[Malaria in 2022: clinical and therapeutic aspects]. / Le paludisme en 2022 : aspects cliniques et thérapeutiques.

In 2022 as in 1884, the clinical presentation of uncomplicated malaria is unspecific: fever of variable intensity, continuous or rhythmic, chills, flu syndrome, headache, respiratory and digestive disorders. At any time, it can evolve into a severe form (ex-pernicious attack or cerebral malaria) or even lethal. By reading again Alphonse Laveran's book on malarial fevers, we realized to what extent the observations made at that time allowed for a methodical and orderly description of the clinical forms of malaria, very close to what we can still observe today. No symptom or sign is pathognomonic of the disease. Only the detection of plasmodia or "malaria microbes" by direct or immuno-chromatographic methods allows for diagnostic confirmation, which is a prerequisite for the implementation of a curative treatment.Serendipity, synthetic chemistry and traditional medicine are the three methods that led to the discovery and large-scale production of antimalarial drugs. Serendipity for quinine, synthetic chemistry for chloroquine, and research conducted around traditional Chinese medicine for artemisinin and its derivatives. The latter have marked a real revolution in the management of malaria, both in its uncomplicated and severe forms. However, as with other antimalarial drugs, its medium- and long-term efficacy is compromised by the emergence and spread of resistance in malaria parasites, particularly P. falciparum. The control and eradication of malaria therefore require continued research in both prevention and therapy.The disease so well described by Alphonse Laveran has not yet said its last word….

What Historical Records Teach Us about the Discovery of Quinine.

The origin of quinine from Peru remains a mystery because of the lack of primary data-in particular, those produced by the Jesuits working in Peru. The discovery of cinchona bark and its use in malaria treatment must have come from the Jesuits, who worked with the native Andeans, the Quichuan people, and learned how the bark of the cinchona tree could be used for chills. Unknown is whether the Andean people used it for fever that may have been the result of malaria. We explored the literature of the 1600s, 1700s, and later to trace the history of quinine that is available. All these secondary sources lack the primary data of the Jesuits in their work with native Andeans, nor is there information on how the discovery of its use for malaria-like fevers came about. One clue comes from the Jesuits who talked with the Andean people and learned about quinine. But was it used for fever? Why did the Jesuits test it against (tertian or quartan) fevers that could have been the result of malaria? The gap in our knowledge can only be resolved with the discovery of written documents by the Jesuits about quinine for malaria.

Modulation of immunological responses by aqueous extract of Datura stramonium L. seeds on cyclophosphamide-induced immunosuppression in Wistar rats.

BACKGROUND: Datura stramonium L. (Solanaceae) is used traditionally in west Africa to treat asthma, epilepsy, rheumatoid arthritis, filariasis microbial infections and conjunctivitis. This study investigated the immunomodulatory effects of aqueous seed extract of D. stramonium L. (ASEDS) on Wistar rats. METHODS: Thirty Wistar albino rats (180-200 g) were randomized into 6 groups (n = 5). Group 1 received distilled water only. Rats in groups 2-6 were pretreated with 10 mg/kg body weight (b.w.) Cyclophosphamide orally for 27-days to induce immunosuppression. Thereafter, they received treatment orally for 28 days as follows: Group 2 (distilled water), group 3 (5 mg/kg b.w. Levamisole), groups 4-6 (60, 90 and 120 mg/kg b.w. ASEDS, respectively). HPLC was used to determine major compounds in ASEDS. The effects of ASEDS on immune cells, immunoglobulins A, G and M levels, lipoproteins, and antioxidant status of rats were evaluated. RESULTS: ASEDS indicated high content of Acutumine, Quinine, Catechin, Chlorogenic acid, Gallic acid, Quercetin, Vanillic acid, Luteolin, Formosanin C, Saponin, Cyanidin, Tannic acid, 3-Carene, Limonene and α-terpineol. Cyclophosphamide triggered significant (p < 0.05) reduction in total leucocyte count and differentials, IgA, IgG, high-density lipoproteins (HDL), catalase, superoxide dismutase, glutathione peroxidase, vitamins A, C and E levels of untreated rats. Administration of ASEDS led to significant (p < 0.05) improvement in immune cell counts, immunoglobulin synthesis, high-density lipoprotein concentration, and antioxidant status of rats in the treated groups. CONCLUSIONS: The results obtained from the study showed the immunomodulatory activity of ASEDS, thereby indicating its potential in immunostimulatory drug discovery.

Taste perception and food preferences in patients with diabetic foot ulcers before and after hyperbaric oxygen therapy.

OBJECTIVE: The aim of the study was to evaluate the effect of hyperbaric oxygen therapy (HBOT) on taste perception and food preferences in patients with diabetic foot ulcers. METHODS: The study involved 75 healthy people (Group C) and 23 patients with diabetic foot ulcers before HBOT (Group Db) and after 25-30 HBOT treatments (Group Da) (2.5 ATA, 87 min). The sip and spit method was used to examine the taste perception for 5 basic flavours. Food preferences were studied using photographs of dishes. RESULTS: The recognition thresholds in Group C were lower than in Group Db for 5 basic flavours. The taste intensity in Group C was higher than in Group Db for: 0.1% and 1.0% monosodium glutamate, 0.02% citric acid, and 0.002% quinine hydrochloride. The hedonic response in Group C was more negative than in Group Db for: 0.18% sodium chloride, 0.3% monosodium glutamate and 0.1% citric acid. The pleasure derived from eating in Group C was lower than in Group Db for sour and salty products. The recognition thresholds in Group Db were higher than in Group Da for umami and sour. The taste intensity in Group Db was lower than in Group Da for: 0.1%, 0.3% and 1.0% monosodium glutamate. The pleasure derived from eating in Group Db was higher than in Group Da for chocolate and crisps. CONCLUSIONS: In people with diabetic foot ulcers, an impaired all 5 basic tastes occurred with different food preferences compared to healthy people. HBOT causes beneficial changes resulting in increased sensitivity to umami and sour taste as well as a decrease in the pleasure derived from eating chocolate and crisps.

An in silico-in vitro pipeline for drug cardiotoxicity screening identifies ionic pro-arrhythmia mechanisms.

BACKGROUND AND PURPOSE: Before advancing to clinical trials, new drugs are screened for their pro-arrhythmic potential using a method that is overly conservative and provides limited mechanistic insight. The shortcomings of this approach can lead to the mis-classification of beneficial drugs as pro-arrhythmic. EXPERIMENTAL APPROACH: An in silico-in vitro pipeline was developed to circumvent these shortcomings. A computational human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model was used as part of a genetic algorithm to design experiments, specifically electrophysiological voltage clamp (VC) protocols, to identify which of several cardiac ion channels were blocked during in vitro drug studies. Such VC data, along with dynamically clamped action potentials (AP), were acquired from iPSC-CMs before and after treatment with a control solution or a low- (verapamil), intermediate- (cisapride or quinine) or high-risk (quinidine) drug. KEY RESULTS: Significant AP prolongation (a pro-arrhythmia marker) was seen in response to quinidine and quinine. The VC protocol identified block of IKr (a source of arrhythmias) by all strong IKr blockers, including cisapride, quinidine and quinine. The protocol also detected block of ICaL by verapamil and Ito by quinidine. Further demonstrating the power of the approach, the VC data uncovered a previously unidentified If block by quinine, which was confirmed with experiments using a HEK-293 expression system and automated patch-clamp. CONCLUSION AND IMPLICATIONS: We developed an in silico-in vitro pipeline that simultaneously identifies pro-arrhythmia risk and mechanism of ion channel-blocking drugs. The approach offers a new tool for evaluating cardiotoxicity during preclinical drug screening.

Target-specific projections of amygdala somatostatin-expressing neurons to the hypothalamus and brainstem.

Somatostatin neurons in the central nucleus of the amygdala (CeA/Sst) can be parsed into subpopulations that project either to the nucleus of the solitary tract (NST) or parabrachial nucleus (PBN). We have shown recently that inhibition of CeA/Sst-to-NST neurons increased the ingestion of a normally aversive taste stimulus, quinine HCl (QHCl). Because the CeA innervates other forebrain areas such as the lateral hypothalamus (LH) that also sends axonal projections to the NST, the effects on QHCl intake could be, in part, the result of CeA modulation of LH-to-NST neurons. To address these issues, the present study investigated whether CeA/Sst-to-NST neurons are distinct from CeA/Sst-to-LH neurons. For comparison purposes, additional experiments assessed divergent innervation of the LH by CeA/Sst-to-PBN neurons. In Sst-cre mice, two different retrograde transported flox viruses were injected into the NST and the ipsilateral LH or PBN and ipsilateral LH. The results showed that 90% or more of retrograde-labeled CeA/Sst neurons project either to the LH, NST, or PBN. Separate populations of CeA/Sst neurons projecting to these different regions suggest a highly heterogeneous population in terms of synaptic target and likely function.

Docking Analysis of Some Bioactive Compounds from Traditional Plants against SARS-CoV-2 Target Proteins.

COVID-19 is still a global pandemic that has not been stopped. Many traditional medicines have been demonstrated to be incredibly helpful for treating COVID-19 patients while fighting the disease worldwide. We introduced 10 bioactive compounds derived from traditional medicinal plants and assessed their potential for inhibiting viral spike protein (S-protein), Papain-like protease (PLpro), and RNA dependent RNA polymerase (RdRp) using molecular docking protocols where we simulate the inhibitors bound to target proteins in various poses and at different known binding sites using Autodock version 4.0 and Chimera 1.8.1 software. Results found that the chicoric acid, quinine, and withaferin A ligand strongly inhibited CoV-2 S -protein with a binding energy of -8.63, -7.85, and -7.85 kcal/mol, respectively. Our modeling work also suggested that curcumin, quinine, and demothoxycurcumin exhibited high binding affinity toward RdRp with a binding energy of -7.80, -7.80, and -7.64 kcal/mol, respectively. The other ligands, namely chicoric acid, demothoxycurcumin, and curcumin express high binding energy than the other tested ligands docked to PLpro with -7.62, -6.81, and -6.70 kcal/mol, respectively. Prediction of drug-likeness properties revealed that all tested ligands have no violations to Lipinski's Rule of Five except cepharanthine, chicoric acid, and theaflavin. Regarding the pharmacokinetic behavior, all ligand predicted to have high GI-absorption except chicoric acid and theaflavin. At the same way chicoric acid, withaferin A, and withanolide D predicted to be substrate for multidrug resistance protein (P-gp substrate). Caffeic acid, cepharanthine, chicoric acid, withaferin A, and withanolide D also have no inhibitory effect on any cytochrome P450 enzymes. Promisingly, chicoric acid, quinine, curcumin, and demothoxycurcumin exhibited high binding affinity on SARS-CoV-2 target proteins and expressed good drug-likeness and pharmacokinetic properties. Further research is required to investigate the potential uses of these compounds in the treatment of SARS-CoV-2.

PQQ Dietary Supplementation Prevents Alkylating Agent-Induced Ovarian Dysfunction in Mice.

Alkylating agents (AAs) that are commonly used for cancer therapy cause great damage to the ovary. Pyrroloquinoline-quinine (PQQ), which was initially identified as a redox cofactor for bacterial dehydrogenases, has been demonstrated to benefit the fertility of females. The aim of this study was to investigate whether PQQ dietary supplementation plays a protective role against alkylating agent-induced ovarian dysfunction. A single dose of busulphan (20 mg/kg) and cyclophosphamide (CTX, 120 mg/kg) were used to establish a mouse model of ovarian dysfunction. Feed containing PQQNa2 (5 mg/kg) was provided starting 1 week before the establishment of the mouse model until the date of sacrifice. One month later, estrous cycle period of mice were examined and recorded for consecutive 30 days. Three months later, some mice were mated with fertile male mice for fertility test. The remaining mice were sacrificed to collect serum samples and ovaries. One day before sacrifice, some mice received a single injection of BrdU to label proliferating cells. Serum samples were used for test hormonal levels. Ovaries were weighted and used to detect follicle counts, cell proliferation, cell apoptosis and cell senescence. In addition, the levels of inflammation, oxidative damage and Pgc1α expression were detected in ovaries. Results showed that PQQ treatment increased the ovarian weight and size, partially normalized the disrupted estrous cycle period and prevented the loss of follicles of mice treated with AAs. More importantly, we found that PQQ treatment significantly increased the pregnancy rate and litter size per delivery of mice treated with AAs. The protective effects of PQQ appeared to be directly mediated by promoting cell proliferation of granulosa, and inhibiting cell apoptosis of granulosa and cell senescence of ovarian stromal cells. The underlying mechanisms may attribute to the anti-oxidative stress, anti-inflammation and pro-mitochondria biogenesis effects of PQQ.Our study highlights the therapeutic potential of PQQ against ovarian dysfunction caused by alkylating agents.

Reflections on quinine and its importance in dermatology today.

Quinine and its D-isomer quinidine have been used medically in Europe since the 1600s. They were originally found within the bark of the cinchona tree in the jungle of the Andes. They were recognized to have multiple beneficial medical properties, ranging from a combined antipyretic and analgesic effect to the first effective treatment for malaria and later atrial fibrillation. With the development of other medications and the recognition of the potential life-threatening toxic reactions to these drugs, their medical use declined. Quinine is available without a prescription in many countries and is present in tonic water. Quinine has an extensive following of users who believe it is salutary and harmless, considering it a food supplement. In the past, dermatologists were frequently the first to recognize disease caused by these drugs owing to early findings of dermatitis or petechiae. Even though the medical use of these drugs has markedly decreased, drug eruptions may still be due to quinine, and patients may even be unaware they are taking this medication.

Effective Treatment of Cutaneous Mold Infections by Antimicrobial Blue Light That Is Potentiated by Quinine.

BACKGROUND: Cutaneous mold infections commonly result from an array of traumatic injuries that involve direct inoculation of contaminated soil into wounds. Here, we explored the use of antimicrobial blue light (aBL; 405 nm wavelength) and the combination of aBL with quinine hydrochloride (aBL + Q-HCL) for the treatment of cutaneous mold infections. METHODS: Efficacy of aBL and aBL + Q-HCL in killing clinically important pathogenic molds (Aspergillus fumigatus, Aspergillus flavus, and Fusarium oxyprorum) was investigated. Ultraperformance liquid chromatography identified and quantified endogenous porphyrins in the mold conidia. Finally, a mouse model of dermabrasion wound infected with a bioluminescent variant of A. fumigatus was developed to investigate the efficacy of aBL in treating cutaneous mold infections. RESULTS: We demonstrated that mold conidia are tolerant to aBL, but Q-HCL enhances efficacy. Transmission electron microscopy revealed intracellular damage by aBL. aBL + Q-HCL resulted in intracellular and cell wall damage. Porphyrins were observed in all mold strains, with A. fumigatus having the highest concentration. aBL and aBL + Q-HCL effectively reduced the burden of A. fumigatus within an established dermabrasion infection and limited recurrence posttreatment. CONCLUSIONS: aBL and aBL + Q-HCL may offer a novel approach for the treatment of mold infections.

Structural investigation and comparative cytotoxic activity of water-soluble polysaccharides from fruit bodies of the medicinal fungus quinine conk.

The structures and cytotoxic activities of water-soluble polysaccharides were investigated to search for biologically active polysaccharides from the fruit bodies of quinine conks (Fomitopsis officinalis). The decoctions of this medical fungus are actively used in folk medicine in many countries and traditional Chinese medicine. From the fungal extract we prepared, only branched ß-glucan had cytotoxic activity among all the water-soluble polysaccharides. This glucan is characterized by a regular structure. Its backbone is formed by 1,3-linked ß-D-Glcp residues, of which every third residue is substituted at O-6 by a single ß-D-Glcp residue. It has a triple helix conformation according to the data obtained from a colorimetric assay with Congo red dye and is characterized by a high-weight average molar mass (Mw > 800 kDa). ß-Glucan possessed cytotoxic activity against HeLa cells (IC50 = 318 ±â€¯47 µg/mL) and induced the formation of apoptotic bodies around most cancer cells at a concentration of 200 µg/mL. It should be noted that extraction with boiling water, which is usually used to obtain extracts and decoctions, is unable to isolate active ß-glucan. Active ß-glucan can be obtained in an individual state by cold alkali extraction after dehydration of the fruit bodies and removal of the components extractable by boiling water.

Quinine-Based Semisynthetic Ion Transporters with Potential Antiproliferative Activities.

Synthetic ion transporters have attracted tremendous attention for their therapeutic potential against various ion-transport-related diseases, including cancer. Inspired by the structure and biological activities of natural products, we synthesized a small series of squaramide and thiourea derivatives of quinine and investigated their ion transport activities. The involvement of a quinuclidine moiety for the cooperative interactions of Cl- and H+ ions with the thiourea or squaramide moiety resulted in an effectual transport of these ions across membranes. The interference of ionic equilibrium by the potent Cl- ion carrier selectively induced cancer cell death by endorsing caspase-arbitrated apoptosis. In vivo assessment of the potent ionophore showed an efficient reduction in tumor growth with negligible immunotoxicity to other organs.

Quinine Enhances Photo-Inactivation of Gram-Negative Bacteria.

BACKGROUND: Antimicrobial resistance is a significant concern to public health, and there is a pressing need to develop novel antimicrobial therapeutic modalities. METHODS: In this study, we investigated the capacity for quinine hydrochloride (Q-HCL) to enhance the antimicrobial effects of antimicrobial blue light ([aBL] 405 nm wavelength) against multidrug-resistant (MDR) Gram-negative bacteria in vitro and in vivo. RESULTS: Our findings demonstrated the significant improvement in the inactivation of MDR Pseudomonas aeruginosa and Acinetobacter baumannii (planktonic cells and biofilms) when aBL was illuminated during Q-HCL exposure. Furthermore, the addition of Q-HCL significantly potentiated the antimicrobial effects of aBL in a mouse skin abrasion infection model. In addition, combined exposure of aBL and Q-HCL did not result in any significant apoptosis when exposed to uninfected mouse skin. CONCLUSIONS: In conclusion, aBL in combination with Q-HCL may offer a novel approach for the treatment of infections caused by MDR bacteria.

Historical chemical annotations of Cinchona bark collections are comparable to results from current day high-pressure liquid chromatography technologies.

ETHNOPHARMACOLOGICAL RELEVANCE: Species of the genus Cinchona (Rubiaceae) have been used in traditional medicine, and as a source for quinine since its discovery as an effective medicine against malaria in the 17th century. Despite being the sole cure of malaria for almost 350 years, little is known about the chemical diversity between and within species of the antimalarial alkaloids found in the bark. Extensive historical Cinchona bark collections housed at the Royal Botanic Gardens, Kew, UK, and in other museums may shed new light on the alkaloid chemistry of the Cinchona genus and the history of the quest for the most effective Cinchona barks. AIM OF THE STUDY: We used High-Pressure Liquid Chromatography (HPLC) coupled with fluorescence detection (FLD) to reanalyze a set of Cinchona barks originally annotated for the four major quinine alkaloids by John Eliot Howard and others more than 150 years ago. MATERIALS AND METHODS: We performed an archival search on the Cinchona bark collections in the Economic Botany Collection housed in Kew, focusing on those with historical alkaloid content information. Then, we performed HPLC analysis of the bark samples to separate and quantify the four major quinine alkaloids and the total alkaloid content using fluorescence detection. Correlations between historic and current annotations were calculated using Spearman's rank correlation coefficient, before paired comparisons were performed using Wilcox rank sum tests. The effects of source were explored using generalized linear modelling (GLM), before the significance of each parameter in predicting alkaloid concentrations were assessed using chi-square tests as likelihood ratio testing (LRT) models. RESULTS: The total alkaloid content estimation obtained by our HPLC analysis was comparatively similar to the historical chemical annotations made by Howard. Additionally, the quantity of two of the major alkaloids, quinine and cinchonine, and the total content of the four alkaloids obtained were significantly similar between the historical and current day analysis using linear regression. CONCLUSIONS: This study demonstrates that the historical chemical analysis by Howard and current day HPLC alkaloid content estimations are comparable. Current day HPLC analysis thus provide a realistic estimate of the alkaloid contents in the historical bark samples at the time of sampling more than 150 years ago. Museum collections provide a powerful but underused source of material for understanding early use and collecting history as well as for comparative analyses with current day samples.

Quinine Improves the Fungicidal Effects of Antimicrobial Blue Light: Implications for the Treatment of Cutaneous Candidiasis.

BACKGROUND AND OBJECTIVE: Candida albicans is an opportunistic fungal pathogen of clinical importance and is the primary cause of fungal-associated wound infections, sepsis, or pneumonia in immunocompromised individuals. With the rise in antimicrobial resistance, it is becoming increasingly difficult to successfully treat fungal infections using traditional antifungals, signifying that alternative non-traditional approaches must be explored for their efficacy. STUDY DESIGN/MATERIALS AND METHODS: We investigated the combination of antimicrobial blue light (aBL) and quinine hydrochloride (Q-HCL) for improved inactivation of C. albicans, in vitro and in vivo, relative to either monotherapy. In addition, we evaluated the safety of this combination therapy in vivo using the TUNEL assay. RESULTS: The combination of aBL (108 J/cm2 ) with Q-HCL (1 mg/mL) resulted in a significant improvement in the inactivation of C. albicans planktonic cells in vitro, where a 7.04 log10 colony forming units (CFU) reduction was achieved, compared with aBL alone that only inactivated 3.06 log10 CFU (P < 0.001) or Q-HCL alone which did not result in a loss of viability. aBL + Q-HCL was also effective at inactivating 48-hour biofilms, with an inactivation 1.73 log10 CFU at the dose of 108 J/cm2 aBL and 1 mg/mL Q-HCL, compared with only a 0.73 or 0.66 log10 CFU by aBL and Q-HCL alone, respectively (P < 0.001). Transmission electron microscopy revealed that aBL + Q-HCL induced morphological and ultrastructural changes consistent with cell wall and cytoplasmic damage. In addition, aBL + Q-HCL was effective at eliminating C. albicans within mouse abrasion wounds, with a 2.47 log10 relative luminescence unit (RLU) reduction at the dose of 324 J/cm2 aBL and 0.4 mg/cm2 Q-HCL, compared with a 1.44 log10 RLU reduction by aBL alone. Q-HCL or nystatin alone did not significantly reduce the RLU. The TUNEL assay revealed some apoptotic cells before and 24 hours following treatment with aBL + Q-HCL. CONCLUSION: The combination of aBL + Q-HCL was effective at eliminating C. albicans both in vitro and in vivo. A comprehensive assessment of toxicity (cytotoxicity and genotoxicity) is required to fully determine the safety of aBL + Q-HCL therapy at different doses. In conclusion, the combination of aBL and Q-HCL may be a viable option for the treatment of cutaneous candidiasis. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Exploring Structure-Activity Relationship in Tacrine-Squaramide Derivatives as Potent Cholinesterase Inhibitors.

Tacrine was the first drug to be approved for Alzheimer's disease (AD) treatment, acting as a cholinesterase inhibitor. The neuropathological hallmarks of AD are amyloid-rich senile plaques, neurofibrillary tangles, and neuronal degeneration. The portfolio of currently approved drugs for AD includes acetylcholinesterase inhibitors (AChEIs) and N-methyl-d-aspartate (NMDA) receptor antagonist. Squaric acid is a versatile structural scaffold capable to be easily transformed into amide-bearing compounds that feature both hydrogen bond donor and acceptor groups with the possibility to create multiple interactions with complementary sites. Considering the relatively simple synthesis approach and other interesting properties (rigidity, aromatic character, H-bond formation) of squaramide motif, we combined this scaffold with different tacrine-based derivatives. In this study, we developed 21 novel dimers amalgamating squaric acid with either tacrine, 6-chlorotacrine or 7-methoxytacrine representing various AChEIs. All new derivatives were evaluated for their anti-cholinesterase activities, cytotoxicity using HepG2 cell line and screened to predict their ability to cross the blood-brain barrier. In this contribution, we also report in silico studies of the most potent AChE and BChE inhibitors in the active site of these enzymes.

Mouse Parabrachial Neurons Signal a Relationship between Bitter Taste and Nociceptive Stimuli.

Taste and somatosensation both mediate protective behaviors. Bitter taste guides avoidance of ingestion of toxins while pain sensations, such as noxious heat, signal adverse conditions to ward off harm. Although brain pathways for taste and somatosensation are typically studied independently, prior data suggest that they intersect, potentially reflecting their common protective role. To investigate this, we applied electrophysiologic and optogenetic techniques in anesthetized mice of both sexes to evaluate relationships between oral somatosensory and taste activity in the parabrachial nucleus (PbN), implicated for roles in gustation and pain. Spikes were recorded from taste-active PbN neurons tested with oral delivery of thermal and chemesthetic stimuli, including agonists of nocisensitive transient receptor potential (TRP) ion channels on somatosensory fibers. Gustatory neurons were also tested to follow electrical pulse stimulation of an oral somatosensory region of the spinal trigeminal subnucleus caudalis (Vc), which projects to the PbN. Neurons composed classic taste groups, including sodium, electrolyte, appetitive, or bitter cells. Across groups, most neurons spiked to Vc pulse stimulation, implying that trigeminal projections reach PbN gustatory neurons. Among such cells, a subpopulation responsive to the bitter taste stimuli quinine and cycloheximide, and aversive concentrations of sodium, cofired to agonists of nocisensitive TRP channels, including capsaicin, mustard oil, and noxious heat. Such neurons populated the lateral PbN. Further, nociceptive activity in PbN bitter taste neurons was suppressed during optogenetic-assisted inhibition of the Vc, implying convergent trigeminal input contributed to such activity. Our results reveal a novel role for PbN gustatory cells in cross-system signaling related to protection.SIGNIFICANCE STATEMENT Prior data suggest that gustatory and trigeminal neural pathways intersect and overlap in the parabrachial area. However, no study has directly examined such overlap and why it may exist. Here we found that parabrachial gustatory neurons can receive afferent projections from trigeminal nuclei and fire to oral nociceptive stimuli that excite somatosensory receptors and fibers. Activation to aversive nociceptive stimuli in gustatory cells was associated with responding to behaviorally avoided bitter tastants. We were further able to show that silencing trigeminal projections inhibited nociceptive activity in parabrachial bitter taste neurons. Our results imply that in the parabrachial area, there is predictable overlap between taste and somatosensory processing related to protective coding and that classically defined taste neurons contribute to this process.

Endophyte composition and Cinchona alkaloid production abilities of Cinchona ledgeriana cultivated in Japan.

New eight endophytic filamentous fungi were isolated from the young stems of Cinchona ledgeriana (Rubiaceae) cultivated in Japan. They were classified into four genera based on phylogenetic analysis of the nucleotide sequences of the internal transcribed spacers (ITS1 and ITS2), including the 5.8S ribosomal DNA region. Of the eight fungi isolated, there were five genera Cladosporium, one Meira sp., one Diaporthe sp. and one Penicillium sp. Genus of Cladosporium and Meira were first isolated fungi from Cinchona plant. In a previous study, we applied the same process to the same plant cultivated in Indonesia. The endophyte compositions for the two cultivation regions were found to differ at the genera level. The ability of Cinchona endophytes cultivated in Japan to produce Cinchona alkaloids was also assessed. We found that three isolates have producing ability of Cinchona alkaloids. However, the amount produced was very small compared to that produced by the endophytes of Indonesian Cinchona ledgeriana. In addition, the total content amount of Cinchona alkaloids, especially quinine, produced by the extract of Cinchona cultivated in Japan was much smaller than that from Indonesia. These finding indicate that endophyte composition has an influence on the Cinchona alkaloid content amount in the Cinchona ledgeriana host.

Use of hyperbaric oxygen therapy in quinine-associated visual disturbances.

INTRODUCTION: Hyperbaric oxygen (HBO2 ) therapy is infrequently reported as a treatment for poison-induced retinal damage. We describe a case in which HBO2 therapy was used to treat suspected retinal toxicity induced by quinine. CASE REPORT: We present a case in which HBO2 was used to treat visual disturbances thought to be caused by quinine-induced retinal damage. The patient intentionally ingested undisclosed amounts of citalopram and quinine. Following a complicated hospital course, including profound shock requiring treatment with four vasopressors and a peripheral left-ventricular assist device, the patient, once extubated, reported visual abnormalities consistent with those described from quinine-induced retinal toxicity. Visual disturbances seemed to show improvement following HBO2 treatment. Several months following hospitalization visual defects continued to be present on examination. However, with corrective lenses the patient's visual acuity was normal. No adverse events were attributed to the use of HBO2. DISCUSSION: HBO2 for treatment of quinine-induced retinal damage is infrequently reported or studied. In the reported case, use of HBO2 appeared to be associated with substantial improvement in visual disturbances occurring in the setting of an overdose of quinine. The patient's improvement is remarkable, given her retinas were also jeopardized by her profound shock. Additional data are needed to understand the risks and benefits of this procedure, but due to limited treatment options for poison-induced retinal toxicity and the low likelihood for implementation of a controlled randomized trial of HBO2 in this population, the procedure may be considered in quinine-induced retinal toxicity.