Circumferential Inferior Vena Cavectomy Without Caval Replacement in the Management of Renal Cell Carcinoma with Tumor Thrombus.

PURPOSE OF REVIEW: Renal cell carcinoma presents a unique proclivity for vascular involvement giving rise to a peculiar form of locally advanced disease so-called tumor thrombus. To date, the only curative strategy for these cases remains surgery, which should aim to remove every vestige of macroscopic disease. Most of the preexisting literature advocates opening the vena cava to allow tumor thrombus removal and subsequent venous suture closure. However, inferior vena cava circumferential resection (cavectomy) without caval replacement is possible in the majority of cases since progressive occlusion facilitates the development of a collateral venous network aimed at maintaining cardiac preload. RECENT FINDINGS: Radical nephrectomy with tumor thrombectomy remains a surgical challenge not exempt of operative complications even in experienced hands. In opposition to what traditional cavotomy and thrombus withdrawal can offer, circumferential cavectomy without caval replacement would provide comparable or even better oncologic control, decrease the likelihood of operative bleeding, and prevent the development of perioperative pulmonary embolism. This review focuses on the rationale of circumferential IVC resection without caval replacement and the important technical aspects of this approach in cases of renal cell carcinoma with vascular involvement. We also include an initial report on the surgical outcomes of a contemporary series of patients managed under this approach at our center.

Beyond uncal herniation: An updated diagnostic reappraisal of ipsilateral hemiparesis and the Kernohan-Woltman notch phenomenon.

PURPOSE: This works comprehensively analyses a modern cohort of patients with ipsilateral hemiparesis (IH) and discusses the pathophysiological theories elaborated to explain this paradoxical neurological sign according to the findings from contemporary neuroimaging and neurophysiological techniques. METHODS: A descriptive analysis of the epidemiological, clinical, neuroradiological, neurophysiological, and outcome data in a series of 102 case reports of IH published on since the introduction of CT/MRI diagnostic methods (years 1977-2021) was performed. RESULTS: IH mostly developed acutely (75.8%) after traumatic brain injury (50%), as a consequence of the encephalic distortions exerted by an intracranial haemorrhage eventually causing contralateral peduncle compression. Sixty-one patients developed a structural lesion involving the contralateral cerebral peduncle (SLCP) demonstrated by modern imaging tools. This SLCP showed certain variability in its morphology and topography, but it seems pathologically consistent with the lesion originally described in 1929 by Kernohan & Woltman. The study of motor evoked potentials was seldom employed for the diagnosis of IH. Most patients underwent surgical decompression, and a 69.1% experienced some improvement of the motor deficit. CONCLUSIONS: Modern diagnostic methods support that most cases in the present series developed IH following the KWNP model. The SLCP is presumably the consequence of either compression or contusion of the cerebral peduncle against the tentorial border, although focal arterial ischemia may also play a contributing role. Some improvement of the motor deficit should be expected even in the presence of a SLCP, provided the axons of the CST were not completely severed.

Legal and ethical implications of defining an optimum means of achieving unconsciousness in assisted dying.

A decision by a society to sanction assisted dying in any form should logically go hand-in-hand with defining the acceptable method(s). Assisted dying is legal in several countries and we have reviewed the methods commonly used, contrasting these with an analysis of capital punishment in the USA. We expected that, since a common humane aim is to achieve unconsciousness at the point of death, which then occurs rapidly without pain or distress, there might be a single technique being used. However, the considerable heterogeneity in methods suggests that an optimum method of achieving unconsciousness remains undefined. In voluntary assisted dying (in some US states and European countries), the common method to induce unconsciousness appears to be self-administered barbiturate ingestion, with death resulting slowly from asphyxia due to cardiorespiratory depression. Physician-administered injections (a combination of general anaesthetic and neuromuscular blockade) are an option in Dutch guidelines. Hypoxic methods involving helium rebreathing have also been reported. The method of capital punishment (USA) resembles the Dutch injection technique, but specific drugs, doses and monitoring employed vary. However, for all these forms of assisted dying, there appears to be a relatively high incidence of vomiting (up to 10%), prolongation of death (up to 7 days), and re-awakening from coma (up to 4%), constituting failure of unconsciousness. This raises a concern that some deaths may be inhumane, and we have used lessons from the most recent studies of accidental awareness during anaesthesia to describe an optimal means that could better achieve unconsciousness. We found that the very act of defining an 'optimum' itself has important implications for ethics and the law.

The first sixty-five craniopharyngioma operations in France.

Craniopharyngiomas (CPs) are benign epithelial tumors that develop along the hypothalamus-hypophyseal axis and were first described by Jakob Erdheim in 1904. These tumors have represented a challenge for surgeons since the rise of modern neurosurgery. The study of CPs is linked to the development of this surgical discipline in parallel with neuroendocrinology within the French school of neurology, led by Joseph Babinski. For the present study, all CP cases published in the French scientific literature before the development of modern neuroradiology were gathered, and 65 cases that underwent surgical procedures between 1921 and 1973 were selected. From our analysis of them, useful information has been obtained that can be applied to the management of CPs today. Most tumors were adamantinomatous CPs (62 patients) with an infundibulo-tuberal location (40.6%). The most frequent surgical route employed was subfrontal (69%). Selection of the surgical approach and degree of removal did not appear to have been influenced by the presumed topography of the tumor, and resulted in a poor outcome in 47% of patients. However, the authors were able to recognize the presence of symptoms indicating that the tumor had caused hypothalamic and/or infundibular damage, such as seen in the infundibulo-tuberal syndrome, first described by Claude and Lhermitte in 1917. At present, the optimal surgical approach and degree of removal are still the subject of debate, although the presence of clinical signs pointing to hypothalamic involvement by CPs should always be preoperatively accurately assessed to improve surgical outcomes.

[When to resume driving after primary total hip arthroplasty?] / ¿Cuándo se reanuda la conducción después del reemplazo total de cadera primario?

INTRODUCTION: the current literature relates the return to driving with multiple variables. For various reasons, the current data on the time to return to driving after a total hip arthroplasty (THA) are diverse and even contradictory. We have proposed the objective of determining the time required to drive a manual gear vehicle again in a group of patients who underwent primary THA through a posterolateral approach with focus on manual gear cars. MATERIAL AND METHODS: we have studied the functional results of 112 patients who underwent primary THA between January 2019 and January 2020 in a high level in Cadiz, Andalusia, Spain. RESULTS: the median return to driving was three weeks (IQR 2-4). We have identified that 89.3% of the patients were able to drive again before the sixth week after surgery and in 92% of the cases they did so feeling even safer than before the THA. CONCLUSION: we consider that after the sixth week of an THA it is safe to resume driving a vehicle.

INTRODUCCIÓN: la literatura actual relaciona el regreso a la conducción vehicular con múltiples variables. Sin embargo, los datos actuales sobre el tiempo de regreso a la conducción luego de una artroplastía total de cadera (ATC) son diversos e incluso contradictorios. Por lo tanto, nos hemos planteado el objetivo de determinar el tiempo requerido para volver a conducir en un grupo de pacientes sometidos a una ATC primaria mediante un abordaje posterolateral, centrándonos específicamente en vehículos de marcha manual. MATERIAL Y MÉTODOS: hemos estudiado los resultados clínico-funcionales de 112 pacientes sometidos a una ATC primaria entre Enero de 2019 y Enero de 2020 en un hospital de alta complejidad en Cádiz, Andalucía, España. RESULTADOS: la mediana del tiempo de regreso a la conducción fue de tres semanas (RIC 2-4). Hemos identificado que 89.3% de los pacientes pudo volver a conducir antes de la sexta semana posterior a la cirugía. Además, en 92% de los casos, los pacientes se sintieron aún más seguros al conducir después de la ATC que antes de la intervención. CONCLUSIÓN: consideramos que a la sexta semana de una ATC es seguro reanudar la conducción de un vehículo.

Duct-like Recess in the Infundibular Portion of Third Ventricle Craniopharyngiomas: An MRI Sign Identifying the Papillary Type.

BACKGROUND AND PURPOSE: Papillary craniopharyngiomas (PCPs) are particularly challenging lesions requiring accurate diagnosis to plan the best therapy. Our aim was to define a narrow duct-like recess identified on MR imaging at the base of papillary craniopharyngiomas with a strict third ventricle location. MATERIALS AND METHODS: A duct-like recess at the infundibular portion of craniopharyngiomas was observed on conventional T1WI and T2WI in 3 strict third ventricle papillary craniopharyngiomas in our craniopharyngioma series (n = 125). We systematically investigated this finding on the MR imaging of 2582 craniopharyngiomas and 10 other categories of third ventricle tumors (n = 690) published in the modern era (1986-2020). The diagnostic value and significance of this finding are addressed. RESULTS: The duct-like recess was recognized in 52 papillary craniopharyngiomas, including 3 of our own cases, as a narrow canal-shaped cavity invaginated at the tumor undersurface, just behind the optic chiasm. This structure largely involves papillary craniopharyngiomas with a strict third ventricle topography (96%), follows the same diagonal trajectory as the pituitary stalk, and finishes at a closed end. The duct-like recess sign identifies the papillary craniopharyngioma type with a specificity of 100% and a sensitivity of 38% in the overall craniopharyngioma population. This finding can also establish the strictly intra-third ventricle location of the lesion with a 90% specificity and 33% sensitivity. These recesses appear as hypointense circular spots on axial/coronal T1WI and T2WI. Their content apparently corresponds to CSF freely flowing within the suprasellar cistern. CONCLUSIONS: The presence of a duct-like recess at the infundibular portion of a third ventricle tumor represents a distinctive hallmark of papillary craniopharyngiomas that can be used as a simple MR imaging sign to reliably diagnose these lesions.

Allergy assessment in children with eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is of growing interest for pediatricians and allergists. There is no general agreement about diagnostic and clinical management procedures. The objective of this prospective, observational study was to evaluate the efficacy of a protocol for the etiologic diagnosis and accurate treatment of EoE in the pediatric population. PATIENTS AND METHODS: Starting in 2001, patients aged 0 to 14 years with a diagnosis of EoE were consecutively included in a protocol which included an allergy study. Depending on the results, an avoidance or elemental diet was established. Topical corticosteroids were prescribed to patients who rejected the diet. Clinical, endoscopic, and histological evaluation was performed to assess response. In the case of disease remission, challenge tests were performed to identify the offending food. RESULTS: Seventeen patients were included. Most of them were male (14/17) and a high percentage (88%) had a history of allergy as well as a history of atopy in parents. Fifteen patients were sensitized to 1 or more foods. With this protocol and the subsequent treatment, 9 out of 17 patients were cured (1 out of 4 with swallowed corticosteroids, 3 out of 3 with an elemental diet, and 5 out of 12 with an avoidance diet). The offending food was identified in 8117 patients. Milk and eggs were the most common foods implicated. CONCLUSIONS: The allergy study was a useful diagnostic tool but it was not sufficient to identify the offending food.An elemental diet should be attempted before food is excluded as the cause of the disease.

Zonisamide versus diazepam in the treatment of alcohol withdrawal syndrome.

INTRODUCTION: Anticonvulsant drugs have been used in the treatment of alcohol detoxification. The purpose of the present study was to evaluate the efficacy and safety of zonisamide in a sample of patients presenting alcohol withdrawal syndrome. METHOD: In this 3-week, randomized, flexible-dose trial, 40 inpatients with alcohol dependence disorder received zonisamide or diazepam for detoxification. Zonisamide was started at a dose of 400-600 mg/day (week 1), tapering to a minimum dose of 100-300 mg/day (week 3). Diazepam was administered using a similar regimen (from 130-50 mg/day tapering to 5-15 mg/day). Subjects were treated initially (weeks 1 and 2) in an inpatient unit and for the final week in an outpatient facility. During the inpatient period, the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) was used to assess the efficacy of each substance. During the outpatient period the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar), Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, and a craving scale were used. RESULTS: All subjects completed the study. During the inpatient period both drugs reduced alcohol withdrawal symptoms, but the decrease was more marked in the zonisamide group. At the end of the study (week 3) participants treated with zonisamide showed lower CIWA-Ar scores than subjects receiving diazepam. Also, individuals in the zonisamide group had less craving for alcohol, less anxiety, and less daytime sedation compared with participants treated with diazepam. CONCLUSION: Zonisamide can be a valuable alternative to benzodiazepines in the prevention of alcohol withdrawal syndrome.

Spontaneous acute hemorrhage within a subependymoma of the lateral ventricle: successful emergent surgical removal through a frontal transcortical approach.

INTRODUCTION. Subependymomas are benign neoplasms intimately related to the ventricular system which only exceptionally associate hemorrhagic events. We present neuroradiological and pathological evidences of intratumoral hemorrhage within a single case of subependymoma operated on at our institution. Additionally we analyze retrospectively the well-defined reports of similar cases published in the scientific literature. CASE REPORT. A 71-year-old man on anticoagulant therapy presented with abrupt and progressive deterioration of his level of consciousness. Emergent computed tomography and magnetic resonance imaging evidenced signs of acute bleeding within a mass located at the frontal horn of the left lateral ventricle, producing obstructive biventricular hydrocephalus. The lesion was immediately and completely removed through a left frontal transcortical approach. Pathological diagnosis was consistent with subependymoma displaying areas of microhemorrhage. After surgery the patient developed global anterograde and retrograde amnesia. CONCLUSIONS. A spontaneous hemorrhagic event within an asymptomatic lateral ventricle subependymoma can result in a surgical emergence as a consequence of sudden obstruction of cerebrospinal fluid pathways. Prompt and radical surgical removal of the mass, which allows a rapid resolution of hydrocephalus and prevents the risk of rebleeding, may constitute the safest management strategy.

Penetrating ballistic-like frontal brain injury caused by a metallic rod.

Penetrating non-missile intracranial injuries caused by metallic foreign bodies are very rare among the civilian population. We present a unique instance of a severe, high-energy, penetrating orbitocranial injury caused by a solid metallic rod that corresponded to the spray valve lever handle of a kitchen sink pre-rinse spray tap, which was fractured and projected at high speed for an unknown reason. To our knowledge, this is the first report of a high-energy, penetrating brain injury caused by such an object. After careful radiological evaluation of the shape and position of the foreign object, a combined right frontal craniotomy and supraorbital osteotomy was performed in order to achieve safe removal of the metal bar. Successful surgical treatment of an orbitocranial injury caused by a similar object has not previously been reported.

[Experimental models of traumatic brain injury]. / Modelos experimentales de traumatismo craneoencefálico.

AIM: To provide a summary of the different experimental models of traumatic brain injury (TBI) designed under both in vivo and in vitro conditions. A comprehensible review of the specific types of brain lesions induced, as well as the technical details to reproduce each model at the laboratory is given. DEVELOPMENT: Outcome of patients suffering from a TBI has significantly improved with the rapid application of vital supporting measures in addition to a strict control of blood and intracranial pressure at the intensive care units. However no specific treatment for post-traumatic brain lesions has proven as efficacious in the clinical settings. A deeper knowledge of the physiopathological events associated with TBI is necessary for the development of new specific therapies. Due to the heterogeneity of the human TBI, each experimental model has been designed to reproduce a different type of brain lesion. Experimental TBI models allow the study of the dynamic evolution of brain injuries under controlled conditions. Usefulness of experimental models is limited by their reliability and reproducibility among different researchers. Small rodents have been the preferred animals to reproduce TBI injuries, mainly due to the similar cerebral physiology shared by these animals and the human beings. CONCLUSION: The use of experimental models of TBI is the most appropriate tool to study the mechanisms underlying this type of injury. However their simplicity precludes an exact reproduction of the heterogeneous cerebral damage observed in clinical settings. This could be the main reason for the discrepancies observed in the therapeutic effects of treatments between experimental and clinical studies.

[Giant cavernous sinus haemangioma. Case report]. / Hemangioma gigante del seno cavernoso. Caso clínico.

INTRODUCTION: Intracranial haemangioma is a benign vascular tumor which seldom affects the cavernous sinus region, being it frequently misdiagnosed as a meningioma. CASE REPORT: A 60-year-old woman presented with a subacute-onset third cranial nerve palsy. A giant extraaxial mass located in the middle cranial fossa which extended into the selar and supraselar areas was diagnosed. It showed homogeneous enhancement after contrast administration. The angiography revealed mild enhancement as well as indirect signs of mass effect, and a tumoral embolization was performed. Surgery and outcome. The tumor was partially removed through a left pterional approach, leaving an intraselar remnant. The patient had an uneventful postoperative course, and did not present new neurological deficits. CONCLUSIONS: The haemangioma must be considered in the differential diagnosis of cavernous sinus tumours. This entity represents a neurosurgical challenge, due to the complexity of this anatomical region and the trend of the tumour to bleed during its dissection.

K+ pore structure revealed by reporter cysteines at inner and outer surfaces.

The structure of the carboxyl half of the pore-forming region of Kv2.1 was studied by replacing each of 15 consecutive residues between positions 383 and 369 with a reporter cysteine residue. Extracellular application of charged, membrane-impermeant methanethiosulfonates irreversibly modified currents at four cysteine-substituted positions, K382, Y380, I379, and D378. Intracellular exposure to methanethiosulfonate ethyltrimethylammonium revealed another set of reactive mutants (V374, T373, T372, and T370). Our results indicate that positions 378 and 374 are exposed at outer and inner mouths of the channel, respectively, and immersed in the aqueous phase. In contrast to present topological models, the 383-369 region appears to span the pore mainly as a nonperiodic structure.

Topographic Diagnosis of Craniopharyngiomas: The Accuracy of MRI Findings Observed on Conventional T1 and T2 Images.

BACKGROUND AND PURPOSE: The topography of craniopharyngiomas has proved fundamental in predicting the involvement of vital brain structures and the possibility of achieving a safe radical resection. Beyond the imprecise term "suprasellar," indiscriminately used for craniopharyngiomas, an accurate definition of craniopharyngioma topography should be assessed by preoperative MR imaging. The objective of this study was to investigate the MRI findings that help define craniopharyngioma topography. MATERIALS AND METHODS: This study retrospectively investigated a cohort of 200 surgically treated craniopharyngiomas with their corresponding preoperative midsagittal and coronal conventional T1- and T2-weighted MR images, along with detailed descriptions of the surgical findings. Radiologic variables related to the occupation of the tumor of intracranial compartments and the distortions of anatomic structures along the sella turcica-third ventricle axis were analyzed and correlated with the definitive craniopharyngioma topography observed during the surgical procedures. A predictive model for craniopharyngioma topography was generated by multivariate analysis. RESULTS: Five major craniopharyngioma topographies can be defined according to the degree of hypothalamic distortion caused by the tumor: sellar-suprasellar, pseudointraventricular, secondary intraventricular, not strictly intraventricular, and strictly intraventricular. Seven key radiologic variables identified on preoperative MRI allowed a correct overall prediction of craniopharyngioma topography in 86% of cases: 1) third ventricle occupation, 2) pituitary stalk distortion, 3) relative level of the hypothalamus in relation to the tumor, 4) chiasmatic cistern occupation, 5) mammillary body angle, 6) type of chiasm distortion, and 7) tumor shape. CONCLUSIONS: Systematic assessment of these 7 variables on conventional preoperative T1 and T2 MRI is a useful and reliable method to ascertain individual craniopharyngioma topography.

Third ventricle glioblastoma. Case report and review of literature.

UNLABELLED: A glioblastoma presenting as a solitary third ventricle mass is exceptional. CASE DESCRIPTION: We report the case of a 29-year-old woman who lost consciousness, was taken to hospital and referred a previous history of depression and diabetes insipidus. Magnetic resonance imaging study revealed a heterogeneous anterior third ventricle mass with ring enhancement after contrast administration. It was approached and subtotally resected by a transcortical-transventricular route and histological diagnosis proved it to be a glioblastoma. There are only two other similar well-described cases and another nine have been previously reported in surgical series of high grade gliomas and glioblastomas. The possible origin of this lesion is discussed.

[Neurological phenocopying]. / Fenocopias neurológicas.

AIMS: To expand the -supposedly- narrow relationships that exist between genes and clinical syndromes by reflecting on several illustrative examples that disturb current simplistic genotype: phenotype correlations, and to explore a variety of biological mechanisms that account for this emerging phenomenon. DEVELOPMENT: Because it is well known that mutations in a single gene can give rise to numerous phenotypes, it would appear, at least intuitively, that the converse relationship might also hold true: that different genotypes may converge on just one single phenotype. Several examples taken from the study of selected neurological diseases illustrate that the latter principle indeed occurs in nature because disparate human genetic anomalies manifest similarly by exhibiting only a relatively limited phenotypic repertoire. This interesting biological phenomenon and vexing clinical problem is best described as phenocopying. Conditions such as spinal muscular atrophy, congenital glycosylation disorders, and mitochondrial diseases are but a few notorious examples of phenocopying. CONCLUSION: The nervous system is endowed with a limited number of genes and of types of molecules and, especially during development, its functional repertoire, at least from an observable point of view, is also limited. Therefore, ample genotyping capabilities are necessary to avoid erring in the process of diagnostic attribution because of phenocopying.

Delimiting the binding site for quaternary ammonium lidocaine derivatives in the acetylcholine receptor channel.

The triethylammonium QX-314 and the trimethylammonium QX-222 are lidocaine derivatives that act as open-channel blockers of the acetylcholine (ACh) receptor. When bound, these blockers should occlude some of the residues lining the channel. Eight residues in the second membrane-spanning segment (M2) of the mouse-muscle alpha subunit were mutated one at a time to cysteine and expressed together with wild-type beta, gamma, and delta subunits in Xenopus oocytes. The rate constant for the reaction of each substituted cysteine with 2-aminoethyl methanethiosulfonate (MTSEA) was determined from the time course of the irreversible effect of MTSEA on the ACh-induced current. The reactions were carried out in the presence and absence of ACh and in the presence and absence of QX-314 and QX-222. These blockers had no effect on the reactions in the absence of ACh. In the presence of ACh, both blockers retarded the reaction of extracellularly applied MTSEA with cysteine substituted for residues from alphaVal255, one third of the distance in from the extracellular end of M2, to alphaGlu241, flanking the intracellular end of M2, but not with cysteine substituted for alphaLeu258 or alphaGlu262, at the extracellular end of M2. The reactions of MTSEA with cysteines substituted for alphaLeu258 and alphaGlu262 were considerably faster in the presence of ACh than in its absence. That QX-314 and QX-222 did not protect alphaL258C and alphaE262C against reaction with MTSEA in the presence of ACh implies that protection of the other residues was due to occlusion of the channel and not to the promotion of a less reactive state from a remote site. Given the 12-A overall length of the blockers and the alpha-helical conformation of M2 in the open state, the binding site for both blockers extends from alphaVal255 down to alphaSer248.

State-dependent accessibility and electrostatic potential in the channel of the acetylcholine receptor. Inferences from rates of reaction of thiosulfonates with substituted cysteines in the M2 segment of the alpha subunit.

Ion channel function depends on the chemical and physical properties and spatial arrangement of the residues that line the channel lumen and on the electrostatic potential within the lumen. We have used small, sulfhydryl-specific thiosulfonate reagents, both positively charged and neutral, to probe the environment within the acetylcholine (ACh) receptor channel. Rate constants were determined for their reactions with cysteines substituted for nine exposed residues in the second membrane-spanning segment (M2) of the alpha subunit. The largest rate constants, both in the presence and absence of ACh, were for the reactions with the cysteine substituted for alpha Thr244, near the intracellular end of the channel. In the open state of the channel, but not in the closed state, the rate constants for the reactions of the charged reagents with several substituted cysteines depended on the transmembrane electrostatic potential, and the electrical distance of these cysteines increased from the extracellular to the intracellular end of M2. Even at zero transmembrane potential, the ratios of the rate constants for the reactions of three positively charged reagents with alpha T244C, alpha L251C, and alpha L258C to the rate constant for the reaction of an uncharged reagent were much greater in the open than in the closed state. This dependence of the rate constants on reagent charge is consistent with an intrinsic electrostatic potential in the channel that is considerably more negative in the open state than in the closed state. The effects of ACh on the rate constants for the reactions of substituted Cys along the length of alpha M2, on the dependence of the rate constants on the transmembrane potential, and on the intrinsic potential support a location of a gate more intracellular than alpha Thr244.

The intrinsic electrostatic potential and the intermediate ring of charge in the acetylcholine receptor channel.

A ring of aligned glutamate residues named the intermediate ring of charge surrounds the intracellular end of the acetylcholine receptor channel and dominates cation conduction (Imoto et al. 1988). Four of the five subunits in mouse-muscle acetylcholine receptor contribute a glutamate to the ring. These glutamates were mutated to glutamine or lysine, and combinations of mutant and native subunits, yielding net ring charges of -1 to -4, were expressed in Xenopus laevis oocytes. In all complexes, the alpha subunit contained a Cys substituted for alphaThr244, three residues away from the ring glutamate alphaGlu241. The rate constants for the reactions of alphaThr244Cys with the neutral 2-hydroxyethyl-methanethiosulfonate, the positively charged 2-ammonioethyl-methanethiosulfonate, and the doubly positively charged 2-ammonioethyl-2'-ammonioethanethiosulfonate were determined from the rates of irreversible inhibition of the responses to acetylcholine. The reagents were added in the presence and absence of acetylcholine and at various transmembrane potentials, and the rate constants were extrapolated to zero transmembrane potential. The intrinsic electrostatic potential in the channel in the vicinity of the ring of charge was estimated from the ratios of the rate constants of differently charged reagents. In the acetylcholine-induced open state, this potential was -230 mV with four glutamates in the ring and increased linearly towards 0 mV by +57 mV for each negative charge removed from the ring. Thus, the intrinsic electrostatic potential in the narrow, intracellular end of the open channel is almost entirely due to the intermediate ring of charge and is strongly correlated with alkali-metal-ion conductance through the channel. The intrinsic electrostatic potential in the closed state of the channel was more positive than in the open state at all values of the ring charge. These electrostatic properties were simulated by theoretical calculations based on a simplified model of the channel.