Can fluconazole be used for inpatient re-treatment of coccidioidomycosis among patients with past fluconazole exposures?

BACKGROUND: Coccidioides spp. may cause significant disease requiring hospitalisation, but optimal antifungal therapy among inpatients following outpatient fluconazole exposures is unknown. OBJECTIVES: The objective of this study is to describe the effectiveness of fluconazole among patients hospitalised for coccidioidomycosis despite recent outpatient fluconazole treatment. PATIENTS/METHODS: Patients were admitted to an academic medical center in Phoenix, Arizona from 1 January 2013 through 31 December 2020 for coccidioidomycosis following at least 30 days of outpatient treatment and re-initiation of fluconazole upon admission. The primary outcome was the proportion of patients with an improved response per the change in the modified Mycosis Study Group (MSG) score (a composite of symptoms, serology and radiographic findings) and clinician impressions. RESULTS: Sixty-seven patients were included, with most (54%) admitted to the intensive care unit. Meningitis was the most common infectious presentation (55%), 17 patients (25%) had multiple infection sites, and 23 (34%) were culture-positive for Coccidioides. Upon admission, the median (IQR) MSG score was 11 (9-14), which dropped to 4 (1-7) at end of therapy or last follow-up. Overall, after initiation of fluconazole therapy at a median daily dose of 800 mg, 48 patients (72%) improved in overall status, 10 (15%) showed stable disease and 9 (13%) were unresponsive. Improved response rates were high across all infection sites, including meningitis (68%) and bone infection (71%). There was no significant difference in response rates between patients with and without reported outpatient fluconazole nonadherence. CONCLUSIONS: The majority of patients admitted to the hospital for coccidioidomycosis appeared responsive to fluconazole therapy despite past outpatient exposures.

Piezo2 Mediates Low-Threshold Mechanically Evoked Pain in the Cornea.

Mammalian Piezo2 channels are essential for transduction of innocuous mechanical forces by proprioceptors and cutaneous touch receptors. In contrast, mechanical responses of somatosensory nociceptor neurons evoking pain, remain intact or are only partially reduced in Piezo2-deficient mice. In the eye cornea, comparatively low mechanical forces are detected by polymodal and pure mechanosensory trigeminal ganglion neurons. Their activation always evokes ocular discomfort or pain and protective reflexes, thus being a unique model to study mechanotransduction mechanisms in this particular class of nociceptive neurons. Cultured male and female mouse mechano- and polymodal nociceptor corneal neurons display rapidly, intermediately and slowly adapting mechanically activated currents. Immunostaining of the somas and peripheral axons of corneal neurons responding only to mechanical force (pure mechano-nociceptor) or also exhibiting TRPV1 (transient receptor potential cation channel subfamily V member 1) immunoreactivity (polymodal nociceptor) revealed that they express Piezo2. In sensory-specific Piezo2-deficient mice, the distribution of corneal neurons displaying the three types of mechanically evoked currents is similar to the wild type; however, the proportions of rapidly adapting neurons, and of intermediately and slowly adapting neurons were significantly reduced. Recordings of mechano- and polymodal-nociceptor nerve terminals in the corneal surface of Piezo2 conditional knock-out mice revealed a reduced number of mechano-sensitive terminals and lower frequency of nerve terminal impulse discharges under mechanical stimulation. Eye blinks evoked by von Frey filaments applied on the cornea were lower in Piezo2-deficient mice compared with wild type. Together, our results provide direct evidence that Piezo2 channels support mechanically activated currents of different kinetics in corneal trigeminal neurons and contributes to transduction of mechanical forces by corneal nociceptors.SIGNIFICANCE STATEMENT The cornea is a richly innervated and highly sensitive tissue. Low-threshold mechanical forces activate corneal receptors evoking discomfort or pain. To examine the contribution of Piezo2, a low-threshold mechanically activated channel, to acute ocular pain, we characterized the mechanosensitivity of corneal sensory neurons. By using Piezo2 conditional knock-out mice, we show that Piezo2 channels, present in the cell body and terminals of corneal neurons, are directly involved in acute corneal mechano-nociception. Inhibition of Piezo2 for systemic pain treatment is hindered because of its essential role for mechano-transduction processes in multiple body organs. Still, topical modulation of Piezo2 in the cornea may be useful to selectively relief unpleasant sensations and pain associated with mechanical irritation accompanying many ocular surface disorders.

The Immunosuppressant Macrolide Tacrolimus Activates Cold-Sensing TRPM8 Channels.

TRPM8 is a polymodal, nonselective cation channel activated by cold temperature and cooling agents that plays a critical role in the detection of environmental cold. We found that TRPM8 is a pharmacological target of tacrolimus (FK506), a macrolide immunosuppressant with several clinical uses, including the treatment of organ rejection following transplants, treatment of atopic dermatitis, and dry eye disease. Tacrolimus is an inhibitor of the phosphatase calcineurin, an action shared with cyclosporine. Tacrolimus activates TRPM8 channels in different species, including humans, and sensitizes their response to cold temperature by inducing a leftward shift in the voltage-dependent activation curve. The effects of tacrolimus on purified TRPM8 in lipid bilayers demonstrates conclusively that it has a direct gating effect. Moreover, the lack of effect of cyclosporine rules out the canonical signaling pathway involving the phosphatase calcineurin. Menthol (TRPM8-Y745H)- and icilin (TRPM8-N799A)-insensitive mutants were also activated by tacrolimus, suggesting a different binding site. In cultured mouse DRG neurons, tacrolimus evokes an increase in intracellular calcium almost exclusively in cold-sensitive neurons, and these responses were drastically blunted in Trpm8 KO mice or after the application of TRPM8 antagonists. Cutaneous and corneal cold thermoreceptor endings are also activated by tacrolimus, and tacrolimus solutions trigger blinking and cold-evoked behaviors. Together, our results identify TRPM8 channels in sensory neurons as molecular targets of the immunosuppressant tacrolimus. The actions of tacrolimus on TRPM8 resemble those of menthol but likely involve interactions with other channel residues.SIGNIFICANCE STATEMENT TRPM8 is a polymodal TRP channel involved in cold temperature sensing, thermoregulation, and cold pain. TRPM8 is also involved in the pathophysiology of dry eye disease, and TRPM8 activation has antiallodynic and antipruritic effects, making it a prime therapeutic target in several cutaneous and neural diseases. We report the direct agonist effect of tacrolimus, a potent natural immunosuppressant with multiple clinical applications, on TRPM8 activity. This interaction represents a novel neuroimmune interface. The identification of a clinically approved drug with agonist activity on TRPM8 channels could be used experimentally to probe the function of TRPM8 in humans. Our findings may explain some of the sensory and anti-inflammatory effects described for this drug in the skin and the eye surface.

Non-inferiority comparative clinical trial between early oral REFEEDING and usual oral REFEEDING in predicted mild acute biliary pancreatitis.

BACKGROUND: The aim of the study was to compare the onset of oral feeding in the first 24 h after hospital admission with usual oral refeeding and determine whether the timing of the onset of oral feeding influences the recurrence of pain or alters the blood levels of pancreatic enzymes in patients with predicted mild acute biliary pancreatitis. METHODS: This non-inferiority randomized controlled trial was carried out between September 2018 and June 2019 after receiving authorization from the ethics committee for health research. Patients with a diagnosis of predicted mild acute biliary pancreatitis were divided into Group A (early oral refeeding, EOR) and Group B (usual oral refeeding, UOR). Outcome measures included pancreatic lipase levels, the systemic inflammatory response (concentrations of leukocytes), feasibility (evaluated by abdominal pain recurrence), the presence and recurrence of gastrointestinal symptoms and the length of hospital stay. RESULTS: Two patients in the EOR group experienced pain relapse (3.2%), and four patients in the UOR group experienced pain relapse (6.77%) after oral refeeding (p = 0.379). The presence of nausea or vomiting after the onset of oral refeeding was not different between the two groups (p = 0.293). The onset of oral refeeding was approximately 48 h later in the UOR group. The length of hospital stay was 5 days in the EOR group and 8 days in the UOR group (p = 0.042), and this difference was also manifested in higher hospital costs in the UOR group (p = 0.0235). CONCLUSION: Compared with usual oral refeeding, early oral refeeding is safe in predicted mild acute biliary pancreatitis patients, does not cause adverse gastrointestinal events, and reduces the length of hospital stay and costs. TRIAL REGISTRATION: Early oral refeeding in mild acute pancreatitis (EORVsUOR). NCT04168801 , retrospectively registered (November 19, 2019).

Struggling bodies at the border: migration, violence and HIV vulnerability in the Mexico/Guatemala border region.

The Mexico-Guatemala border is the site of significant movement of people whose principal destination is the USA. The first step, to cross Mexico, is considered as one of the most dangerous routes in the world for undocumented migrants. For some male migrants and displaced persons from Honduras, El Salvador and Guatemala, initiating sex work in the Mexican border city of Tapachula has become a way to earn money to survive during the trip northward - providing funds to keep traveling and decrease the danger of being killed or kidnaped by organized crime groups. Non-injected drug use during sex work with men and/or women is a common praxis for this purpose, and is linked to HIV risk activities such as unprotected sex. Our study is based on ethnographic fieldwork with observation and interviews and within a relational approach understanding the processes subject/structure, sociopolitical/cultural and global/local, not as oppositions, rather as linkages visible through actors' points of view and praxis. The productions of politics and cultures related to structural vulnerability to HIV infection are embedded in local and global borderization processes where legal and illegal transnational forces, states' frameworks and social groups play a linked role. The economies of structural, symbolic and direct violence affect migratory patterns, institutional interactions and social and cultural relations with the local population. In this context, social representations and praxis about unprotected sex and drug use are the locus of struggling bodies at the border.

Non-ribosomal Peptide Synthases from Pseudomonas aeruginosa Play a Role in Cyclodipeptide Biosynthesis, Quorum-Sensing Regulation, and Root Development in a Plant Host.

Diverse molecules mediate cross-kingdom communication between bacteria and their eukaryotic partners and determine pathogenic or symbiotic relationships. N-acyl-L-homoserine lactone-dependent quorum-sensing signaling represses the biosynthesis of bacterial cyclodipeptides (CDPs) that act as auxin signal mimics in the host plant Arabidopsis thaliana. In this work, we performed bioinformatics, biochemical, and plant growth analyses to identify non-ribosomal peptide synthase (NRPS) proteins of Pseudomonas aeruginosa, which are involved in CDP synthesis. A reverse genetics strategy allowed the identification of the genes encoding putative multi-modular-NRPS (MM-NRPS). Mutations in these genes affected the synthesis of the CDPs cyclo(L-Pro-L-Val), cyclo(L-Pro-L-Leu), and cyclo(L-Pro-L-Tyr), while showing wild-type-like levels of virulence factors, such as violacein, elastase, and pyocyanin. When analyzing the bioactivity of purified, naturally produced CDPs, it was found that cyclo(L-Pro-L-Tyr) and cyclo(L-Pro-L-Val) were capable of antagonizing quorum-sensing-LasR (QS-LasR)-dependent signaling in a contrasting manner in the cell-free supernatants of the selected NRPS mutants, which showed QS induction. Using a bacteria-plant interaction system, we further show that the pvdJ, ambB, and pchE P. aeruginosa mutants failed to repress primary root growth, but improved root branching in A. thaliana seedlings. These results indicated that the CDP production in P. aeruginosa depended on the functional MM-NRPS, which influences quorum-sensing of bacteria and plays a role in root architecture remodeling.

Cost of Deep Brain Stimulation Infection Resulting in Explantation.

BACKGROUND: Deep brain stimulation (DBS) hardware infection is a serious complication, often resulting in multiple hardware salvage attempts, hospitalizations, and long-term antibiotic therapy. OBJECTIVES: We aimed to quantify the costs of DBS hardware-related infections in patients undergoing eventual device explantation. METHODS: Of 362 patients who underwent 530 electrode placements (1 January 2010 to 30 December 2014), 16 (4.4%) had at least 2 hardware salvage procedures. Most (n = 15 [93.8%]) required complete explantation due to recurrent infection. Financial data (itemized hospital and physician costs) were available for 13 patients and these were analyzed along with the demographic data. RESULTS: Each patient underwent 1-5 salvage procedures (mean 2.5 ± 1.4; median 2). The mean total cost for a patient undergoing the median number of revisions (n = 2), device explantation, and subsequent reimplantation after infection clearance was USD 75,505; just over half this cost (54.2% [USD 40,960]) was attributable to reimplantation, and nearly one-third (28.9% [USD 21,816]) was attributable to hardware salvage procedures. Operating-room costs were the highest cost category for hardware revision and explantation. Medical and surgical supplies accounted for the highest reimplantation cost. CONCLUSIONS: DBS infection incurs significant health care costs associated with hardware salvage attempts, explantation, and reimplantation. The highest cost categories are operating-room services and medical and surgical supplies.

Role of Coccidioides Antigen Testing in the Cerebrospinal Fluid for the Diagnosis of Coccidioidal Meningitis.

BACKGROUND: Coccidioidal meningitis (CM), a common cause of chronic meningitis in endemic area, is usually diagnosed by detection of anti-Coccidioides antibodies in cerebrospinal fluid (CSF), and findings may be negative in up to one-third of cases. CSF cultures and cytology are infrequently positive. Antigen detection has been used for the diagnosis of other forms of coccidioidomycosis and meningitis caused by other mycoses. The purpose of this study was to assess the diagnostic utility of CSF Coccidioides antigen (CAg) detection for the diagnosis of CM. METHODS: The medical records of patients with clinically suspected meningitis, in whom CSF was tested for Coccidioides antibodies and CAg, were retrospectively reviewed, and CSF CAg testing was prospectively conducted in patients with CM. All specimens were submitted for CAg testing. RESULTS: Thirty-six patients with 42 episode of CM were studied. The sensitivity and specificity of CAg were 93% and 100%, respectively. Cultures of CSF were positive in 7%, antibodies were demonstrated by immunodiffusion in 67% and complement fixation in 70%, and immunoglobulin M and G antibodies were demonstrated by enzyme immunoassay in 8% and 85%, respectively. CONCLUSIONS: Testing CSF for CAg is a useful addition to diagnostic methods in suspected CM and complements testing with CSF antibodies and culture.

Muscarinic presynaptic modulation in GABAergic pallidal synapses of the rat.

The external globus pallidus (GPe) is central for basal ganglia processing. It expresses muscarinic cholinergic receptors and receives cholinergic afferents from the pedunculopontine nuclei (PPN) and other regions. The role of these receptors and afferents is unknown. Muscarinic M1-type receptors are expressed by synapses from striatal projection neurons (SPNs). Because axons from SPNs project to the GPe, one hypothesis is that striatopallidal GABAergic terminals may be modulated by M1 receptors. Alternatively, some M1 receptors may be postsynaptic in some pallidal neurons. Evidence of muscarinic modulation in any of these elements would suggest that cholinergic afferents from the PPN, or other sources, could modulate the function of the GPe. In this study, we show this evidence using striatopallidal slice preparations: after field stimulation in the striatum, the cholinergic muscarinic receptor agonist muscarine significantly reduced the amplitude of inhibitory postsynaptic currents (IPSCs) from synapses that exhibited short-term synaptic facilitation. This inhibition was associated with significant increases in paired-pulse facilitation, and quantal content was proportional to IPSC amplitude. These actions were blocked by atropine, pirenzepine, and mamba toxin-7, suggesting that receptors involved were M1. In addition, we found that some pallidal neurons have functional postsynaptic M1 receptors. Moreover, some evoked IPSCs exhibited short-term depression and a different kind of modulation: they were indirectly modulated by muscarine via the activation of presynaptic cannabinoid CB1 receptors. Thus pallidal synapses presenting distinct forms of short-term plasticity were modulated differently.

TFIIH is an elongation factor of RNA polymerase I.

TFIIH is a multisubunit factor essential for transcription initiation and promoter escape of RNA polymerase II and for the opening of damaged DNA double strands in nucleotide excision repair (NER). In this study, we have analyzed at which step of the transcription cycle TFIIH is essential for transcription by RNA polymerase I. We demonstrate that TFIIH associates with the rDNA promoter and gene-internal sequences and leaves the rDNA promoter in a complex with RNA polymerase I after start of transcription. Moreover, mutations in the TFIIH subunits XPB and XPD found in Cockayne syndrome impair the interaction of TFIIH with the rDNA, but do not influence initiation complex formation or promoter escape of RNA polymerase I, but preclude the productivity of the enzyme by reducing transcription elongation in vivo and in vitro. Our results implicate that reduced RNA polymerase I transcription elongation and ribosomal stress could be one factor contributing to the Cockayne syndrome phenotype.

Early Experiences with Intrathecal Administration of Amphotericin B Liposomal Formulation at a Neurosurgical Center.

BACKGROUND: Intrathecal administration of amphotericin B represents an important adjunctive therapy for management of severe fungal meningitis. Intrathecal preparations have traditionally used amphotericin B deoxycholate. Liposomal amphotericin B is an alternative formulation with good clinical outcomes as systemic therapy, but scant data exist investigating intrathecal use. OBJECTIVE: The aim of this exploratory study was to evaluate outcomes following intrathecal administration of liposomal amphotericin B for treatment of severe fungal meningitis. METHODS: A national shortage of amphotericin B deoxycholate necessitated revision of institutional protocols at a southwestern neurosurgical center in Spring 2023. A starting intrathecal daily dose of 0.125-0.5 mg liposomal amphotericin B was recommended (dependent on insertion device), with 0.125-0.25 mg slow titration every 48 h and up to a 2 mg maximum daily dose. RESULTS: Four cases of fungal meningitis treated with adjunctive intrathecal amphotericin B liposomal formulation were reviewed. This included three cases of coccidioidal meningitis and one case of presumed Fusarium solani meningitis following an outbreak. All patients had initial disease improvement following initiation of intrathecal amphotericin B and were able to tolerate long-term therapy. One coccidioidal meningitis patient expired of neurologic complications shortly after being moved from the intensive care unit (ICU) to a floor unit. All other patients were successfully discharged from the hospital. New headache was the only reported adverse effect, which was managed with dose reduction and did not require therapy discontinuation. CONCLUSIONS: Liposomal amphotericin B may be feasibly administered intrathecally for the adjunctive treatment of severe fungal meningitis.

Observer-based control for plasma glucose regulation in type 1 diabetes mellitus patients with unknown input delay.

This article introduces an observer-based control strategy tailored for regulating plasma glucose in type 1 diabetes mellitus patients, addressing challenges like unknown time-varying delays and meal disturbances. This control strategy is based on an extended Bergman minimal model, a nonlinear glucose-insulin model to encompass unknown inputs, such as unplanned meals, exercise disturbances, or delays. The primary contribution lies in the design of an observer-based state feedback control in the presence of unknown long delays, which seeks to support and enhance the performance of the traditional artificial pancreas by considering realistic scenarios. The observer and control gains for the observer-based control are computed through linear matrix inequalities formulated from Lyapunov conditions that guarantee closed-loop stability. This design deploys a soft and gentle dynamic response, similar to a natural pancreas, despite meal disturbances and input delays. Numerical tests demonstrate the scheme's effectiveness in glycemic level regulation and hypoglycemic episode avoidance.

Agave-Laurate-Bioconjugated Fructans Decrease Hyperinsulinemia and Insulin Resistance, Whilst Increasing IL-10 in Rats with Metabolic Syndrome Induced by a High-Fat Diet.

Metabolic syndrome (MetS) comprises a cluster of metabolic risk factors, which include obesity, hypertriglyceridemia, high blood pressure, and insulin resistance. The purpose of this study was to evaluate the effects of laurate-bioconjugated fructans on pro- and anti-inflammatory cytokines in Wistar rats with MetS induced by a high-fat diet. Laurate-bioconjugated fructans were synthesized with agave fructans, immobilized lipase B, and vinyl laureate as the acylant. Groups were fed a standard diet (NORMAL), a high-fat diet (HFD), or a high-fat diet plus laurate-bioconjugated fructans (FL PREV) for 9 weeks. A fourth group received a high-fat diet for 6 weeks, followed by simultaneous exposure to a high-fat diet and laurate-bioconjugated fructans for 3 additional weeks (FL REV). The dose of laurate-bioconjugated fructans was 130 mg/kg. Laurate-bioconjugated fructans reduced food and energy intake, body weight, body mass index, abdominal circumference, adipose tissue, adipocyte area, serum triglycerides, insulin, insulin resistance, and C-reactive protein but they increased IL-10 protein serum levels and mRNA expression. The impact of laurate-bioconjugated fructans on zoometric and metabolic parameters supports their potential as therapeutic agents to improve obesity, obesity comorbidities, insulin resistance, type 2 diabetes mellitus, and MetS.

The leachate from the Urban Solid Waste Transfer Station produces neurotoxicity in Wistar rats.

Leachate from municipal solid waste is a mixture of xenobiotics capable of contaminating bodies of water and causing damage to the health of living beings that inhabit or consume contaminated water. A previous study revealed the presence of heavy metals in Urban Solid Waste Transfer Station (USWTS) leachate above the permissible national and international limits. In the present study, we demonstrate that subchronic oral administration (5 and 25 % v/v) of leachate to male Wistar rats caused changes in the immunoreactivity of the glial markers: GFAP and Iba-1, accompanied by an increase in the expression of caspase-3, and a decrease in the expression of the NeuN protein. Results indicate that the heavy metals present in the leachate induced neuronal loss in the prefrontal cortex, suggesting that these contaminants can cause neurological problems in mammals that consume surface water with xenobiotics, since the leachate could contaminate water bodies and underground water.

Structure factor and rheology of chain molecules from molecular dynamics.

Equilibrium and non-equilibrium molecular dynamics were performed to determine the relationship between the static structure factor, the molecular conformation, and the rheological properties of chain molecules. A spring-monomer model with Finitely Extensible Nonlinear Elastic and Lennard-Jones force field potentials was used to describe chain molecules. The equations of motion were solved for shear flow with SLLOD equations of motion integrated with Verlet's algorithm. A multiple time scale algorithm extended to non-equilibrium situations was used as the integration method. Concentric circular patterns in the structure factor were obtained, indicating an isotropic Newtonian behavior. Under simple shear flow, some peaks in the structure factor were emerged corresponding to an anisotropic pattern as chains aligned along the flow direction. Pure chain molecules and chain molecules in solution displayed shear-thinning regions. Power-law and Carreau-Yasuda models were used to adjust the generated data. Results are in qualitative agreement with rheological and light scattering experiments.

Antibacterial and Antibiofilm Activity of Chemically and Biologically Synthesized Silver Nanoparticles.

Bacterial biofilms are a significant problem in the food industry, as they are difficult to eradicate and represent a threat to consumer health. Currently, nanoparticles as an alternative to traditional chemical disinfectants have garnered much attention due to their broad-spectrum antibacterial activity and low toxicity. In this study, silver nanoparticles (AgNPs) were synthesized by a biological method using a Jacaranda mimosifolia flower aqueous extract and by a chemical method, and the factors affecting both syntheses were optimized. The nanoparticles were characterized by Ultraviolet-visible (UV-Vis) spectrophotometry, Fourier-transform infrared spectroscopy (FTIR), Dynamic light scattering (DLS), X-ray diffraction (XRD), and Transmission electron microscopy (TEM) with a spherical and uniform shape. The antibacterial and antibiofilm formation activity was carried out on bacterial species of Pseudomonas aeruginosa and Staphylococcus aureus with the capacity to form biofilm. The minimum inhibitory concentration was 117.5 µg/mL for the chemical and 5.3 µg/mL for the biological nanoparticles. Both types of nanoparticles showed antibiofilm activity in the qualitative Congo red test and in the quantitative microplate test. Antibiofilm activity tests on fresh lettuce showed that biological nanoparticles decreased the population of S. aureus and P. aeruginosa by 0.63 and 2.38 logarithms, respectively, while chemical nanoparticles had little microbial reduction. In conclusion, the biologically synthesized nanoparticles showed greater antibiofilm activity. Therefore, these results suggest their potential application in the formulation of sanitizing products for the food and healthcare industries.

Role of Ih in the firing pattern of mammalian cold thermoreceptor endings.

Mammalian peripheral cold thermoreceptors respond to cooling of their sensory endings with an increase in firing rate and modification of their discharge pattern. We recently showed that cultured trigeminal cold-sensitive (CS) neurons express a prominent hyperpolarization-activated current (I(h)), mainly carried by HCN1 channels, supporting subthreshold resonance in the soma without participating in the response to acute cooling. However, peripheral pharmacological blockade of I(h), or characterization of HCN1(-/-) mice, reveals a deficit in acute cold detection. Here we investigated the role of I(h) in CS nerve endings, where cold sensory transduction actually takes place. Corneal CS nerve endings in mice show a rhythmic spiking activity at neutral skin temperature that switches to bursting mode when the temperature is lowered. I(h) blockers ZD7288 and ivabradine alter firing patterns of CS nerve endings, lengthening interspike intervals and inducing bursts at neutral skin temperature. We characterized the CS nerve endings from HCN1(-/-) mouse corneas and found that they behave similar to wild type, although with a lower slope in the firing frequency vs. temperature relationship, thus explaining the deficit in cold perception of HCN1(-/-) mice. The firing pattern of nerve endings from HCN1(-/-) mice was also affected by ZD7288, which we attribute to the presence of HCN2 channels in the place of HCN1. Mathematical modeling shows that the firing phenotype of CS nerve endings from HCN1(-/-) mice can be reproduced by replacing HCN1 channels with the slower HCN2 channels rather than by abolishing I(h). We propose that I(h) carried by HCN1 channels helps tune the frequency of the oscillation and the length of bursts underlying regular spiking in cold thermoreceptors, having important implications for neural coding of cold sensation.

Bilateral ligation of the anterior trunk of the internal iliac artery in uterine atony secondary to uterine inversion: case report.

Postpartum hemorrhage is one of the leading causes of maternal mortality worldwide. Uterine atony is the main cause, representing up to 90% of cases, and is a risk factor for uterine inversion. Morbidity and mortality occur in 41% of uterine inversion cases, including massive obstetric hemorrhage. Massive obstetric hemorrhage is a medical emergency that puts life and reproductive function at risk, and therefore, its treatment must be timely and immediate. If there is no favorable response with the initial measures, surgical intervention proceeds. When choosing the surgical procedure, priority should be given to the technique with the easiest access and which is the least invasive, the safest, and in which the surgeon has more experience. We present a case report with our technique of bilateral ligation of the anterior trunk of the hypogastric artery, after a uterine compression suture failed, with excellent results and preserved fertility in an adolescent patient. We describe the technique and the result. The response time of the uterus with normal tone was 5 minutes, and postligation bleeding was only 50 mL after the patient had bled 1200 mL without complications; thus, it is an adequate and cost-effective technique. The bilateral ligation of the anterior trunk of the hypogastric artery technique in the case of postpartum hemorrhage is an effective, safe, and fertility-preserving surgical procedure that constitutes an alternative to emergency obstetrical hysterectomy when other, less invasive methods have failed.

Toxicological Evaluation of Silver Nanoparticles Synthesized with Peel Extract of Stenocereus queretaroensis.

Silver nanoparticles (AgNPs) synthesized with plants are widely used in different industries, such as the medical, industrial, and food industries; however, their hazards and risks remain unclear. Here, we aimed to evaluate the toxicological effects of AgNPs in both in vitro and in vivo models. Previously, we developed and characterized green synthesized AgNPs based on Stenocereus queretaroensis (S. queretaroensis). The present study evaluates the toxicity of these AgNPs through cytotoxicity and mutagenicity tests in vitro, as well as genotoxicity tests, including the evaluation of acute oral, dermal, and inhalation toxicity, along with dermal and ocular irritation, in vivo, according to guidelines of The Organization for Economic Co-operation and Development (OECD). We evaluated cell cytotoxicity in L929 cells, and the half-maximal inhibitory concentration was 134.76 µg/mL. AgNPs did not cause genotoxic or mutagenic effects. Furthermore, in vivo oral, dermal, and acute inhalation toxicity results did not show any adverse effects or mortality in the test animals, and after the dermal and ocular irritation assessments, the in vivo models did not exhibit irritation or corrosion. Therefore, the results show that these previously synthesized S. queretaroensis AgNPs do not represent a risk at the tested concentrations; however, little is known about the effects that AgNPs induce on physiological systems or the possible risk following long-term exposure.

Dopamine D2 and Adenosine A2A Receptors Interaction on Ca2+ Current Modulation in a Rodent Model of Parkinsonism.

SUMMARY STATEMENT: A2A receptor required previous D2 receptor activation to modulate Ca2+ currents. Istradefylline decreases pramipexole modulation on Ca2+ currents. Istradefylline reduces A2A + neurons activity in striatial microcircuit, but pramipexole failed to further reduce neuronal activity.