We report the first use of adjunctive bacteriophage therapy for Escherichia coli related malakoplakia in a kidney transplant recipient with progressive disease. Adjunctive CRISPR-enhanced phage cocktail SNIPR001 combined with prolonged antibiotics, ascorbic acid, and bethanechol was associated with cutaneous lesion resolution and sustained radiographic regression without phage-related adverse events.

Rattlesnake envenomation is a common emergency in horses in California. Rattlesnakes belong to a group of venomous snakes: pit vipers. The Northern Pacific Rattlesnake (Crotalus oreganus oreganus), a subspecies of the Western Rattlesnake, is the most widespread rattlesnake in California (1). A 5-year-old miniature horse mare presented for a presumed Western Rattlesnake bite. The owners found the horse the morning of presentation with severe facial swelling and the horse was housed in an area where rattlesnakes are commonly observed. The horse was reported to be normal the day prior to presentation. On blood examination, severe thrombocytopenia, elevated AST, and elevated creatine kinase (CK) were identified. On physical examination the horse was noted to have severe facial swelling, to be dribbling urine, and to have a hypermetric gate in the hind limbs. Treatment was initiated with antivenom, bethanechol, and supportive care. After 6 days of hospitalization, the horse regained urinary function, the facial swelling significantly improved, the neurologic gait resolved, and the horse was discharged. This is the first case report describing neurologic manifestations from a presumed Western Rattlesnake bite.

Aqueous zinc-iodine (Zn-I2) batteries, leveraging four-electron I[-]/I[0]/I[+] redox chemistry, offer advantages such as high voltage, low cost, and high safety. However, their widespread application is hindered by hydrolysis reactions and the shuttle effect of iodine species. Here, a multifunctional electrolyte additive, bethanechol chloride (AChR), is employed to simultaneously stabilize I[+] and inhibit the polyiodide shuttle, thereby prolonging the cycling life of aqueous Zn-I2 batteries. The AChR additive, possessing positively charged -N[+](CH3)3 functional groups, electrostatically traps I3[-] anions with an adsorption energy of -0.45 eV, significantly suppressing the polyiodide shuttle. Meanwhile, its nucleophilic -NH2 and C=O groups effectively disrupt hydrogen-bond networks and reduce water activity, thereby protecting I[+] from water nucleophilic attack. In situ Raman spectroscopy confirms that the signal intensity of ICl charging product in the AChR-containing aqueous electrolyte is 20 times higher than that in the baseline electrolyte (BE), demonstrating that AChR restrains I[+] hydrolysis. Benefiting from these advantages, the Zn-I2 cell achieves a high areal capacity of 5.64 mAh cm[-2] and exhibits a high capacity retention ratio of 78.2% after 1000 cycles, even with a high I2 cathode mass loading of 16.6 mg cm[-2], representing a 21.7-fold improvement over the cell in the BE.

The role of cholinergic system in hair biology is poorly understood. In M4 muscarinic receptor (mAChR) knockout mice, the hair follicles have a prolonged telogen phase and fail to produce hair shafts. Here, we reported that hair growth was regulated by cholinergic signalling via mAChRs. Dermal papilla cells expressed different cholinergic biomarkers. Inhibiting AChE or activating mAChR in dermal papilla cells, cultured vibrissae and mouse skin epidermis promoted the hair growth. In cultured papilla cells treated with bethanechol, an agonist of mAChR, an activation of Wnt/β-catenin signalling was illustrated by various indicative biomarkers, including phosphorylation of GSK-3β and mRNA expression of various molecules for Wnt/β-catenin signalling. Activation of Wnt/β-catenin signalling was mediated by PI3K/AKT and ERK signalling upon the stimulation of bethanechol. Moreover, the bethanechol-mediated signalling was blocked by specific antagonist of M4 mAChR. In addition, an increase in hair shaft elongation was observed in mouse vibrissae upon the treatment of bethanechol, suggesting the cholinergic role in hair growth.

Bungarus multicinctus is one of the most venomous and lethal snake species in mainland China, with envenomation resulting in a mortality rate as high as 23%. Currently, antivenin against B. multicinctus remains the gold standard for treating bites from this species. However, in remote mountainous areas or rural regions of China, access to antivenin may be delayed or unavailable following a bite. The lethal components of B. multicinctus venom include α-, β-, γ- and κ-bungarotoxins, which act on either the presynaptic or postsynaptic membrane, thereby altering acetylcholine levels in the synaptic cleft. This study aims to evaluate pharmaceutical agents that confer prophylactic or protective effects against bungarotoxins and neurotoxin-rich snake venoms. Based on theoretical considerations, we postulate that certain anticholinergic or anticholinesterase agents may exhibit potential protective efficacy against these venom components. This study investigated the protective effects of clinically standard anticholinergic and anticholinesterase agents-scopolamine, neostigmine methylsulfate, bethanechol chloride, pilocarpine hydrochloride, and atropine sulfate-against different bungarotoxins and wide distribution neurotoxin-rich crude snake venoms (B. multicinctus, Naja atra and Ophiophagus hannah). Our results showed that neostigmine methylsulfate and atropine sulfate exerted significant protective effects (P < 0.01) against three-finger toxins contained in B. multicinctus venom, including α-bungarotoxin, γ-bungarotoxin, α-bungarotoxin+γ-bungarotoxin combinations, β-bungarotoxin+α-bungarotoxin combinations, and β-bungarotoxin+γ-bungarotoxin combinations. In mice animal models treated with B. multicinctus antivenin, neostigmine methylsulfate and atropine sulfate retained profound protective effects (P < 0.01) against β-bungarotoxin+α-bungarotoxin and β-bungarotoxin+γ-bungarotoxin mixtures. However, these clinic-used drugs showed no significant protective effect against B. multicinctus crude venom, with only modest survival time prolongation without statistical significance observed. Under the same conditions, theses drugs showed no effects on king cobra venoms and significantly prompted the death of the tested animals. Present investigation provides a scientific basis for the treatment of B. multicinctus bites in remote mountainous areas or rural regions of southern China. Upon confirming victims were bitten by B. multicinctus, administering atropine sulfate or neostigmine methylsulfate as emergency treatment might provide supplementary benefits for subsequent care. Importantly, the administration of clinic used drugs does not interfere with the efficacy of B. multicinctus antivenin in later treating stages.

Bethanechol chloride, a nonselective muscarinic agonist, is the most frequently employed drug in dogs and cats to induce detrusor smooth muscle contraction under conditions characterized by poor or absent bladder emptying. Although this drug has minimal or absent nicotinic activity, at higher doses, weak stimulation of neuronal nicotinic receptors may occur, causing the release of noradrenaline, which induces contraction of the urethral smooth muscle by activating α-adrenergic receptors. In the presence of total or partial suprasacral lesions, the elaboration and initiation phase of the urination process is absent due to an interruption of afferent signals from the bladder to the brainstem. In such cases, hypertonicity of the urethral sphincters is expected, and bethanechol is contraindicated. Bethanechol is also not indicated for reflex dyssynergia. In the presence of complete injuries involving the sacral segments, cauda equina, or pelvic nerve, both reflex and voluntary micturition are abolished, and bethanechol is usually ineffective. However, in cases of partial injuries, bethanechol is likely to be effective, as partial integrity of the micturition reflex is required to produce sustained bladder contraction. Bethanechol may benefit patients with myopathic decompensated bladder, although its effectiveness depends on the severity of detrusor damage.

Gastrin-releasing peptide (GRP) and neuromedin B (NMB) are found in the stomach's myenteric plexus and muscular layers. When exogenously administered, they contract stomach muscle in several species, but their ability to modulate enteric nerve functions has rarely been studied. We investigated the effects of GRP on cholinergic-mediated contractions of the stomach, after first characterizing the contractile effects of GRP, NMB, and bombesin (BB). Circular muscle rings, cut from the mouse gastric fundus, were studied using tissue bath techniques. Contractions evoked by electrical field stimulation (EFS; 5 Hz) were examined under non-adrenergic, non-nitrergic conditions. Contractions were expressed as % of the maximum contraction induced by carbachol (100 μM). GRP (0.0001-1 μM), NMB (0.0001-3 μM), and BB (0.0001-1 μM) induced concentration-dependent tonic muscle contractions. The pD2 and Emax were, respectively, GRP: 7.2 ± 0.1, 54.6% ± 3.6% (n = 14); BB: 7.4 ± 0.2, 47.2% ± 3.9% (n = 9); and NMB: 6.3 ± 0.1, 38.1% ± 5.6% (n = 10). GRP- and NMB-induced contractions were inhibited by the BB2 receptor antagonist BW-10, not by the BB1 receptor antagonist PD168368. EFS-evoked contractions were blocked by atropine (1 μM) or tetrodotoxin (1 μM), and concentration-dependently potentiated by GRP (0.0001-1 μM), with pD2 and Emax values 7.8 ± 0.1 and 81.2% ± 14.0%, respectively (n = 17). This activity was inhibited by BW-10, not PD168368. BW-10 alone also reduced EFS-evoked contraction amplitudes. GRP and BW-10 did not affect contractions induced by bethanechol (1-300 μM). In conclusion, in mouse gastric fundus, GRP causes muscle contraction and also facilitates electrically evoked cholinergic activity (facilitating ACh release), both actions most likely involving BB2 receptor activation. Further experiments must ascertain the physiological significance of these actions, alone and together.

The incretin peptides glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors coordinate β cell secretion that is proportional to nutrient intake. This effect permits consistent and restricted glucose excursions across a range of carbohydrate intake. The canonical signaling downstream of ligand-activated incretin receptors involves coupling to Gαs protein and generation of intracellular cAMP. However, recent reports have highlighted the importance of additional signaling nodes engaged by incretin receptors, including other G proteins and β-arrestin proteins. Here, the importance of Gαs signaling was tested in mice with conditional, postdevelopmental β cell deletion of Gnas (encoding Gαs) under physiological and pharmacological conditions. Deletion of Gαs/cAMP signaling induced immediate and profound hyperglycemia that responded minimally to incretin receptor agonists, a sulfonylurea, or bethanechol. While islet area and insulin content were not affected in Gnasβcell-/-, perifusion of isolated islets demonstrated impaired responses to glucose, incretins, acetylcholine, and IBMX In the absence of Gαs, incretin-stimulated insulin secretion was impaired but not absent, with some contribution from Gαq signaling. Collectively, these findings validate a central role for cAMP in mediating incretin signaling, but also demonstrate broad impairment of insulin secretion in the absence of Gαs that causes both fasting hyperglycemia and glucose intolerance.