormal pH monitoring (increased total reflux time, increased diurnal reflux time, increased number of reflux episodes) predicted the development of complications and especially pouch dilatation and food intolerance. The mean De Meester score was higher among patients who developed complications than in the remaining ones (25.4 vs 17.7, P=0.03). High lower esophageal sphincter pressure also predicted progressive long-term food intolerance. Endoscopic findings were not predictive of the long-term outcome. CONCLUSIONS: There is some association between the function of the upper digestive tract and long-term complications after gastric banding. Abnormal pH monitoring predicts overall long-term complications, especially food intolerance with or without reflux, and pouch dilatation, and a high lower esophageal sphincter pressure predicts long-term food intolerance. Extended upper gastrointestinal testing with endoscopy, 24-h pH monitoring, and esophageal manometry is probably worthwhile in selecting patients for gastric banding.

Structure and kinematics of the Siviez-Mischabel nappe in the Mattertal (western Alps of Switzerland) = Structure et cinématique de la nappe de Siviez-Mischabel le long de la vallée de Zermatt (Alpes de Suisse occidentale)

Résumé Cette étude porte sur le flanc inverse de la nappe de Siviez-Mischabel et sur les unités tectoniques sous jacentes (zone de Stalden supérieur et zone Houillère) dans la vallée menant à Zermatt. L'étude structurale du granite permien de Randa (orthogneiss oeillé) permet de mieux comprendre les effets de la déformation alpine sur les roches de socle. La cartographie détaillée de l'orthogneiss et de son encaissant, ainsi que l'étude lithostratigraphique des terrains sédimentaires associés permettent de proposer un schéma structural et cinématique du flanc inverse de la nappe de Siviez-Mischabel et de mieux comprendre ses relations avec les unités tectoniques sous-jacentes. L'analyse structurale de l'orthogneiss de Randa et de son encaissant révèle la superposition de plusieurs phases de déformation ductile. Cet orthogneiss formé sous des conditions métamorphiques du faciès schiste vert possède une forte schistosité alpine avec au moins deux linéations d'extension. La première, L1, orientée NW-SE est associée à la mise en place de la nappe. La seconde, L2, orientée SW-NE, se corrèle au cisaillement ductile du Simplon. La quantification de la déformation au moyen de la méthode de Fry sur les faciès porphyriques donne des ellipses à rapports axiaux compris entre 1.9 et 5.3, en accord avec les valeurs obtenues par d'autres marqueurs {tourmalines étirées, fibres). Les valeurs mesurées parallèlement à L1 ou L2 sont très semblables. La méthode de Fry a nécessité une étude théorique préalable afin de vérifier son applicabilité aux orthogneiss oeillés. La méthode requiert une distribution spatiale homogène et isotrope des marqueurs utilisés. Les tests statistiques effectués ont révélé que les phénocristaux de feldspath alcalin satisfont à cette condition et qu'ils peuvent être utilisés comme marqueur de la déformation au moyen de la méthode de Fry. Les valeurs obtenues révèlent l'importance du cisaillement ductile du Simplon sur la géométrie de la nappe dans la région d'étude. Le levé cartographique a permis d'améliorer la lithostratigraphie de la base de la nappe de Siviez-Mischabel. Trois formations en position renversée peuvent être observées sous les gneiss formant le coeur de la nappe. Ces trois formations forment le coeur du synclinal de St-Niklaus qui connecte la nappe de Siviez-Mischabel à la zone de Stalden supérieur. La datation par U-Pb de zircons détritiques et magmatiques par LA-ICP-MS permet de contraindre l'âge des formations observées (probablement Carbonifère à Trias précoce). Ces données ont des répercussions importantes sur la structure de la nappe dans la région, prouvant l'existence de plusieurs plis avec des séries normales et renversées bien préservées. La définition et la datation de ces formations, ainsi que leur identification dans la-Zone- Houillère avoisinante permettent de mieux comprendre la géométrie initiale et les relations tectoniques des nappes du Pennique moyen dans la vallée de Zermatt. Summary This study investigates the overturned limb of the Siviez-Mischabel nappe and underlying tectonic units (Upper Stalden zone and Houillère zone) in the Mattertal area. Detailed structural analysis in the Permian Randa granite (augen orthogneiss) allows a better understanding of the Alpine deformation effects on basement rocks. Detailed mapping of this orthogneiss and surrounding rocks, and the study of the lithostratigraphy in the related sedimentary horizons allow the proposition of a structural and kinematic model for the overturned limb of the Siviez-Mischabel and to better understand the relations with the underlying tectonic units. The structural analysis of the Randa orthogneiss and surrounding rocks revealed the superposition of several phases of ductile deformation. This orthogneiss formed under greenschist facies metamorphic conditions displays a strong Alpine foliation with at least two stretching lineations. The first lineation, L1, is oriented NW-SE and is related to the nappe emplacement northward. The second one, L2, is related to the Simplon ductile shear zone. Strain estimation using the Fry method has been performed on porphyritic facies of the Randa orthogneiss. The obtained ellipses have axial ratios varying between 1.9 and 5.3, in agreement with strain estimation obtained from other markers (stretched turmalines, fringes). The strain values are very similar if measured parallel to L1 or to L2. A theoretical approach was necessary to verify the relevant application of the Fry method to augen orthogneiss. This method requires that the distribution of the used markers has to be homogeneous and isotropic. Statistical tests have been done and revealed that K-feldspar phenocrysts satisfy these conditions and can be used as strain markers with the Fry method. The obtained strain measurements revealed the importance of the Simplon ductile shear zone on the geometry of the nappe in the studied area. Mapping has improved the lithostratigraphy at the base of the Siviez-Mischabel nappe. Three overturned formations can be observed below the gneisses forming the core of the nappe. These three formations form the St-Niklaus syncline, which connects the Siviez-Mischabel nappe to the underlying Upper Stalden zone. U-Pb dating of detrital and magmatic zircons by LA-ICPMS allowed the age of the observed formations to be constrained (presumably Carboniferous to Early Triassic). This data has critical implications for nappe structure in the region, composed of few recumbent folds with well preserved normal and overturned limbs. The definition and dating of these formations, as well as their identification in the adjacent "Houillère Zone" improve the understanding of the geometry and tectonic relations of the Middle Penninic nappes in the Mattertal.

Long-term monitoring of post-stroke plasticity after transient cerebral ischemia in mice using in vivo and ex vivo diffusion tensor MRI.

WE USED A MURINE MODEL OF TRANSIENT FOCAL CEREBRAL ISCHEMIA TO STUDY: 1) in vivo DTI long-term temporal evolution of the apparent diffusion coefficient (ADC) and diffusion fractional anisotropy (FA) at days 4, 10, 15 and 21 after stroke 2) ex vivo distribution of a plasticity-related protein (GAP-43) and its relationship with the ex vivo DTI characteristics of the striato-thalamic pathway (21 days). All animals recovered motor function. In vivo ADC within the infarct was significantly increased after stroke. In the stroke group, GAP-43 expression and FA values were significantly higher in the ipsilateral (IL) striatum and contralateral (CL) hippocampus compared to the shams. DTI tractography showed fiber trajectories connecting the CL striatum to the stroke region, where increased GAP43 and FA were observed and fiber tracts from the CL striatum terminating in the IL hippocampus.Our data demonstrate that DTI changes parallel histological remodeling and recovery of function.

Long-term follow-up of patients with congenital myasthenic syndrome caused by COLQ mutations.

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous inherited disorders characterized by impaired neuromuscular transmission. Mutations in the acetylcholinesterase (AChE) collagen-like tail subunit gene (COlQ) cause recessive forms of synaptic CMS with end plate AChE deficiency. We present data on 15 COLQ -mutant CMS carrying 16 different mutations (9 novel ones identified) followed-up for an average period of 10 ears. The mean age at the first examination was 19 ears old (range from 3 to 48). We report relapses during short or long-term periods characterized by worsening of muscle weakness sometimes associated with respiratory crises. All the relapses ended spontaneously or with 3-4 DAP or ephedrine with no residual impairment. The triggering factors identified were esterase inhibitors, effort, puberty or pregnancy highlighting the importance of hormonal factors. There was no genotype-phenotype correlation. At the end of the follow-up, 80% of patients were ambulant and 87% of patients had no respiratory trouble in spite of severe relapses.

Role of fat oxidation in the long-term stabilization of body weight in obese women.

Two studies were performed to investigate the association between body fat mass and fat oxidation. The first, a cross-sectional study of 106 obese women maintaining stable body weight, showed that these two variables were significantly correlated (r = 0.56, P less than 0.001) and the regression coefficient indicated that a 10-kg change in fat mass corresponded to a change in fat oxidation of approximately 20 g/d. The second, a prospective study, validated this estimate and quantifies the long-term adaptations in fat oxidation resulting from body fat loss. Twenty-four moderately obese women were studied under controlled dietary conditions at stable weight before and after mean weight and fat losses of 12.7 and 9.8 kg, respectively. The reduction in fat oxidation was identical to that predicted by the above regression. We conclude that changes in fat mass significantly affect fat oxidation and that this process may contribute to the long-term regulation of fat and energy balance in obese individuals.

Long-term antiretroviral treatment initiated at primary HIV-1 infection affects the size, composition, and decay kinetics of the reservoir of HIV-1-infected CD4 T cells.

Initiation of antiretroviral therapy during the earliest stages of HIV-1 infection may limit the seeding of a long-lasting viral reservoir, but long-term effects of early antiretroviral treatment initiation remain unknown. Here, we analyzed immunological and virological characteristics of nine patients who started antiretroviral therapy at primary HIV-1 infection and remained on suppressive treatment for >10 years; patients with similar treatment duration but initiation of suppressive therapy during chronic HIV-1 infection served as controls. We observed that independently of the timing of treatment initiation, HIV-1 DNA in CD4 T cells decayed primarily during the initial 3 to 4 years of treatment. However, in patients who started antiretroviral therapy in early infection, this decay occurred faster and was more pronounced, leading to substantially lower levels of cell-associated HIV-1 DNA after long-term treatment. Despite this smaller size, the viral CD4 T cell reservoir in persons with early treatment initiation consisted more dominantly of the long-lasting central-memory and T memory stem cells. HIV-1-specific T cell responses remained continuously detectable during antiretroviral therapy, independently of the timing of treatment initiation. Together, these data suggest that early HIV-1 treatment initiation, even when continued for >10 years, is unlikely to lead to viral eradication, but the presence of low viral reservoirs and durable HIV-1 T cell responses may make such patients good candidates for future interventional studies aiming at HIV-1 eradication and cure. IMPORTANCE: Antiretroviral therapy can effectively suppress HIV-1 replication to undetectable levels; however, HIV-1 can persist despite treatment, and viral replication rapidly rebounds when treatment is discontinued. This is mainly due to the presence of latently infected CD4 T cells, which are not susceptible to antiretroviral drugs. Starting treatment in the earliest stages of HIV-1 infection can limit the number of these latently infected cells, raising the possibility that these viral reservoirs are naturally eliminated if suppressive antiretroviral treatment is continued for extremely long periods of time. Here, we analyzed nine patients who started on antiretroviral therapy within the earliest weeks of the disease and continued treatment for more than 10 years. Our data show that early treatment accelerated the decay of infected CD4 T cells and led to very low residual levels of detectable HIV-1 after long-term therapy, levels that were otherwise detectable in patients who are able to maintain a spontaneous, drug-free control of HIV-1 replication. Thus, long-term antiretroviral treatment started during early infection cannot eliminate HIV-1, but the reduced reservoirs of HIV-1 infected cells in such patients may increase their chances to respond to clinical interventions aiming at inducing a drug-free remission of HIV-1 infection.