The development of hair follicles and nail.

The hair follicle and nail unit develop and regenerate through epithelial-mesenchymal interactions. Here, we review some of the key signals and molecular interactions that regulate mammalian hair follicle and nail formation during embryonic development and how these interactions are reutilized to promote their regeneration during adult homeostasis and in response to skin wounding. Finally, we highlight the role of some of these signals in mediating human hair follicle and nail conditions.

Angiogenesis inhibitors for the treatment of epithelial ovarian cancer.

BACKGROUND: Many women, and other females, with epithelial ovarian cancer (EOC) develop resistance to conventional chemotherapy drugs. Drugs that inhibit angiogenesis (development of new blood vessels), essential for tumour growth, control cancer growth by denying blood supply to tumour nodules. OBJECTIVES: To compare the effectiveness and toxicities of angiogenesis inhibitors for treatment of epithelial ovarian cancer (EOC). SEARCH METHODS: We identified randomised controlled trials (RCTs) by searching CENTRAL, MEDLINE and Embase (from 1990 to 30 September 2022). We searched clinical trials registers and contacted investigators of completed and ongoing trials for further information. SELECTION CRITERIA: RCTs comparing angiogenesis inhibitors with standard chemotherapy, other types of anti-cancer treatment, other angiogenesis inhibitors with or without other treatments, or placebo/no treatment in a maintenance setting, in women with EOC.  DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our outcomes were overall survival (OS), progression-free survival (PFS), quality of life (QoL), adverse events (grade 3 and above) and hypertension (grade 2 and above). MAIN RESULTS: We identified 50 studies (14,836 participants) for inclusion (including five studies from the previous version of this review): 13 solely in females with newly-diagnosed EOC and 37 in females with recurrent EOC (nine studies in platinum-sensitive EOC; 19 in platinum-resistant EOC; nine with studies with mixed or unclear platinum sensitivity). The main results are presented below.  Newly-diagnosed EOC Bevacizumab, a monoclonal antibody that binds vascular endothelial growth factor (VEGF), given with chemotherapy and continued as maintenance, likely results in little to no difference in OS compared to chemotherapy alone (hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.88 to 1.07; 2 studies, 2776 participants; moderate-certainty evidence). Evidence is very uncertain for PFS (HR 0.82, 95% CI 0.64 to 1.05; 2 studies, 2746 participants; very low-certainty evidence), although the combination results in a slight reduction in global QoL (mean difference (MD) -6.4, 95% CI -8.86 to -3.94; 1 study, 890 participants; high-certainty evidence). The combination likely increases any adverse event (grade ≥ 3) (risk ratio (RR) 1.16, 95% CI 1.07 to 1.26; 1 study, 1485 participants; moderate-certainty evidence) and may result in a large increase in hypertension (grade ≥ 2) (RR 4.27, 95% CI 3.25 to 5.60; 2 studies, 2707 participants; low-certainty evidence). Tyrosine kinase inhibitors (TKIs) to block VEGF receptors (VEGF-R), given with chemotherapy and continued as maintenance, likely result in little to no difference in OS (HR 0.99, 95% CI 0.84 to 1.17; 2 studies, 1451 participants; moderate-certainty evidence) and likely increase PFS slightly (HR 0.88, 95% CI 0.77 to 1.00; 2 studies, 2466 participants; moderate-certainty evidence). The combination likely reduces QoL slightly (MD -1.86, 95% CI -3.46 to -0.26; 1 study, 1340 participants; moderate-certainty evidence), but it increases any adverse event (grade ≥ 3) slightly (RR 1.31, 95% CI 1.11 to 1.55; 1 study, 188 participants; moderate-certainty evidence) and may result in a large increase in hypertension (grade ≥ 3) (RR 6.49, 95% CI 2.02 to 20.87; 1 study, 1352 participants; low-certainty evidence).  Recurrent EOC (platinum-sensitive) Moderate-certainty evidence from three studies (with 1564 participants) indicates that bevacizumab with chemotherapy, and continued as maintenance, likely results in little to no difference in OS (HR 0.90, 95% CI 0.79 to 1.02), but likely improves PFS (HR 0.56, 95% CI 0.50 to 0.63) compared to chemotherapy alone. The combination may result in little to no difference in QoL (MD 0.8, 95% CI -2.11 to 3.71; 1 study, 486 participants; low-certainty evidence), but it increases the rate of any adverse event (grade ≥ 3) slightly (RR 1.11, 1.07 to 1.16; 3 studies, 1538 participants; high-certainty evidence). Hypertension (grade ≥ 3) was more common in arms with bevacizumab (RR 5.82, 95% CI 3.84 to 8.83; 3 studies, 1538 participants).  TKIs with chemotherapy may result in little to no difference in OS (HR 0.86, 95% CI 0.67 to 1.11; 1 study, 282 participants; low-certainty evidence), likely increase PFS (HR 0.56, 95% CI 0.44 to 0.72; 1 study, 282 participants; moderate-certainty evidence), and may have little to no effect on QoL (MD 6.1, 95% CI -0.96 to 13.16; 1 study, 146 participants; low-certainty evidence). Hypertension (grade ≥ 3) was more common with TKIs (RR 3.32, 95% CI 1.21 to 9.10). Recurrent EOC (platinum-resistant) Bevacizumab with chemotherapy and continued as maintenance increases OS (HR 0.73, 95% CI 0.61 to 0.88; 5 studies, 778 participants; high-certainty evidence) and likely results in a large increase in PFS (HR 0.49, 95% CI 0.42 to 0.58; 5 studies, 778 participants; moderate-certainty evidence). The combination may result in a large increase in hypertension (grade ≥ 2) (RR 3.11, 95% CI 1.83 to 5.27; 2 studies, 436 participants; low-certainty evidence). The rate of bowel fistula/perforation (grade ≥ 2) may be slightly higher with bevacizumab (RR 6.89, 95% CI 0.86 to 55.09; 2 studies, 436 participants). Evidence from eight studies suggest TKIs with chemotherapy likely result in little to no difference in OS (HR 0.85, 95% CI 0.68 to 1.08; 940 participants; moderate-certainty evidence), with low-certainty evidence that it may increase PFS (HR 0.70, 95% CI 0.55 to 0.89; 940 participants), and may result in little to no meaningful difference in QoL (MD ranged from -0.19 at 6 weeks to -3.40 at 4 months). The combination increases any adverse event (grade ≥ 3) slightly (RR 1.23, 95% CI 1.02 to 1.49; 3 studies, 402 participants; high-certainty evidence). The effect on bowel fistula/perforation rates is uncertain (RR 2.74, 95% CI 0.77 to 9.75; 5 studies, 557 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: Bevacizumab likely improves both OS and PFS in platinum-resistant relapsed EOC. In platinum-sensitive relapsed disease, bevacizumab and TKIs probably improve PFS, but may or may not improve OS. The results for TKIs in platinum-resistant relapsed EOC are similar. The effects on OS or PFS in newly-diagnosed EOC are less certain, with a decrease in QoL and increase in adverse events. Overall adverse events and QoL data were more variably reported than were PFS data. There appears to be a role for anti-angiogenesis treatment, but given the additional treatment burden and economic costs of maintenance treatments, benefits and risks of anti-angiogenesis treatments should be carefully considered.

ANTECEDENTES: Muchas mujeres con cáncer de ovario epitelial (COE) desarrollan resistencia a los fármacos de quimioterapia convencional. Los fármacos que inhiben la angiogénesis (desarrollo de vasos sanguíneos de neoformación), esencial para el crecimiento tumoral, controlan el crecimiento del cáncer al impedir el riego sanguíneo a los nódulos tumorales. OBJETIVOS: Comparar la efectividad y los efectos adversos de los inhibidores de la angiogénesis para el tratamiento del cáncer de ovario epitelial (COE). MÉTODOS DE BÚSQUEDA: Se identificaron ensayos controlados aleatorizados (ECA) mediante búsquedas en CENTRAL, MEDLINE y Embase (desde 1990 hasta el 30 de septiembre de 2022). Se realizaron búsquedas en los registros de ensayos clínicos y se estableció contacto con los investigadores de ensayos finalizados y en curso para obtener información adicional. CRITERIOS DE SELECCIÓN: ECA que compararan los inhibidores de la angiogénesis con la quimioterapia estándar, otros tipos de tratamiento anticancerígeno, otros inhibidores de la angiogénesis con o sin otros tratamientos, o placebo/ningún tratamiento en un contexto de mantenimiento, en mujeres con COE. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Se utilizaron los procedimientos metodológicos estándar previstos por Cochrane. Los desenlaces fueron la supervivencia general (SG), la supervivencia sin progresión (SSP), la calidad de vida (CdV), los eventos adversos (de grado 3 o superior) y la hipertensión (de grado 2 o superior). RESULTADOS PRINCIPALES: Se identificaron 50 estudios (14 836 participantes) para inclusión (incluidos cinco estudios de la versión anterior de esta revisión): 13 únicamente en mujeres con COE recién diagnosticado y 37 en mujeres con COE recidivante (nueve estudios en COE sensible al platino; 19 en COE resistente al platino; nueve con estudios con sensibilidad mixta o incierta al platino). A continuación se presentan los principales resultados. COE recién diagnosticado El bevacizumab, un anticuerpo monoclonal que se une al factor de crecimiento endotelial vascular (VEGF), administrado con quimioterapia y continuado como mantenimiento, probablemente da lugar a poca o ninguna diferencia en la SG en comparación con la quimioterapia sola (cociente de riesgos instantáneos [CRI] 0,97; intervalo de confianza [IC] del 95%: 0,88 a 1,07; dos estudios, 2776 participantes; evidencia de certeza moderada). La evidencia es muy incierta para la SSP (CRI 0,82; IC del 95%: 0,64 a 1,05; dos estudios, 2746 participantes; evidencia de certeza muy baja), aunque la combinación produce una ligera reducción de la CdV global (diferencia de medias [DM] ­6,4; IC del 95%: ­8,86 a ­3,94; un estudio, 890 participantes; evidencia de certeza alta). La combinación probablemente aumenta cualquier evento adverso (grado ≥ 3) (razón de riesgos [RR] 1,16; IC del 95%: 1,07 a 1,26; un estudio, 1485 participantes; evidencia de certeza moderada) y podría dar lugar a un gran aumento de la hipertensión (grado ≥ 2) (RR 4,27; IC del 95%: 3,25 a 5,60; dos estudios, 2707 participantes; evidencia de certeza baja). Los inhibidores de la tirosina cinasa (ITK) para bloquear los receptores del VEGF (VEGF­R), administrados con quimioterapia y continuados como mantenimiento, probablemente den lugar a poca o ninguna diferencia en la SG (CRI 0,99; IC del 95%: 0,84 a 1,17; dos estudios, 1451 participantes; evidencia de certeza moderada) y podrían aumentar ligeramente la SSP (CRI 0,88; IC del 95%: 0,77 a 1,00; dos estudios, 2466 participantes; evidencia de certeza moderada). Es probable que la combinación reduzca ligeramente la CdV (DM ­1,86; IC del 95%: ­3,46 a ­0,26; un estudio, 1340 participantes; evidencia de certeza moderada), pero aumente ligeramente cualquier evento adverso (grado ≥ 3) (RR 1,31; IC del 95%: 1,11 a 1,55; un estudio, 188 participantes; evidencia de certeza moderada) y podría dar lugar a un gran aumento de la hipertensión (grado ≥ 3) (RR 6,49; IC del 95%: 2,02 a 20,87; un estudio, 1352 participantes; evidencia de certeza baja). COE recidivante (sensible al platino) La evidencia de certeza moderada de tres estudios (con 1564 participantes) indica que el bevacizumab con quimioterapia, y continuado como mantenimiento, probablemente da lugar a poca o ninguna diferencia en la SG (CRI 0,90; IC del 95%: 0,79 a 1,02), pero posiblemente mejora la SSP (CRI 0,56; IC del 95%: 0,50 a 0,63) en comparación con la quimioterapia sola. La combinación podría dar lugar a poca o ninguna diferencia en la CdV (DM 0,8; IC del 95%: ­2,11 a 3,71; un estudio, 486 participantes; evidencia de certeza baja), pero aumenta ligeramente la tasa de cualquier evento adverso (grado ≥ 3) (RR 1,11; 1,07 a 1,16; tres estudios, 1538 participantes; evidencia de certeza alta). La hipertensión (grado ≥ 3) fue más frecuente en los grupos con bevacizumab (RR 5,82; IC del 95%: 3,84 a 8,83; tres estudios, 1538 participantes). Los ITK con quimioterapia podrían dar lugar a poca o ninguna diferencia en la SG (CRI 0,86; IC del 95%: 0,67 a 1,11; un estudio, 282 participantes; evidencia de certeza baja), probablemente aumenten la SSP (CRI 0,56; IC del 95%: 0,44 a 0,72; un estudio, 282 participantes; evidencia de certeza moderada) y podrían tener poco o ningún efecto en la CdV (DM 6,1; IC del 95%: ­0,96 a 13,16; un estudio, 146 participantes; evidencia de certeza baja). La hipertensión (grado ≥ 3) fue más frecuente con los ITK (RR 3,32; IC del 95%: 1,21 a 9,10). COE recidivante (resistente al platino) El bevacizumab con quimioterapia y continuado como mantenimiento aumenta la SG (CRI 0,73; IC del 95%: 0,61 a 0,88; cinco estudios, 778 participantes; evidencia de certeza alta) y probablemente da lugar a un gran aumento de la SSP (CRI 0,49; IC del 95%: 0,42 a 0,58; cinco estudios, 778 participantes; evidencia de certeza moderada). La combinación podría dar lugar a un gran aumento de la hipertensión (grado ≥ 2) (RR 3,11; IC del 95%: 1,83 a 5,27; dos estudios, 436 participantes; evidencia de certeza baja). La tasa de fístula/perforación intestinal (grado ≥ 2) podría ser ligeramente superior con bevacizumab (RR 6,89; IC del 95%: 0,86 a 55,09; dos estudios, 436 participantes). La evidencia de ocho estudios indica que es probable que los ITK con quimioterapia den lugar a poca o ninguna diferencia en la SG (CRI 0,85; IC del 95%: 0,68 a 1,08; 940 participantes; evidencia de certeza moderada), con evidencia de certeza baja de que podrían aumentar la SSP (CRI 0,70; IC del 95%: 0,55 a 0,89; 940 participantes), y podrían dar lugar a poca o ninguna diferencia significativa en la CdV (la DM varió de ­0,19 a las seis semanas a ­3,40 a los cuatro meses). La combinación aumenta ligeramente cualquier evento adverso (grado ≥ 3) (RR 1,23; IC del 95%: 1,02 a 1,49; tres estudios, 402 participantes; evidencia de certeza alta). El efecto sobre las tasas de fístula/perforación intestinal es incierto (RR 2,74; IC del 95%: 0,77 a 9,75; cinco estudios, 557 participantes; evidencia de certeza muy baja). CONCLUSIONES DE LOS AUTORES: Es probable que el bevacizumab mejore tanto la SG como la SSP en el COE recidivante resistente al platino. En la enfermedad recidivante sensible al platino, el bevacizumab y los ITK probablemente mejoran la SSP, pero podrían o no mejorar la SG. Los resultados para los ITK en el COE recidivante resistente al platino son similares. Existe menos certeza en cuanto a los efectos sobre la SG o la SSP en el COE recién diagnosticado, con una disminución de la CdV y un aumento de los eventos adversos. Los eventos adversos globales y los datos de CdV se informaron de forma más variable que los datos de SSP. El tratamiento antiangiogénico parece tener una función, pero dada la carga adicional de tratamiento y los costes económicos de los tratamientos de mantenimiento, se deben considerar cuidadosamente sus beneficios y riesgos.

Management of Malignant Vulval Melanoma: A Retrospective Case Series and Review of the Literature.

OBJECTIVES: The aims of the study were to evaluate clinicopathologic features, management, and outcomes in vulval melanoma and to review the literature. MATERIALS AND METHODS: Data were collected retrospectively on patients with vulval melanoma from 2001 to 2017 in 5 gynecological oncology cancer centers (Bristol, Taunton, Truro, Plymouth, and Cheltenham). SPSS software was used for univariate and multivariate statistical analysis. Disease-specific median survival was calculated using Kaplan-Meier curves. RESULTS: Forty-four patients with vulval melanoma were included, with a median age of 71 years. Forty-three of 44 had wide local excision with full inguinal lymphadenectomy if abnormal lymph nodes. Seven patients had sentinel lymph nodes. However, 2 patients with negative sentinel lymph nodes had distant recurrences within 16 months.On univariate analysis, presence of ulceration (p = .012), perineural invasion (p = .03), and area of lesion (p = .016) were associated with risk of recurrence but only presence of microsatellites (p = .01) was associated with risk of death.There were 31 deaths (70%): 29 (94%) of 31 from melanoma and 28 (64%) of 44 recurrences: 17 local (10 groin, 7 vulval) and 9 distant. Overall median survival was 32.5 months (95% CI, 17.8-46.5 months) and median recurrence-free survival 12.6 months (95% CI, 7.7-17.4 months). CONCLUSIONS: This retrospective multicenter study highlights the high recurrence rate and poor prognosis of vulval melanoma. Lymph node surgery did not make any difference to recurrence-free survival or overall survival. The presence of microsatellites was associated with a statistically increased risk of death.

Completion surgery after chemoradiotherapy for cervical cancer - is there a role? UK Cancer Centre experience of hysterectomy post chemo-radiotherapy treatment for cervical cancer.

The standard treatment for locally advanced cervical cancer is chemo-radiotherapy. The presence of the residual disease after treatment is directly related to the relapse risk and to poor survival. There is a lack of consensus on the role of a subsequent surgery due to morbidity concerns. Oncological and peri-operative outcomes of completion surgery for cervical cancer were reviewed by retrospective descriptive analysis of the eligible cases between March 2012 and March 2016. Fifteen women were identified. Ten (66.7%) had a residual tumour on their post-treatment MRI. Surgical histology indicated a residual cancer in 26.7%. There were three distant recurrences. Bowel and urinary complications were most commonly reported. Offering surgery to women with a residual cervical tumour found on MRI after chemo-radiation is beneficial, despite clear risks from the dual-modality treatment. A less radical surgery is preferable. An MRI has a reasonable negative predictive value, but this study has highlighted the need to further examine the role of MRI in predicting the residual disease and recurrence. Impact statement What is already known on this subject? The standard treatment for locally advanced cervical cancer is chemo-radiotherapy. The presence of residual disease after treatment is directly related to the relapse risk and poor survival. There is a lack of consensus on the role of a subsequent surgery due to morbidity concerns. The current evidence in the UK is limited, but across the world it appears that surgery can be beneficial for patients with incomplete chemo-radiotherapy, for certain histological subtypes of cervical cancer or for bulky residual disease. What do the results of this study add? The mode of surgery is more debateable, and this study concludes that both the laparoscopic and open surgeries are acceptable, but that radical surgery should be avoided as this contributes to a significant post-operative morbidity. This study explores the role of MRI imaging in predicting the residual disease and cervical cancer recurrence, concluding that a negative MRI post-chemoradiotherapy has a good negative predictive value for squamous cell cervical cancer, but otherwise can be unreliable. What are the implications of these findings for clinical practice and/or further research? An additional explored role of the MRI in predicting a recurrence in a larger cohort will be required, and it is likely that an additional assessment with PET-CT scanning will improve specificity.

Unsatisfactory colposcopy: clinical decision-making in conditions of uncertainty.

BACKGROUND: Unsatisfactory colposcopy, where the cells of interest are not visible in women with a positive cervical screening test, is a common area of clinical uncertainty due to the lack of clear evidence and guidance. Colposcopists' opinions and experiences are likely to have a significant influence on service provision and the development of national policy. The aim of this study was to analyse decision-making when applied to women with unsatisfactory colposcopy. METHODS: A multi-centre qualitative study utilizing a series of focus groups in an English healthcare region. Sampling aimed to ensure heterogeneity of experience and healthcare provider demographics. A topic guide covered a range of clinical and cytological variables and was compiled by the researchers and three expert Colposcopists. Using an iterative approach, thematic analysis was selected as the most appropriate method to identify factors affecting decision-making. RESULTS: Twenty-three Colposcopists from four units participated. The decision to treat was easier in women with high-grade cytology and high risk women with low-grade cytology such as heavy smokers, poor attenders, older women, those who had completed their families and women opting for treatment. Where decision-making was more complex, intuition and a multi-disciplinary approach were used to guide management. Areas of dissonance, which are affected by paucity of evidence and emotive factors, included cytological collection device, clinical setting and length of conservative follow-up and depth of excision in women at high risk of treatment-related morbidity. CONCLUSIONS: Anxiety of missing a cancer deters long-term cytological follow-up, resulting in heterogeneity of care and higher than anticipated excisional treatments in women with low-grade screening and unsatisfactory colposcopy. In areas of clinical uncertainty when decisions are dominated by affect, clinical guidance can reduce the difficulty and anxiety of decision-making.

Gene trajectory inference for single-cell data by optimal transport metrics.

Single-cell RNA sequencing has been widely used to investigate cell state transitions and gene dynamics of biological processes. Current strategies to infer the sequential dynamics of genes in a process typically rely on constructing cell pseudotime through cell trajectory inference. However, the presence of concurrent gene processes in the same group of cells and technical noise can obscure the true progression of the processes studied. To address this challenge, we present GeneTrajectory, an approach that identifies trajectories of genes rather than trajectories of cells. Specifically, optimal transport distances are calculated between gene distributions across the cell-cell graph to extract gene programs and define their gene pseudotemporal order. Here we demonstrate that GeneTrajectory accurately extracts progressive gene dynamics in myeloid lineage maturation. Moreover, we show that GeneTrajectory deconvolves key gene programs underlying mouse skin hair follicle dermal condensate differentiation that could not be resolved by cell trajectory approaches. GeneTrajectory facilitates the discovery of gene programs that control the changes and activities of biological processes.

Co-infection in critically ill patients with COVID-19: an observational cohort study from England.

Introduction. During previous viral pandemics, reported co-infection rates and implicated pathogens have varied. In the 1918 influenza pandemic, a large proportion of severe illness and death was complicated by bacterial co-infection, predominantly Streptococcus pneumoniae and Staphylococcus aureus.Gap statement. A better understanding of the incidence of co-infection in patients with COVID-19 infection and the pathogens involved is necessary for effective antimicrobial stewardship.Aim. To describe the incidence and nature of co-infection in critically ill adults with COVID-19 infection in England.Methodology. A retrospective cohort study of adults with COVID-19 admitted to seven intensive care units (ICUs) in England up to 18 May 2020, was performed. Patients with completed ICU stays were included. The proportion and type of organisms were determined at <48 and >48 h following hospital admission, corresponding to community and hospital-acquired co-infections.Results. Of 254 patients studied (median age 59 years (IQR 49-69); 64.6 % male), 139 clinically significant organisms were identified from 83 (32.7 %) patients. Bacterial co-infections/ co-colonisation were identified within 48 h of admission in 14 (5.5 %) patients; the commonest pathogens were Staphylococcus aureus (four patients) and Streptococcus pneumoniae (two patients). The proportion of pathogens detected increased with duration of ICU stay, consisting largely of Gram-negative bacteria, particularly Klebsiella pneumoniae and Escherichia coli. The co-infection/ co-colonisation rate >48 h after admission was 27/1000 person-days (95 % CI 21.3-34.1). Patients with co-infections/ co-colonisation were more likely to die in ICU (crude OR 1.78,95 % CI 1.03-3.08, P=0.04) compared to those without co-infections/ co-colonisation.Conclusion. We found limited evidence for community-acquired bacterial co-infection in hospitalised adults with COVID-19, but a high rate of Gram-negative infection acquired during ICU stay.

Identification of amino acids involved in histamine potentiation of GABA A receptors.

Histamine is a neurotransmitter involved in a number of physiological and neuronal functions. In mammals, such as humans, and rodents, the histaminergic neurons found in the tuberomamillary nucleus project widely throughout the central nervous system. Histamine acts as positive modulator of GABAA receptors (GABAARs) and, in high concentrations (10 mM), as negative modulator of the strychnine-sensitive glycine receptor. However, the exact molecular mechanisms by which histamine acts on GABAARs are unknown. In our study, we aimed to identify amino acids potentially involved in the modulatory effect of histamine on GABAARs. We expressed GABAARs with 12 different point mutations in Xenopus laevis oocytes and characterized the effect of histamine on GABA-induced currents using the two-electrode voltage clamp technique. Our data demonstrate that the amino acid residues ß2(N265) and ß2(M286), which are important for modulation by propofol, are not involved in the action of histamine. However, we found that histamine modulation is dependent on the amino acid residues α1(R120), ß2(Y157), ß2(D163), ß3(V175), and ß3(Q185). We showed that the amino acid residues ß2(Y157) and ß3(Q185) mediate the positive modulatory effect of histamine on GABA-induced currents, whereas α1(R120) and ß2(D163) form a potential histamine interaction site in GABAARs.