Fine-tuning GPCR-mediated neuromodulation by biasing signaling through different G protein subunits.

G-protein-coupled receptors (GPCRs) mediate neuromodulation through the activation of heterotrimeric G proteins (Gαßγ). Classical models depict that G protein activation leads to a one-to-one formation of Gα-GTP and Gßγ species. Each of these species propagates signaling by independently acting on effectors, but the mechanisms by which response fidelity is ensured by coordinating Gα and Gßγ responses remain unknown. Here, we reveal a paradigm of G protein regulation whereby the neuronal protein GINIP (Gα inhibitory interacting protein) biases inhibitory GPCR responses to favor Gßγ over Gα signaling. Tight binding of GINIP to Gαi-GTP precludes its association with effectors (adenylyl cyclase) and, simultaneously, with regulator-of-G-protein-signaling (RGS) proteins that accelerate deactivation. As a consequence, Gαi-GTP signaling is dampened, whereas Gßγ signaling is enhanced. We show that this mechanism is essential to prevent the imbalances of neurotransmission that underlie increased seizure susceptibility in mice. Our findings reveal an additional layer of regulation within a quintessential mechanism of signal transduction that sets the tone of neurotransmission.

INTEREST OF REGULAR ASSAYS OF AQUEOUS HUMOR INTERLEUKIN-10 LEVELS IN MONITORING OF VITREORETINAL LYMPHOMA.

PURPOSE: To investigate the variation of interleukin-10 (IL-10) levels in the aqueous humor (AH) of patients with vitreoretinal lymphoma (VRL) throughout therapy and follow-up and analyze the relation of these variations with VRL clinical course and relapse. METHODS: This study retrospectively included consecutive patients diagnosed with VRL in a single center. AH IL-10 samples and patient clinical course were evaluated. The response to treatment was evaluated according to the criteria set by the International Primary Central Nervous System Lymphoma Collaborative Group. RESULTS: A total of 59 eyes of 34 patients were included. Interleukin-10 levels decreased significantly at first AH sample after therapy induction (median [IQR] 3.0 [2.8-3.6] months) among patients in complete clinical remission (P < 0.001). Among patients in complete clinical remission with residual detectable IL-10 in AH after therapy induction (85.3% systemic chemotherapy, 11.8% intravitreal methotrexate, 2.9% palliative care), 87.5% experienced ocular relapse within 5 years. The detection of IL-10 in AH at the first visit after induction for complete clinical remission obtained a sensitivity of 77.8% (95% CI 0.45-0.96) and a specificity of 96.4% (95% CI 0.82-0.99) to predict ocular relapse. For relapsing eyes (N = 26), IL-10 significantly increased between the last IL-10 measurement and the time of the first ocular relapse (P < 0.001). In 76.0% of cases, an increase in IL-10 was detected earlier than clinical relapse with a mean (SD) of 4.0 (2.4) months. CONCLUSION: The present study suggested the usefulness of IL-10 in the prognosis of VRL. This study showed a relation between IL-10 in AH and tumoral activity, and for the first time with disease relapse.

Visual outcomes of macular melanocytic lesions after early or delayed proton beam therapy.

PURPOSE: During their initial management, some macular melanocytic lesions can be closely monitored to wait for a documented growth before advocating a treatment by irradiation. However, the visual outcomes of this strategy have not yet been assessed. This study compares the visual outcomes of macular melanocytic lesions that underwent delayed proton beam therapy (PBT) after an initial observation to those treated early. METHODS: A total of 162 patients with suspicious melanocytic lesions whose margins were located within 3 mm of the fovea were recruited from two French ocular oncology centers. RESULTS: Overall, 82 patients treated with PBT within 4 months after the initial visit (early PBT group) were compared to 24 patients treated with delayed PBT (delayed PBT group) and 56 patients not treated with PBT (observation group). Visual acuity was not significantly different between baseline and last visit in the observation group (p = 0.325). Between baseline and last visit, the median [IQR] loss in visual acuity was significant in both the early (0.7 [0.2; 1.8], p < 0.001) and the delayed (0.5 [0.2; 1.5], p < 0.001) PBT groups. After irradiation, there was no significant difference between the early and delayed PBT groups for visual loss (p = 0.575), diameter reduction (p = 0.190), and thickness lowering (p = 0.892). In multivariate analysis, history of diabetes mellitus and Bruch's membrane rupture remained significantly associated with greater visual loss (p = 0.036 and p = 0.002, respectively). CONCLUSION: For small lesions in which there is no clear diagnosis of malignant melanoma, an initial close monitoring to document tumor growth does not impact visual prognosis, despite the potential complications associated with the untreated tumor. However, the survival should remain the main outcome of the treatment of these lesions.

3D Object Detection for Self-Driving Cars Using Video and LiDAR: An Ablation Study.

Methods based on 64-beam LiDAR can provide very precise 3D object detection. However, highly accurate LiDAR sensors are extremely costly: a 64-beam model can cost approximately USD 75,000. We previously proposed SLS-Fusion (sparse LiDAR and stereo fusion) to fuse low-cost four-beam LiDAR with stereo cameras that outperform most advanced stereo-LiDAR fusion methods. In this paper, and according to the number of LiDAR beams used, we analyzed how the stereo and LiDAR sensors contributed to the performance of the SLS-Fusion model for 3D object detection. Data coming from the stereo camera play a significant role in the fusion model. However, it is necessary to quantify this contribution and identify the variations in such a contribution with respect to the number of LiDAR beams used inside the model. Thus, to evaluate the roles of the parts of the SLS-Fusion network that represent LiDAR and stereo camera architectures, we propose dividing the model into two independent decoder networks. The results of this study show that-starting from four beams-increasing the number of LiDAR beams has no significant impact on the SLS-Fusion performance. The presented results can guide the design decisions by practitioners.

CLINICAL FEATURES OF RETINAL METASTASES: New Cases Integrated in a Systematic Review of the Literature.

PURPOSE: To report a cohort of patients diagnosed with retinal metastases (RM), and to integrate these new cases in a systematic review of the literature, analyzing the clinical features and prognosis factors of patients with RM. METHODS: We conducted a retrospective multicenter study including patients with RM. We also performed a full literature review of all published cases with a diagnosis of RM. RESULTS: A total of six new cases were described on multimodal imaging. By combining the data from the literature and from our patients, we report the characteristics of a total of 69 patients. The most frequent primary tumor sites were cutaneous melanoma (36%), lung (23%), gastrointestinal tract (17%), and breast (12%). Multimodal imaging highlighted specific characteristics of RM. Fluorescein and indocyanine green angiography revealed early hypofluorescence followed by progressive filling of intrinsic dilated vessels. Optical coherence tomography demonstrated a hyperreflective intraretinal mass in all cases with or without subretinal fluid, hyperreflective intraretinal dots, or intraretinal fluid. Ultrasonography revealed a medium-high reflective dome-shaped tumor. Fifty-nine percent of the patients died during the follow-up with a mean survival time of 8.8 ± 8.7 months. CONCLUSION: We described here the clinical spectrum of RM and highlighted specific features of the disease.

QUANTITATIVE ANALYSIS OF CHORIOCAPILLARIS ALTERATIONS IN SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY-ANGIOGRAPHY DURING RADIATION RETINOPATHY.

PURPOSE: To evaluate choriocapillaris alterations following proton beam therapy irradiation using swept-source optical coherence tomography-angiography, and to assess their correlation with the grade of radiation retinopathy (RR). METHODS: Eyes with uveal melanoma evaluated before and after irradiation with proton beam therapy were included, as well as the healthy fellow eye. The gradation of RR was based on a previously published classification. Choriocapillaris flow voids area was analyzed using Phansalkar thresholding. Retinal vascularization was described by foveal avascular zone (FAZ) perimeter, FAZ area, FAZ circularity index, and percentage of nonperfusion area (PAN) in the superficial capillary plexus (SCP) or deep capillary plexus. RESULTS: A total of 157 eyes of 83 patients were analyzed. Overall, there was a significant difference between the control group, the uveal melanoma before proton beam therapy group, and the grades of RR in the uveal melanoma after proton beam therapy group for FAZ perimeter ( P < 0.001), FAZ area ( P < 0.001), FAZ-circularity index ( P < 0.001), PAN-SCP ( P < 0.001), PAN-deep capillary plexus ( P < 0.001), and choriocapillaris flow voids area ( P < 0.001). Moreover, choriocapillaris flow voids area was significantly increased in the early stages of RR ( P = 0.003) and was further significantly correlated with FAZ perimeter ( P < 0.001), FAZ area ( P < 0.001), FAZ-circularity index ( P = 0.010), PAN-SCP ( P < 0.001), and PAN-deep capillary plexus ( P < 0.001). CONCLUSION: Quantitative optical coherence tomography-angiography alterations in the choriocapillaris microvascularization are an early biomarker of RR and are correlated to the severity of the disease.

COMPARATIVE EFFECTIVENESS OF PROTON BEAM VERSUS PHOTODYNAMIC THERAPY TO SPARE THE VISION IN CIRCUMSCRIBED CHOROIDAL HEMANGIOMA.

PURPOSE: The aim of this study was to compare the functional and anatomical effectiveness of photodynamic therapy (PDT) versus proton beam therapy (PBT) in a real-life setting for the treatment of circumscribed choroidal hemangioma. METHODS: A total of 191 patients with a diagnosis of circumscribed choroidal hemangioma and treated by PBT or PDT were included for analyses. RESULTS: The 119 patients (62.3%) treated by PDT were compared with the 72 patients treated by PBT. The final best-corrected visual acuity did not differ significantly between the two groups (P = 0.932) and final thickness was lower in the PBT compared with the PDT group (P = 0.001). None of the patients treated by PBT needed second-line therapy. In comparison, 53 patients (44.5%) initially treated by PDT required at least one other therapy and were associated with worse final best-corrected visual acuity (P = 0.037). In multivariate analysis, only an initial thickness greater than 3 mm remained significant (P = 0.01) to predict PDT failure with an estimated odds ratio of 2.72, 95% confidence interval (1.25-5.89). CONCLUSION: Photodynamic therapy and PBT provide similar anatomical and functional outcomes for circumscribed choroidal hemangioma ≤3 mm, although multiple sessions are sometimes required for PDT. For tumors >3 mm, PBT seems preferable because it can treat the tumor in only 1 session with better functional and anatomical outcomes.

3D Object Detection with SLS-Fusion Network in Foggy Weather Conditions.

The role of sensors such as cameras or LiDAR (Light Detection and Ranging) is crucial for the environmental awareness of self-driving cars. However, the data collected from these sensors are subject to distortions in extreme weather conditions such as fog, rain, and snow. This issue could lead to many safety problems while operating a self-driving vehicle. The purpose of this study is to analyze the effects of fog on the detection of objects in driving scenes and then to propose methods for improvement. Collecting and processing data in adverse weather conditions is often more difficult than data in good weather conditions. Hence, a synthetic dataset that can simulate bad weather conditions is a good choice to validate a method, as it is simpler and more economical, before working with a real dataset. In this paper, we apply fog synthesis on the public KITTI dataset to generate the Multifog KITTI dataset for both images and point clouds. In terms of processing tasks, we test our previous 3D object detector based on LiDAR and camera, named the Spare LiDAR Stereo Fusion Network (SLS-Fusion), to see how it is affected by foggy weather conditions. We propose to train using both the original dataset and the augmented dataset to improve performance in foggy weather conditions while keeping good performance under normal conditions. We conducted experiments on the KITTI and the proposed Multifog KITTI datasets which show that, before any improvement, performance is reduced by 42.67% in 3D object detection for Moderate objects in foggy weather conditions. By using a specific strategy of training, the results significantly improved by 26.72% and keep performing quite well on the original dataset with a drop only of 8.23%. In summary, fog often causes the failure of 3D detection on driving scenes. By additional training with the augmented dataset, we significantly improve the performance of the proposed 3D object detection algorithm for self-driving cars in foggy weather conditions.

Influence of N-Methylation and Conformation on Almiramide Anti-Leishmanial Activity.

The almiramide N-methylated lipopeptides exhibit promising activity against trypanosomatid parasites. A structure-activity relationship study has been performed to examine the influences of N-methylation and conformation on activity against various strains of leishmaniasis protozoan and on cytotoxicity. The synthesis and biological analysis of twenty-five analogs demonstrated that derivatives with a single methyl group on either the first or fifth residue amide nitrogen exhibited greater activity than the permethylated peptides and relatively high potency against resistant strains. Replacement of amino amide residues in the peptide, by turn inducing α amino γ lactam (Agl) and N-aminoimidazalone (Nai) counterparts, reduced typically anti-parasitic activity; however, peptide amides possessing Agl residues at the second residue retained significant potency in the unmethylated and permethylated series. Systematic study of the effects of methylation and turn geometry on anti-parasitic activity indicated the relevance of an extended conformer about the central residues, and conformational mobility by tertiary amide isomerization and turn geometry at the extremities of the active peptides.

USE OF A THRESHOLD OF INTERLEUKIN-10 AND IL-10/IL-6 RATIO IN OCULAR SAMPLES FOR THE SCREENING OF VITREORETINAL LYMPHOMA.

PURPOSE: To determine a threshold for interleukin (IL)-10 and IL-10/IL-6 ratio in the aqueous humor (AH) and the vitreous for the screening of vitreoretinal lymphoma (VRL). METHODS: One hundred nineteen patients for whom IL-10 and IL-6 in the AH and/or vitreous had been measured were included: 16 patients with a final diagnosis of VRL and 103 patients with final diagnosis of uveitis. Groups were compared according to IL-10 and IL-6 levels and demographic data. RESULTS: In patients with VRL (Group 1), mean IL-10 values were 5,636 pg/mL, and in patients with uveitis (Group 2), 6.7 pg/mL in the vitreous and 190 pg/mL in Group 1 and 8.6 pg/mL in the AH. In Group 1, the mean IL-10/IL-6 ratio was 29.02 in the vitreous and 10.9 in the AH; in Group 2, ratio was 0.1 in both humors. These values were significantly different between patients with VRL and with uveitis (P < 0.001). A cutoff of 65 pg/mL and 30 pg/mL IL-10 in the vitreous and AH, respectively, was associated with sensitivity of 93% and 78%, respectively, and specificity of 100% and 97%, respectively. A ratio higher than 1 in the vitreous had sensitivity of 93% and specificity of 100%. CONCLUSION: Vitreoretinal lymphoma diagnosis is difficult, and tools like interleukin measurements in AH and vitreous can make it easier. The use of a cutoff for IL-10 and IL-10/IL-6 ratio could allow for an earlier diagnosis that may improve prognosis.

Synthesis of Ce2O2S and Gd2(1-y)Ce2yO2S Nanoparticles and Reactivity from in Situ X-ray Absorption Spectroscopy and X-ray Photoelectron Spectroscopy.

Lanthanide oxysulfide nanoparticles have recently attracted interest in view of their potential applications, such as lighting devices and MRI contrast agents, which requires a good stability in air and a controlled surface. In order to address these issues, in this work, air-sensitive Ce2O2S nanoparticles of hexagonal shape were successfully prepared and characterized under inert conditions. Bimetallic Gd2(1-y)Ce2yO2S nanoparticles of similar shape and size were also synthesized for the whole composition range (y from 0 to 1). X-ray diffraction structural data are found to follow Vegard's law up to y = 0.4, which is attributed to the loss of stability in air of Ce-rich nanocrystals beyond this threshold. This picture is supported by X-ray absorption spectra taken at the S K-edge and Ce L3-edge that show the partial oxidation of sulfide species and of CeIII to CeIV in the presence of air or water. A complementary near-ambient-pressure X-ray photoelectron spectroscopy study shows that at least two types of oxidized sulfur species form on the nanoparticle surface. Even in Gd2O2S nanoparticles that are generally considered to be air-stable, we found that sulfide ions are partially oxidized to sulfate in air. These results unveil the physicochemical mechanisms responsible for the surface reactivity of lanthanide oxysulfides nanoparticles in air.

TOLERANCE OF INTRAVITREAL DEXAMETHASONE IMPLANTS IN PATIENTS WITH OCULAR HYPERTENSION OR OPEN-ANGLE GLAUCOMA.

PURPOSE: Evaluate the pressure tolerance of dexamethasone implants in open-angle glaucoma (OAG+) patients and ocular hypertension (OHT+) patients compared with nonglaucomatous and nonhypertensive patients. METHODS: Retrospective observational 2-center, controlled study including 100 patients treated with intravitreal injections of dexamethasone, divided into 2 groups: Group 1, OAG+/OHT+ (n = 50), and Group 2, OAG-/OHT- (n = 50), matched for age and disease. Intraocular pressure (IOP) and hypotensive treatment were evaluated initially, at 8 days, and every month for 6 months after intravitreal treatment. The primary endpoint was IOP increase greater than 10 mmHg. RESULTS: Thirty-four percent of glaucomatous patients experienced a transient IOP increase greater than 10 mmHg versus 16% in the OAG-/OHT- group (P = 0.06). Intraocular pressure greater than 25 mmHg was recorded early on Day 8 in 6% of the OAG+ patients versus 2% of the OAG- patients. Fifty-four percent of the glaucoma patients increased their treatment, and hypotensive treatment was initiated in 38% of the OAG- patients (P = 0.1). Filtering surgery was only required in the OAG+/OHT+ group (6% versus 0%), particularly in dual-therapy and triple-therapy patients, who had a higher risk of filtering surgery (P = 0.008). CONCLUSION: Half of the OAG+ and OHT+ patients needed an add-on treatment, with early onset beginning on Day 8 in 6%. This emphasizes the need for IOP monitoring during treatment, especially for OAG+/OHT+ patients.

Risk Factors for In-Hospital Seizure and New-Onset Epilepsy in Coiling and Clipping Treatment of Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVE: To identify risk factors associated with in-hospital seizures and new-onset epilepsy in patients with aneurysmal subarachnoid hemorrhage (SAH) who underwent coiling embolization or clipping surgery. METHODS: This retrospective descriptive study included 195 patients diagnosed with aneurysmal SAH and treated with coiling embolization or clipping surgery between January 2018 and June 2022. RESULTS: Among the 195 patients meeting inclusion criteria, 9 experienced an onset seizure at the time of SAH. In-hospital seizures were observed in 33 patients, of which 24 were electrographic seizures detected in 24 patients with suspected subclinical seizures. After 12 months of follow-up, 11 patients met criteria for diagnosis of epilepsy. The incidence of epilepsy after discharge at 12 months was 2.41% in the coiling group and 8.03% in the clipping group. The risk of in-hospital seizures was significantly higher in the clipping group (P = 0.007), although the difference was not statistically significant after 12 months of follow-up (P = 0.121). CONCLUSIONS: Epilepsy following aneurysmal SAH was relatively common. Clipping surgery and brain edema emerged as independent predictive factors for in-hospital seizures, while onset seizures and in-hospital seizures were identified as independent predictors of epilepsy during follow-up. Patients presenting with these risk factors may benefit from long-term electroencephalogram monitoring and should be considered for prophylactic antiepileptic drugs. Additionally, lumbar drainage proved effective in improving both early and late epileptic outcomes in the group with Fisher grades 3 and 4.

Guidance of Nerve Stimulator and Ultrasound for Transforaminal Epidural Steroid Injection in Lumbosacral Radicular Pain : A Single Institution Experience in Vietnam.

OBJECTIVE: This study aimed to evaluate the clinical feasibility of the combination of ultrasound and nerve stimulator guidance in transforaminal epidural steroid injections (TESIs) to manage lumbosacral chronic radicular pain. METHODS: Using the combination of nerve stimulator and ultrasound guidance, TESIs were performed in 125 segments of 78 patients who presented with chronic lumbar radicular pain. Demographic characteristics and surgical outcomes were recorded on admission, pre-procedural and post-procedural for 1-week, 1-month, 3-month, and 6-month follow-ups. The result was measured using the Numeric rating scale (NRS) and Oswestry disability index (ODI). RESULTS: Patients who received TESIs showed significant improvements on two evaluation tools (NRS, ODI), compared to that before procedure (p<0.001). No significant complications were observed for 6 months' follow-up. CONCLUSION: The result suggests that a combination of ultrasound and nerve stimulator guidance in transforaminal epidural injections is safe, reliable and effective for short-term management of lumbar disc herniation. It is a promising technique and has shown good results in providing intermediate pain relief.

Ultrasound-guided lateral branch radiofrequency neurotomy for sacroiliac joint pain after lumbosacral spinal fusion surgery.

Our study evaluated the clinical feasibility of ultrasound-guided lateral branch radiofrequency neurotomy for sacroiliac joint (SIJ) pain after lumbosacral spinal fusion surgery (LSFS). This prospective study included a total of 46 patients who were diagnosed with SIJ pain after LSFS, did not respond to conservative treatment and therefore underwent ultrasound-guided SIJ radiofrequency neurotomy (RFN) from January 2019 to January 2022. These patients were followed up for twelve months after the procedure. Patients were assessed with the Numeric Rating Scale (NRS) and the Oswestry Disability Index (ODI) preprocedural and postprocedural for 1 month, 6 months and 12 months follow-ups. There was a significant improvement in postprocedural NRS and ODI scores (p < 0.001). Thirty-eight patients (82.6%) had a satisfactory response and good global perceived effect (GPE) after twelve months. No significant complications were observed during the 12-month follow-up. The ultrasound-guided radiofrequency device designed as a safe, easily applied and encouraging method could avoid revision surgery. It is a promising technique and has shown good results in providing intermediate pain relief. In addition to the limited series reported in the literature, future studies will add meaning to this topic by including it in routine practice.

Transforaminal injection of autologous platelet-rich plasma for lumbar disc herniation: A single-center prospective study in Vietnam.

OBJECTIVE: Lumbar radiculopathy is a major health problem, which often treated by neurosurgery or guided lumbar epidural steroids for pain relief. We used autologous Platelet Rich Plasma (PRP) as a novel pharmaceutical agent that has strongly emerged in recent years to treat patients of lumbar disc herniation. From that, we evaluated the efficacy of PRP via transforaminal route in treatment of radicular pain in patients with lumbar disc herniation. METHODS: Twenty-five patients were enrolled and injected with 4 ml of autologous platelet rich plasma under fluoroscopic guidance via transforaminal epidural injection into area of affected nerve root. They were followed using Visual Analogue Scale (VAS), Modified Oswestry Disability Index (ODI) and Straight Leg Raising Test (SLRT) for clinical assessment. RESULTS: Patients who received transforaminal injections with autologous PRP showed statistically significant improvements on all three evaluation tools (VAS, ODI, SLRT). The improvements were sustained over twelve-month follow-up and there were no associated complications. CONCLUSION: Transforaminal injection with autologous PRP helps patients relieve chronic pains and be able return to work. Besides, autologous PRP can be considered as a good alternative to epidural steroids in management of lumbar disc herniation.

Tumor-related epilepsy and post-surgical outcomes: tertiary hospital experience in Vietnam.

Seizures have a significant impact on the quality of life of those who suffer. This study aimed to evaluate the variables that influence the incidence of seizures during the perioperative period and effective measures to enhance epilepsy outcomes among individuals undergoing surgical resection of brain tumors. The authors carried out a prospective observational analysis of all patients who experienced seizures before their brain tumor surgery at UMC, HCMC between 2020 and 2022. 54 cases presented with seizures were enrolled for the study, generalized seizure was the most prevalent seizure type (61.1%), followed by focal seizure (29.6%). The majority of patients presented with seizures are those who were diagnosed with glioma. Low-grade gliomas and frontotemporal lobe tumors increase the postoperative risk of seizure. Other predictive factors are a prolonged history of seizure, especially resistant epilepsy and major peritumoral edema. In contrast, gross total resection reduces postoperative seizure incidence. There was correlation between Ki67 proliferation index and seizure incidence in both low-grade and high-grade gliomas. ECoG made insubstantial difference in enhancing the epilepsy surgery outcome. Overall, 88.9% of patients were seizure-free at 6 months of follow-up (Engel Class I), 7.4% were almost seizure-free (Class II), and 3.7% had significant improvement (Class III), figures for 12-month follow-up were 87.0%, 9.3%, and 3.7% respectively. A shorter history of seizure and gross-total resection appear to be associated with a favorable prognosis for seizure control.

Systematic Exploration of Functional Group Relevance for Anti-Leishmanial Activity of Anisomycin.

Assessment of structure-activity relationships for anti-protozoan activity revealed a strategy for preparing potent anisomycin derivatives with reduced host toxicity. Thirteen anisomycin analogs were synthesized by modifying the alcohol, amine, and aromatic functional groups. Examination of anti-protozoal activity against various strains of Leishmania and cytotoxicity against leucocytes with comparison against the parent natural product demonstrated typical losses of activity with modifications of the alcohol, amine, and aromatic meta-positions. On the other hand, the para-phenol moiety of anisomycin proved an effective location for introducing substituents without significant loss of anti-protozoan potency. An entry point for differentiating activity against Leishmania versus host has been uncovered by this systematic study.