A First Estimate of the Annual Prevalence of Basivertebral Nerve Ablation Candidates in a Spine Clinic.

BACKGROUND: Emerging literature supports the use of basivertebral nerve ablation (BVNA) for a specific cohort of patients with chronic low back pain and Type 1 or Type 2 Modic changes from vertebral levels L3-S1. The early literature warrants further evaluation. Studies establishing the efficacy of BVNA use highly selective patient criteria. OBJECTIVE: Provide a first estimate of the prevalence of BVNA candidates in a spine clinic over a year using the foundational studies patient selection criteria? METHODS: A retrospective review of four fellowhsip trained spine physiatrists patient encounters at a large academic medical center using relevant ICD-10 codes to isolate chronic low back pain without radiating symptoms from January 1, 2019 to January 1, 2020. Charts were then reviewed by a team of physicians for exclusionary criteria from the foundational studies which have demonstrated benefit from BVNA. MRI's from qualifying charts which did not meet exclusionary criteria were then independently reviewed by four physician for localization and characterization of Modic changes. RESULTS: The relevant diagnostic codes query yielded 338 unique patient records. Based on exclusionary criteria or lack of imaging availability, 318 charts were eliminated. The remaining 20 charts qualified for imaging review. There were 11 charts in which there was 100% agreement between all reviewers regarding the presence and either Type 1 or Type 2 Modic changes between vertebral levels L3 to S1. Accordingly, the prevalence of eligibility for BVNA was 3% (11/338, 95% CI 1-5%). CONCLUSION: The population which may benefit from BVNA is small. Our study demonstrated that over a year, the prevalence for BVNA candidacy using the foundational studies criteria was 3% (95% CI 1% - 5%). While physicians may be tempted to use less stringent selection criteria in practice, upon doing so they cannot cite the foundational studies as evidence for the outcomes they expect to achieve. Those outcomes will require more studies which formally assess the benefits of BVNA when selection criteria are relaxed.

Reviving through human hippocampal newborn neurons.

Recent contradictory data has renewed discussion regarding the existence of adult hippocampal neurogenesis (AHN) in humans, i.e., the continued production of new neurons in the brain after birth. The present review revisits the debate of AHN in humans from a historical point of view in the face of contradictory evidence, analyzing the methods employed to investigate this phenomenon. Thus, to date, of the 57 studies performed in humans that we reviewed, 84% (48) concluded in favor of the presence of newborn neurons in the human adult hippocampus. Besides quality of the tissue (such as postmortem intervals below 26hours as well as tissue conservation and fixation), considerations for assessing and quantify AHN in the human brain require the use of stereology and toxicological analyses of clinical data of the patient.

[Consequences of the monoaminergic systems cross-talk in the antidepressant activity]. / Conséquences de l'inter-relation des systèmes monoaminergiques dans l'activité antidépressive.

Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressant treatment for treat major depressive disorders. Despite their effectiveness, only 30% of SSRI-treated patients reach remission of depressive symptoms. SSRIs by inhibiting the serotonin transporter present some limits with residual symptoms. Increasing not only serotonin but also norepinephrine and dopamine levels in limbic areas seems to improve remission. Anatomical relationships across serotoninergic, dopaminergic and noradrenergic systems suggest tight reciprocal regulations among them. This review attempts to present, from acute to chronic administration the consequences of SSRI administration on monoaminergic neurotransmission. The serotonin neurons located in the raphe nucleus (RN) are connected to the locus coeruleus (locus coeruleus), the key structure of norepinephrine synthesis, through GABAergic-inhibiting interneurons. Activation of the 5-HT2A receptors expressed on GABAergic interneurons following SERT-inhibition induces an increase in serotonin leading to inhibitory effect on NE release. Similarly, the serotonin neurons exert negative regulation on dopaminergic neurons from the ventral tegmental area (VTA) through a GABAergic interneuron. These interneurons express the 5-HT2C and 5-HT3 receptors inducing an inhibitory effect of 5-HT on DA release. Positive reciprocal connections are also observed through direct projections from the locus coeruleus to the RN and from the VTA to the RN through α1 and D2 receptors respectively, both stimulating the serotoninergic activity. Acute SSRI treatment induces only a slight increase in 5-HT levels in limbic areas due to the activation of presynaptic 5-HT1A and 5-HT1B autoreceptors counteracting the effects of the transporter blockade. No change in NE levels and a small decrease in the dopaminergic neurotransmission is also observed. These weak changes in monoamine in the limbic areas after acute SSRI treatment seems to be one of key point involved in the onset of action. Following desensitization of the 5-HT1A and 5-HT1B autoreceptors, chronic SSRI treatment induces a large increase in the 5-HT neurotransmission. Changes in 5-HT levels at the limbic areas results in a decrease in NE transmission and an increase in DA transmission through an increase in the post-synaptic D2 receptors sensitivity and not from a change in DA levels, which is mainly due to a desensitization of the 5-HT2A receptor. The observed decrease of NE neurotransmission could explain some limits of the SSRI therapy and the interest to activate NE system for producing more robust effects. On the other hand, the D2 sensitization, especially in the nucleus accumbens, stimulates the motivation behavior as well as remission of anhedonia considering the major role of DA release in this structure. Finally, we need to take into account the key role of each monoaminergic neurotransmission to reach remission. Targeting only one system will limit the therapeutic effectiveness. Clinical evidences, including the STAR*D studies, confirmed this by an increase of the remission rate following the mobilization of several monoaminergic transmissions. However, these combinations cannot constitute first line of treatment considering the observed increase of side effects. Such an approach should be adapted to each patient in regard to its particular symptoms as well as clinical history. The next generation of antidepressant therapy will need to take into consideration the interconnections and the interrelation between the monoaminergic systems.

[The pharmacological basis of the serotonin system: Application to antidepressant response]. / Les bases de pharmacologie fondamentale du système sérotoninergique : application à la réponse antidépressive.

If serotonin (5-hydroxytryptamin [5-HT]) is well known for its role in mood regulation, it also impacts numerous physiological functions at periphery. Serotonin is synthetized at the periphery into the gut by intestinal enterochromaffin cells and in the central nervous system (CNS) in the raphe nucleus from the essential amino acid tryptophan. Physiological effects of 5-HT are mediated by about 15 serotoninergic receptors grouped into seven broad families (5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, 5-HT7 receptor families). Except 5-HT3 receptor, a ligand-gated ion channels, all the others are G protein-coupled receptors. Serotonin's homeostasis involves serotoninergic autoreceptor such as 5-HT1A, 5-HT1B, 5-HT1D, the enzymatic degradation of serotonin by monoamine oxidase A (MAO-A), and a transporter (serotoninergic transporter [SERT]). In the CNS, the SERT is a key target for various antidepressant drugs such as Selective Serotonin Reuptake Inhibitors (SSRI), Serotonin Norepinephrin Reuptake Inhibitors (SNRI) and tricyclics family. However, antidepressant activity of SERT inhibitors is not directly mediated by the SERT inhibition, but a consequence of postsynaptic 5-HT receptor activation following the increase in 5-HT levels in the synaptic cleft. In pharmacology, SSRIs are defined as indirect agonist of postsynaptic receptor. Among all the 5-HT receptors, 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2B and 5-HT4 receptors activation would mediate antidepressant effects. In the meanwhile, 5-HT2A, 5-HT2C, 5-HT3, 5-HT6 and 5-HT7 receptors activation would induce opposite effects. The best serotoninergic antidepressant would directly activate 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2B and 5-HT4 and would block 5-HT2A, 5-HT2C, 5-HT3, 5-HT6 and 5-HT7 receptor. If the chemical synthesis of such a compound may be compromised, SERT inhibition associated with the blockade of some but not all 5-HT receptor could shorten onset of action and/or improve antidepressant efficacy on the overall symptomatology of depression.

[Antidepressant and tolerance: Determinants and management of major side effects]. / Antidépresseurs et tolérance : déterminants et prise en charge des principaux effets indésirables.

Antidepressant therapy aims to reach remission of depressive symptoms while reducing the complications and risks of relapse. Even though they have proven their efficacy, it takes several weeks for antidepressants to demonstrate full effectiveness, and adverse effects occur more quickly or (quicker) which can be a source of poor compliance. This latest aspect often leads to dose reduction and/or change of molecule that have the effect of delaying remission. This review attempts to present, from the pharmacological properties of the major classes of antidepressants (monoamine oxidase inhibitor [MAOI], tricyclic antidepressants [TCA], selective serotonin reuptake inhibitor [SSRI] and serotonin and noradrenaline reuptake inhibitor [SNRI]), to the pharmacological mechanisms involved in adverse effects by focusing on sexual dysfunction, nausea/vomiting, and weight changes and sleep disruption. If the activation of dopamine D1/2 or norepinephrine receptors through the autonomic nervous system controls and facilitates sexual desire, increasing serotoninergic transmission through 5-HT1B/2A/2C receptors activation inhibits this process. The pharmacological properties of drugs inducing nausea/vomiting activate opiate receptors µ, increase dopaminergic and serotoninergic transmission activating the dopamine D2 and serotonin 5-HT3 receptors, respectively. Among the causes responsible for weight gain under antidepressant therapy, monoamine neurotransmission still plays an important role. The blockade of serotonin 5-HT2C or histamine H1 receptors is directly responsible for weight gain. Finally, the activation of 5-HT1A/1B/3/7 serotoninergique receptors modulates wakefulness, raid eyes movement or sleep duration. In conclusion, if antidepressant activity of SERT or MAO inhibitors is an indirect consequence of postsynaptic 5-HT, DA, NA receptor activation, it is also responsible for side effects, causes of poor compliance and hence therapeutic failures. Finally, we need to take into account the key role of the nocebo effect in the occurrence of adverse effects. The next generation of antidepressant would aim to have a rapid efficacy in patients unresponsive or resistant to drugs currently available while improving certain effects of tolerance through an optimization of their psychopharmacological properties leading to a reduction of their side effects.

[Pharmacological properties of vortioxetine and its pre-clinical consequences]. / Propriétés pharmacologiques de la vortioxetine et leurs conséquences pré-cliniques.

Selective Serotonin Reuptake Inhibitors (SSRIs) are extensively used for the treatment of major depressive disorder (MDD). SSRIs are defined as indirect receptor agonists since the activation of postsynaptic receptors is a consequence of an increase in extracellular concentrations of serotonin (5-HT) mediated by the blockade of serotonin transporter. The activation of some serotoninergic receptors (5-HT1A, post-synaptic, 5-HT1B post-synaptic, 5-HT2B, and 5-HT4), but not all (5-HT1A, pre-synaptic, 5-HT1B pre-synaptic, 5-HT2A, 5-HT2C, 5-HT3, and probably 5-HT6), induces anxiolytic/antidepressive - like effects. Targetting specifically some of them could potentially improve the onset of action and/or efficacy and/or prevent MD relapse. Vortioxetine (Brintellix, 1- [2-(2,4-dimethylphenyl-sulfanyl)-phenyl]-piperazine) is a novel multi-target antidepressant drug approved by the Food and Drug Administration (FDA) and by European Medicines Agency. Its properties are markedly different from the extensively prescribed SSRIs. Compared to the SSRIs, vortioxetine is defined as a multimodal antidepressant drug since it is not only a serotonin reuptake inhibitor, but also a 5-HT1D, 5-HT3, 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist and 5-HT1A receptor agonist. This specific pharmacological profile enables vortioxetine to affect not only the serotoninergic and noradrenergic systems, but also the histaminergic, cholinergic, gamma-butyric acid (GABA) ergic and glutamatergic ones. Thus, vortioxetine not only induces antidepressant-like or anxiolytic-like activity but also improves cognitive parameters in several animal models. Indeed, vortioxetine was shown to improve working memory, episodic memory, cognitive flexibility and spatial memory in young adult rodents and also in old animal models. These specific effects of the vortioxetine are of interest considering that cognitive dysfunction is a common comorbidity to MDD. Altogether, even though this molecule still needs to be investigated further, especially in the insufficient-response to antidepressant drugs, vortioxetine is already an innovative therapeutic option for the treatment of major depression.

Testing an Imagery Rescripting Exercise Targeting Fear of Self.

A feared possible self refers to the unwanted characteristics that a person may possess or develop. We tested an experimental paradigm to target fear of possible self using imagery rescripting. A student sample (n = 91), with moderate obsessive-compulsive disorder symptoms, engaged in written and audio-guided exercises to evoke episodic future mental imagery that represented their feared possible self. Participants were then randomized between imagery rescripting or neutral imagery control tasks. The results revealed no difference between conditions in fear of self or general obsessional beliefs following the manipulation. State anxiety and the urge to neutralize the imagery reduced more in the control condition than in the rescripting condition. These findings suggest that the current paradigm is emotionally engaging but not effective at addressing fear of self as measured. Methodological improvements such as removing a written component of the rescripting task and idiosyncratic measuring of fear of self are proposed.

Basic processes and clinical applications of mental imagery in worry: A systematic review.

BACKGROUND: In this systematic review, we aimed to synthesise existing research on the phenomenology of mental imagery among high worriers compared to healthy individuals, and to characterise the nature and effectiveness of existing imagery-related interventions in treatment of worry. METHODS: PsycInfo, CENTRAL, EMBASE, Medline, Medline Epub, and PubMed were searched for studies examining the relationship between worry/GAD and mental imagery, or interventions using imagery in treatment of worry/GAD. We assessed study quality and used qualitative narrative synthesis to comprehensively map study results. RESULTS: The search yielded 2589 abstracts that were assessed for eligibility independently by two authors. From this, 183 full texts were screened and 50 qualitatively synthesised. Twenty-seven reported an association between worry/GAD and an aspect of mental imagery. Here, overactive negative and worry imagery, and diminished positive future imagining, were associated with worry/GAD. Twenty-three studies reported an intervention. This literature suggested mixed findings regarding efficacy, including for imaginal exposure as an independent technique for GAD. CONCLUSIONS: Findings support dysfunctional negative imagining and diminished positive prospective imagery in GAD. General imagining abilities remain intact, which is promising for efforts to utilise imagery in treatment. Further research is warranted to develop innovative clinical applications of imagery in treatment of GAD.

Altered skeletal muscle mitochondrial biogenesis but improved endurance capacity in trained OPA1-deficient mice.

The role of OPA1, a GTPase dynamin protein mainly involved in the fusion of inner mitochondrial membranes, has been studied in many cell types, but only a few studies have been conducted on adult differentiated tissues such as cardiac or skeletal muscle cells. Yet OPA1 is highly expressed in these cells, and could play different roles, especially in response to an environmental stress like exercise. Endurance exercise increases energy demand in skeletal muscle and repeated activity induces mitochondrial biogenesis and activation of fusion-fission cycles for the synthesis of new mitochondria. But currently no study has clearly shown a link between mitochondrial dynamics and biogenesis. Using a mouse model of haploinsufficiency for the Opa1 gene (Opa1(+/-)), we therefore studied the impact of OPA1 deficiency on the adaptation ability of fast skeletal muscles to endurance exercise training. Our results show that, surprisingly, Opa1(+/-) mice were able to perform the same physical activity as control mice. However, the adaptation strategies of both strains after training differed: while in control mice mitochondrial biogenesis was increased as expected, in Opa1(+/-) mice this process was blunted. Instead, training in Opa1(+/-) mice led to an increase in endurance capacity, and a specific adaptive response involving a metabolic remodelling towards enhanced fatty acid utilization. In conclusion, OPA1 appears necessary for the normal adaptive response and mitochondrial biogenesis of skeletal muscle to training. This work opens new perspectives on the role of mitochondrial dynamics in skeletal muscle cells and during adaptation to stress.

Genotype and clinical care correlations in craniosynostosis: findings from a cohort of 630 Australian and New Zealand patients.

Craniosynostosis is one of the most common craniofacial disorders encountered in clinical genetics practice, with an overall incidence of 1 in 2,500. Between 30% and 70% of syndromic craniosynostoses are caused by mutations in hotspots in the fibroblast growth factor receptor (FGFR) genes or in the TWIST1 gene with the difference in detection rates likely to be related to different study populations within craniofacial centers. Here we present results from molecular testing of an Australia and New Zealand cohort of 630 individuals with a diagnosis of craniosynostosis. Data were obtained by Sanger sequencing of FGFR1, FGFR2, and FGFR3 hotspot exons and the TWIST1 gene, as well as copy number detection of TWIST1. Of the 630 probands, there were 231 who had one of 80 distinct mutations (36%). Among the 80 mutations, 17 novel sequence variants were detected in three of the four genes screened. In addition to the proband cohort there were 96 individuals who underwent predictive or prenatal testing as part of family studies. Dysmorphic features consistent with the known FGFR1-3/TWIST1-associated syndromes were predictive for mutation detection. We also show a statistically significant association between splice site mutations in FGFR2 and a clinical diagnosis of Pfeiffer syndrome, more severe clinical phenotypes associated with FGFR2 exon 10 versus exon 8 mutations, and more frequent surgical procedures in the presence of a pathogenic mutation. Targeting gene hot spot areas for mutation analysis is a useful strategy to maximize the success of molecular diagnosis for individuals with craniosynostosis.

5-HT2A receptor inactivation potentiates the acute antidepressant-like activity of escitalopram: involvement of the noradrenergic system.

Evidence suggests that the serotonin 2A receptor (5-HT2AR) modulates the therapeutic activity of selective serotonin reuptake inhibitors (SSRIs). Indeed, among the genetic factors known to influence the individual response to antidepressants, the HTR2A gene has been associated with SSRIs response in depressed patients. However, in these pharmacogenetic studies, the consequences of HTR2A gene polymorphisms on 5-HT2AR expression or function are lacking and the precise role of this receptor is still matter of debate. This study examined the effect of 5-HT2AR agonism or antagonism with DOI and MDL100907, respectively, on the serotonergic system and the antidepressant-like activity of the SSRI escitalopram in mouse. The 5-HT2AR agonist DOI decreased the firing rate of 5-HT neurons in the dorsal raphe (DR) nucleus of 5-HT2AR(+/+) anesthetized mice. This inhibitory response persisted in 5-HT2CR(-/-) but was completely blunted in 5-HT2AR(-/-) mutants. Moreover, the suppressant effect of DOI on DR 5-HT neuronal activity in 5-HT2AR(+/+) mice was attenuated by the loss of noradrenergic neurons induced by the neurotoxin DSP4. Conversely, in 5-HT2AR(+/+) mice, the pharmacological inactivation of the 5-HT2AR by the selective antagonist MDL100907 reversed escitalopram-induced decrease in DR 5-HT neuronal activity. Remarkably, in microdialysis experiments, a single injection of escitalopram increased cortical extracellular 5-HT, but not NE, levels in awake 5-HT2AR(+/+) mice. Although the addition of MDL100907 did not potentiate 5-HT neurotransmission, it allowed escitalopram to increase cortical NE outflow and consequently to elicit an antidepressant-like effect in the forced swimming test. These results suggest that the blockade of the 5-HT2AR may strengthen the antidepressant-like effect of escitalopram by facilitating the enhancement of the brain NE transmission. They provide support for the use of atypical antipsychotics with SSRIs as a relevant antidepressant augmentation strategy.

Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome.

Apert syndrome is a distinctive human malformation comprising craniosynostosis and severe syndactyly of the hands and feet. We have identified specific missense substitutions involving adjacent amino acids (Ser252Trp and Pro253Arg) in the linker between the second and third extracellular immunoglobulin (Ig) domains of fibroblast growth factor receptor 2 (FGFR2) in all 40 unrelated cases of Apert syndrome studied. Crouzon syndrome, characterized by craniosynostosis but normal limbs, was previously shown to result from allelic mutations of the third Ig domain of FGFR2. The contrasting effects of these mutations provide a genetic resource for dissecting the complex effects of signal transduction through FGFRs in cranial and limb morphogenesis.

Adult hippocampal neurogenesis: an actor in the antidepressant-like action.

Depression and anxiety are psychiatric illnesses that are major burdens in society and affect as much as 7% of the world's population. The heterogeneous nature of depression suggests an involvement of multiple distinct brain regions including amygdala, prefrontal cortex and the hippocampus, which may be responsible for the diversity of the symptoms. Besides its critical role in learning and memory, the hippocampus is one of only two areas in mammalian brain where adult neurogenesis occurs. Of the current leading hypotheses of the pathophysiology and treatment of depression, the neurogenesis hypothesis of depression deserves particular attention because changes in neurogenesis are only seen after chronic, but not acute, antidepressant treatment. This review revisits the role of adult hippocampal neurogenesis in the pathophysiology of mood disorders, especially anxiety/depression, and also in the antidepressant-like responses, especially in stressed rodents.

Learning from intermittent water supply schedules: Visualizing equality, equity, and hydraulic capacity in Bengaluru and Delhi, India.

Intermittent distribution affects one in five piped water users, threatens water quality, and magnifies inequity. Research and regulations to improve intermittent systems are hindered by system complexity and missing data. We created four new methods to visually harness insights from intermittent supply schedules and demonstrate these methods in two of the world's most complicated intermittent systems. First, we created a new way to visualize the varieties of supply continuities (hours/week of supply) and supply frequencies (days between supplies) within complicated intermittent systems. We demonstrated using Delhi and Bengaluru, where 3278 water schedules vary from continuous to only 30 minutes/week. Second, we quantified equality based on how uniformly supply continuity and frequency were divided between neighbourhoods and cities. Delhi provides 45 % more supply continuity than Bengaluru, but with similar inequality. Bengaluru's infrequent schedules require consumers to store four times more water (for four times longer) than in Delhi, but Bengaluru's storage burden is more equally shared. Third, we considered supply inequitable where affluent neighbourhoods (using census data) received better service. Neighbourhood wealth was inequitably correlated with the percent of households with piped connections. In Bengaluru, supply continuity and required storage were also inequitably divided. Finally, we inferred hydraulic capacity from the coincidence of supply schedules. Delhi's highly coincident schedules result in city-wide peak flows 3.8 times their average - sufficient for continuous supply. Bengaluru's inconvenient nocturnal schedules may indicate upstream hydraulic limitations. Towards improved equity and quality, we provided four new methods to harness key insights from intermittent water supply schedules.

Culex Y Virus: A Native Virus of Culex Species Characterized In Vivo.

Mosquitoes are vectors of various pathogens that cause diseases in humans and animals. To prevent the outbreak of mosquito-borne diseases, it is essential to control vector populations, as treatment or vaccination for mosquito-borne diseases are often unavailable. Insect-specific viruses (ISVs) have previously been described as being potentially helpful against arboviral disease outbreaks. In this study, we present the first in vivo characterization of the ISV Culex Y virus (CYV). CYV was first isolated from free-living Culex pipiens mosquitoes in 2010; then, it was found in several mosquito cell lines in a further study in 2018. For mammalian cells, we were able to confirm that CYV does not replicate as it was previously described. Additionally, we found that CYV does not replicate in honey bees or locusts. However, we detected replication in the Culex pipiens biotype molestus, Aedes albopictus, and Drosophila melanogaster, thus indicating dipteran specificity. We detected significantly higher mortality in Culex pipiens biotype molestus males and Drosophila melanogaster, but not in Aedes albopictus and female Culex pipiens biotype molestus. CYV could not be transmitted transovarially to offspring, but we detected venereal transmission as well as CYV in mosquitos' saliva, indicating that an oral route of infection would also be possible. CYV's dipteran specificity, transmission routes, and killing effect with respect to Culex males may be used as powerful tools with which to destabilize arbovirus vector populations in the future.

Effects of hydraulically disconnecting consumer pumps in an intermittent water supply.

We estimate 250 million people receive water using private pumps connected directly to intermittently pressurized distribution networks. Yet no previous studies have quantified the presumed effects of these pumps. In this paper, we investigate the effects of installing pressure-sustaining valves at consumer connections. These valves mimic pump disconnection by restricting flow. Installing these valves during the dry season at 94% of connections in an affluent neighborhood in Delhi, India, cut the prevalence of samples with turbidity > 4 NTU by two thirds. But considering the poor reputation of pumps, installed valves had surprisingly small average effects on turbidity (-8%; p<0.01) and free chlorine (+0.05 mg/L; p<0.001; N = 1,031). These effects were much smaller than the high variability in water quality supplied to both control and valve-installed neighborhoods. Site-specific responses to this variability could have confounded our results. At the study site, installed valves increased network pressure during 88% of the typical supply window; valves had a maximum pressure effect of +0.62 m (95% CI [0.54, 0.71]; a 40% increase vs. control). Further research is needed to generalize beyond our study site. Nevertheless, this paper provides unique evidence showing how the deployed valves mitigated pump effects, increased network pressure and improved water safety.

Impact of Low-Cost Point-of-Use Water Treatment Technologies on Enteric Infections and Growth among Children in Limpopo, South Africa.

Enteric infections early in life have been associated with poor linear growth among children in low-resource settings. Point-of-use water treatment technologies provide effective and low-cost solutions to reduce exposure to enteropathogens from drinking water, but it is unknown whether the use of these technologies translates to improvements in child growth. We conducted a community-based randomized controlled trial of two water treatment technologies to estimate their effects on child growth in Limpopo, South Africa. We randomized 404 households with a child younger than 3 years to receive a silver-impregnated ceramic water filter, a silver-impregnated ceramic tablet, a safe-storage water container alone, or no intervention, and these households were followed up quarterly for 2 years. We estimated the effects of the interventions on linear and ponderal growth, enteric infections assessed by quantitative molecular diagnostics, and diarrhea prevalence. The silver-impregnated ceramic water filters and tablets consistently achieved approximately 1.2 and 3 log reductions, respectively, in total coliform bacteria in drinking water samples. However, the filters and tablets were not associated with differences in height (height-for-age z-score differences compared with no intervention: 0.06, 95% CI: -0.29, 0.40, and 0.00, 95% CI: -0.35, 0.35, respectively). There were also no effects of the interventions on weight, diarrhea prevalence, or enteric infections. Despite their effectiveness in treating drinking water, the use of the silver-impregnated ceramic water filters and tablets did not reduce enteric infections or improve child growth. More transformative water, sanitation, and hygiene interventions that better prevent enteric infections are likely needed to improve long-term child growth outcomes.

Management of cranial deformity following ventricular shunting.

PURPOSE: Ventricular shunt-induced craniosynostosis is a widely recognised cause of secondary craniosynostosis. We reviewed the management and long-term outcome of the cases of cranial deformity post cerebrospinal fluid shunting in our unit and compared these with previously published series. METHODS: The Australian Craniofacial Unit and Department of Neurosurgery database was searched to identify cases of ventricular shunt-induced cranial deformity and a case note review was undertaken. RESULTS: Eight cases were identified, and all were shunted within 6 months of birth. Our patients required shunting with a low pressure valve for hydrocephalus secondary to either aqueduct stenosis or intraventricular haemorrhage. The diagnosis was made following computed tomography (CT) three-dimensional surface reconstruction of the skull. Two cases of confirmed suture fusion were treated with cranial vault remodelling and programmable shunt insertion. In six cases, the sutures were not completely fused on the CT images despite a scaphocephalic head shape. These patients were managed conservatively with close monitoring. CONCLUSION: Cranial vault remodelling together with insertion of programmable shunt valve is indicated in CT confirmed cases of secondary craniosynostosis.

Behavioral and serotonergic consequences of decreasing or increasing hippocampus brain-derived neurotrophic factor protein levels in mice.

Antidepressants such as Selective Serotonin Reuptake Inhibitors (SSRI) act as indirect agonists of serotonin (5-HT) receptors. Although these drugs produce a rapid blockade of serotonin transporters (SERTs) in vitro, several weeks of treatment are necessary to observe clinical benefits. This paradox has not been solved yet. Recent studies have identified modifications of intracellular signaling proteins and target genes that could contribute to antidepressant-like activity of SSRI (e.g., increases in neurogenesis and BDNF protein levels), and may explain, at least in part, their long delay of action. Although these data suggest a positive regulation of 5-HT on the expression of the gene coding for BDNF, the reciprocal effects of BDNF on brain 5-HT neurotransmission remains poorly documented. To study the impact of BDNF on serotonergic activity, a dual experimental strategy was used to analyze neurochemical and behavioral consequences of its decrease (strategy 1) or increase (strategy 2) in the brain of adult male mice. (1) In heterozygous BDNF+/- mice in which brain BDNF protein levels were decreased by half, an enhancement of basal extracellular 5-HT levels (5-HText) that induced a down-regulation of SERT, i.e., a decrease in its capacity to reuptake 5-HT, was found in the hippocampus. In addition, the SSRI, paroxetine, failed to increase hippocampal 5-HText in BDNF+/- mice, while it produces robust effects in wild-type littermates. Thus, BDNF+/- mice can be viewed as an animal model of genetic resistance to serotonergic antidepressant drugs. (2) In wild-type BDNF+/+ mice, the effects of intra-hippocampal (vHi) injection of BDNF (100 ng) in combination with a SSRI was examined by using intracerebral microdialysis and behavioral paradigms that predict an antidepressant- and anxiolytic-like activity of a molecule [the forced swim test (FST) and the open field paradigm (OF) respectively]. BDNF induced a rapid and transient increase in paroxetine response on 5-HText in the adult hippocampus, which was correlated with a potentiation of its antidepressant-like activity in the FST. The effects of BDNF were selectively blocked by K252a, an antagonist of its high-affinity TrkB receptor. Such a correlation between neurochemical and behavioral effects of [BDNF+SSRI] co-administration suggests that its antidepressant-like activity is linked to the activation of 5-HT neurotransmission in the adult hippocampus. BDNF also had a facilitatory effect on anxiety-like behavior in the OF test, and paroxetine prevented this anxiogenesis. What was the mechanism by which BDNF exerted these latter effects? Surprisingly, by using zero net flux method of quantitative microdialysis in vivo, we found that an intra-hippocampal BDNF injection in wild-type mice decreased the functional activity of SERT as observed in BDNF+/- mice. However, the decreased capacity of SERT to reuptake 5-HT was not associated to an increase in basal 5-HText in the hippocampus of WT mice. Interestingly, using in situ hybridization experiments indicated that TrkB receptor mRNA was expressed in the hippocampus and dorsal raphe nucleus in adult mice suggesting that the neurochemical and behavioral effects of intra-hippocampal BDNF injection can mobilize both pre- and post-synaptic elements of the brain 5-HT neurotransmission. Taken together, these set of experiments unveiled a relative opposition of neurochemical and behavioral responses following either a decrease (in BDNF+/- mutant mice) or an increase in brain BDNF levels (bilateral intra-hippocampal injection) in adult mice. In view of developing new antidepressant drug strategy, a poly-therapy combining BDNF with a chronic SSRI treatment could thus improve the efficacy of current medications.