Disruption of the HIF-1 pathway in individuals with Ollier disease and Maffucci syndrome.

Ollier disease (OD) and Maffucci Syndrome (MS) are rare disorders characterized by multiple enchondromas, commonly causing bone deformities, limb length discrepancies, and pathological fractures. MS is distinguished from OD by the development of vascular anomalies. Both disorders are cancer predisposition syndromes with malignancies developing in ~50% of the individuals with OD or MS. Somatic gain-of-function variants in IDH1 and IDH2 have been described in the enchondromas, vascular anomalies and chondrosarcomas of approximately 80% of the individuals with OD and MS. To date, however, no investigation of germline causative variants for these diseases has been comprehensively performed. To search for germline causative variants, we performed whole exome sequencing or whole genome sequencing of blood or saliva DNA in 94 unrelated probands (68 trios). We found that 7 had rare germline missense variants in HIF1A, 6 had rare germline missense variants in VHL, and 3 had IDH1 variants including 2 with mosaic IDH1-p.Arg132His variant. A burden analysis using 94 probands assigned as cases and 2,054 unrelated individuals presenting no OD- or MS-related features as controls, found that variants in HIF1A, VHL, and IDH1 were all significantly enriched in cases compared to controls. To further investigate the role of HIF-1 pathway in the pathogenesis of OD and MS, we performed RNA sequencing of fibroblasts from 4 probands with OD or MS at normoxia and at hypoxia. When cultured in hypoxic conditions, both proband and control cells showed altered expression of a subset of HIF-1 regulated genes. However, the set of differentially expressed genes in proband fibroblasts included a significantly reduced number of HIF-1 regulated genes compared to controls. Our findings suggest that germline or early post-zygotic variants identified in HIF1A, VHL, and IDH1 in probands with OD and MS underlie the development of the phenotypic abnormalities in a subset of individuals with OD and MS, but extensive functional studies are needed to further confirm it.

Precision Dermatology: A Review of Molecular Biomarkers and Personalized Therapies.

The evolution of personalized medicine in dermatology signifies a transformative shift towards individualized treatments, driven by the integration of biomarkers. These molecular indicators serve beyond diagnostics, offering insights into disease staging, prognosis, and therapeutic monitoring. Specific criteria guide biomarker selection, ensuring attributes like specificity, sensitivity, cost feasibility, stability, rapid detection, and reproducibility. This literature review, based on data from PubMed, SCOPUS, and Web of Science, explores biomarkers in Hidradenitis Suppurativa (HS), Psoriasis, Atopic Dermatitis (AD), Alopecia Areata (AA), Vitiligo, and Chronic Spontaneous Urticaria (CSU). In HS, TNF-α, IL-1ß, and MMPs serve as biomarkers, influencing targeted therapies like adalimumab and anakinra. Psoriasis involves biomarkers such as TNF-α, IL-23, and HLA genes, shaping treatments like IL23 and IL17 inhibitors. AD biomarkers include ECP, IL-4, IL-13, guiding therapies like dupilumab and tralokinumab. For AA, lipocalin-2, cytokines, and genetic polymorphisms inform JAK inhibitors' use. Vitiligo biomarkers range from cytokines to genetic markers like TYR, TYRP1, guiding treatments like JAK inhibitors. CSU biomarkers encompass IgE, cytokines, and autologous serum tests, influencing therapies like omalizumab and cyclosporine. Comparing conditions, common proinflammatory markers reveal limited specificity. While some biomarkers aid diagnosis and standard treatments, others hold more scientific than clinical value. Precision medicine, driven by biomarkers, has shown success in skin malignancies. Future directions involve AI-powered algorithms, nanotechnology, and multi-omics integration for personalized dermatological care.

Acne and the cutaneous microbiome: A systematic review of mechanisms and implications for treatments.

Acne vulgaris is a pervasive skin disease characterized by inflammation of sebaceous units surrounding hair follicles. It results from the complex interplay between skin physiology and the intricate cutaneous microbiome. Current acne treatments, while effective, have major limitations, prompting a shift towards microbiome-based therapeutic approaches. This study aims to determine the relationship between acne and the cutaneous microbiome, assess the effects of current treatments on the cutaneous microbiome and explore the implications for developing new therapies. A systematic review was performed using PubMed and SCOPUS databases within the last 10 years. Methodological quality was assessed independently by two authors. The search retrieved 1830 records, of which 26 articles met the inclusion criteria. Meta-analysis of alpha diversity change was assessed using fixed and randomized effect models per therapeutic group. Eight studies pertain to the role of the cutaneous microbiome in acne, identifying C. acnes, S. aureus and S. epidermidis as key contributors through overproliferation, commensalism or dysbiosis. Eleven studies discuss current acne treatments, including doxycycline (1), topical benzoyl peroxide (BPO) (4), isotretinoin (2), sulfacetamide-sulfur (SSA) (2) and aminolevulinic acid-photodynamic therapy (ALA-PDT) (2), identified as modulating the cutaneous microbiome as a mechanism of efficacy in acne treatment. Seven studies discuss new treatments with topical probiotics, plant derivatives and protein derivatives, which contribute to acne clearance via modulation of dysbiosis, inflammatory markers and diversity indexes. A meta-analysis of the effects of existing therapeutics on the cutaneous microbiome identified benzoyl peroxide as the only treatment to facilitate significant change in diversity. Despite the heterogeneity of study types and microbiome classifications limiting the analysis, this review underscores the complexity of microbial involvement in acne pathogenesis. It delineates the effects of acne therapeutics on microbial diversity, abundance and composition, emphasizing the necessity for personalized approaches in acne management based on microbiome modulation.

Chest wall bruising from 5-point car seat harness as a mimicker of child abuse.

Bruising rarely presents in infants younger than 9 months who are not ambulatory and is more prevalent among children beginning to walk, or "cruisers." We present the case of a healthy 3-month-old infant with asymptomatic, symmetric, bilateral, large bruises on the bony chest sparing the mid-chest/sternum with a negative non-accidental trauma work-up. The noted pattern of bruises matched the bilateral shoulder straps of a 5-point harness of the car seat belt designed for infants. Awareness of this unique pattern of bruises will help elicit a better-informed history to guide care in an appropriate setting.

Management of tinea capitis in infants and children in the United States: A national survey of pediatric dermatologists.

This study aimed to evaluate the current management of tinea capitis in the United States, specifically focusing on patients aged 0-2 months, 2 months to 2 years, and 2 years to 18 years. An online survey, distributed through the Pediatric Dermatology Research Alliance and the Society of Pediatric Dermatology, revealed the following preferences: fluconazole for those under 2 months, griseofulvin for those aged 2 months to 2 years, and terbinafine for those aged 2 years and older. There exists inter-provider variation in tinea capitis treatment regimens within the pediatric dermatology community.

Genetic testing in the evaluation of individuals with clinical diagnosis of atypical Sturge-Weber syndrome.

Sturge-Weber Syndrome (SWS) is a rare vascular malformation disorder characterized by abnormal blood vessels in the brain, skin, and eye. SWS is most commonly caused by a somatic mosaic GNAQ-p.Arg183Gln variant. In this series, 12 patients presented for clinical evaluation of SWS but were noted to have atypical features, and therefore germline and/or somatic genetic testing was performed. Atypical features included extensive capillary malformation on the body as well as the face, frontal bossing, macrocephaly, telangiectasia, overgrowth of extremities, absence of neurologic signs and symptoms, and family history of vascular malformations. Five patients had a somatic GNAQ or GNA11 pathogenic variant, one patient had a somatic mosaic likely-pathogenic variant in PIK3CA, and another one had a somatic mosaic deletion that disrupted PTPRD. The other five patients had germline variants in RASA1, EPHB4, or KIT. Our findings suggest that patients presenting for SWS evaluation who have atypical clinical characteristics may have pathogenic germline or somatic variants in genes other than GNAQ or GNA11. Broad germline and somatic genetic testing in these patients with atypical findings may have implications for medical care, prognosis, and trial eligibility.

Mucocutaneous manifestations of congenital syphilis in the neonate: A review of a surging disease.

Syphilis is an infection caused by Treponema pallidum. It is most commonly acquired through sexual transmission, although it can also be transmitted vertically across the placenta, resulting in congenital syphilis. Even with improved public health measures, testing, and treatment capabilities, primary, secondary, and congenital syphilis have all surged since 2012. Given this marked increase in both incidence and prevalence, here we present a comprehensive review of the clinical presentation, treatment, and management of congenital syphilis, with particular consideration given to the mucocutaneous manifestations of the disease in neonates.

A Retrospective Study of Tinea Capitis Management in General Pediatric Clinics and Pediatric Emergency Departments at 2 US Centers.

We examine management practices of tinea capitis at 2 US academic centers. The majority of providers treated tinea capitis with the oral antifungal agent griseofulvin and did not obtain a fungal culture. We recommend newer antifungal treatments such as terbinafine and fluconazole and obtaining a fungal culture for effective treatment.

Tinea capitis: advances and a needed paradigm shift.

PURPOSE OF REVIEW: Tinea capitis, a superficial infection of the scalp, is the most common pediatric dermatophyte fungal infection worldwide and is particularly common in the USA in low-income, low-resource settings. There are still gaps in knowledge and heterogeneities in practice in terms of diagnostic and management strategies. Furthermore, there are no clinical guidelines for management and treatment of tinea capitis in the USA. This review aims to summarize recent advances, recommend optimal management for the practicing pediatrician, and identify areas for future research for tinea capitis. RECENT FINDINGS: Trichophyton tonsurans infections are best treated with terbinafine and Microsporum canis infections are best treated with griseofulvin. Trichophyton tonsurans is the predominant cause of tinea capitis in the USA, although the main gold standard of treatment in the USA is griseofulvin. Dermatophyte antifungal resistance is an active area of investigation but seems to not be of current concern for tinea capitis in the USA. SUMMARY: We recommend all clinical providers ascertain the causative organism in fungal infection, either through fungal culture or newer methods which may become more readily available and cost-effective in the future, such as polymerase chain reaction assay. We also recommend terbinafine as first-line treatment of tinea capitis, with adjustment as necessary after species identification.

Psoriasis and mortality in the United States: Data from the National Health and Nutrition Examination Survey.

BACKGROUND: Psoriasis is a multifactorial disease that has been associated with multiple systemic disorders. Despite its role in mediating cardiovascular, metabolic, and pulmonary disorders, few studies have examined the independent mortality risk associated with psoriasis. OBJECTIVE: To determine the independent relationship between psoriasis and all-cause mortality in a nationally representative sample of the US population. METHODS: Retrospective population-based cohort study of adults and adolescents older than 10 years (N = 13 031) who participated in National Health and Nutrition Examination Surveys (2003-2006 and 2009-2010). Psoriasis status was determined from a self-reported medical history questionnaire. Mortality data are linked from national databases. RESULTS: Psoriasis was present in 2.7% of the study population. Over an average median follow-up of 52.3 months, psoriasis was significantly associated with increased mortality risk (HR, 1.99; 95% CI, 1.01-3.93; P = .047) with adjustment for demographics, smoking, and comorbidities including cardiovascular disease, diabetes, chronic obstructive pulmonary disease, cancer, chronic kidney disease, and stroke. These comorbidities mediated 15.5%, 5.9%, 8.7%, 11.7%, 4.2%, and 4.7% of the association between psoriasis and mortality, respectively. CONCLUSION: Psoriasis is independently associated with an increased risk of mortality. This relationship is partially mediated by an increased prevalence of the cardiovascular, infectious, and neoplastic disorders seen among patients with psoriasis.

Anesthetic techniques used for pulsed dye laser (PDL) in the treatment of port-wine birthmarks: An exploratory assessment of current attitudes and practice patterns among pediatric dermatologists in the United States.

BACKGROUND/OBJECTIVES: Pulsed dye laser (PDL) is the gold standard for treating port-wine birthmarks (PWBs), but no consensus exists regarding anesthetic techniques when performing PDL for PWB. Given potential adverse neurocognitive effects from general anesthesia (GA) exposure in early childhood, we sought to establish current attitudes and practice patterns regarding anesthesia when treating PWB with PDL. METHODS: An electronic REDCap survey was distributed to members of the Pediatric Dermatology Research Alliance (PeDRA) and the Society for Pediatric Dermatology (SPD) via email. Aggregate, anonymized results were reported. RESULTS: Among 47 respondents, the majority (83%) identified as board-certified pediatric dermatologists. When treating children <4 years old, 70% endorsed some use of topical anesthesia. Although 87% reported concerns about long-term side effects on development and school performance affecting their pursuit of GA, 61% reported use of GA for PDL in children <4 years old. All 4 (100%) respondents whose PDL was located in the operating room (OR) setting reported use of GA, compared to 6 of 17 (35%) respondents whose PDL machine was not located in the OR. Providers were more likely to use GA in patients between 1 and 4 years old (70%) compared to those <1 year old (2%). CONCLUSIONS: Diverse practice patterns reiterate the need for a standardized anesthetic approach for PDL in young children and continued research on other factors (ie, location/accessibility of PDL, lesion size) impacting anesthesia choices. Given potential neurodevelopmental risks associated with GA, specific guidance to effectively minimize its use in favor of topical anesthetics should be provided.

Heterogeneous cutaneous findings associated with intrauterine HSV infection: A case series and literature review.

BACKGROUND/OBJECTIVE: Herpes simplex virus (HSV) infection acquired in utero may present with non-vesicular dermatologic findings in affected newborns, which may pose a diagnostic dilemma. We aimed to describe and assess the range of non-vesiculobullous skin lesions that neonates with intrauterine HSV infection may manifest at birth. METHODS: We collected a multicenter case series and conducted a literature review of neonates with intrauterine HSV infection presenting with non-vesiculobullous cutaneous lesions. RESULTS: Twenty-two cases were reviewed, including six managed clinically by members of our team and 16 identified in the literature. Four (18%) were associated with twin pregnancies, and thirteen (59%) cases occurred in premature infants. Only four (18%) mothers had a documented history of HSV infection. Twelve (55%) cases resulted in poor outcomes, including long-term neurologic sequelae or death. Cutaneous manifestations included erosions, ulcerations, crusted papules or plaques, calcinosis cutis, excoriations, macules (erythematous, hypopigmented, or hyperpigmented), cutaneous atrophy, contractures, and bruising. About one-third of neonates developed new-onset vesicular lesions within a week of birth; in each of these cases, accurate diagnosis and therapy were delayed until appearance of vesicles. CONCLUSIONS: The range of dermatologic findings associated with intrauterine HSV is extremely broad, and the various morphologies present at birth likely reflect different stages of the ongoing evolution of an HSV infection that began in utero. Clinicians should have a low threshold for HSV testing in premature neonates born with atypical cutaneous lesions, since early detection and treatment of HSV may reduce morbidity and mortality from systemic complications.

Natural history of Ollier disease and Maffucci syndrome: Patient survey and review of clinical literature.

Ollier disease (OD) and Maffucci syndrome (MS) are characterized by multiple enchondromas. Patients with MS also have benign vascular overgrowths that become malignant in 8.5% of cases. OD is characterized by multiple enchondromas, typically unilateral in distribution with a predilection for the appendicular skeleton. MS is characterized by multiple enchondromas bilaterally distributed in most of the cases. Both disorders feature multiple swellings on the extremity, deformity around the joints, limitations in joint mobility, scoliosis, bone shortening, leg-length discrepancy, gait disturbances, pain, loss of function, and pathological fractures. About 50% of patients with OD or MS develop a malignancy, such as chondrosarcoma, glioma, and ovarian juvenile granulosa cell tumor. To better understand the natural history of OD and MS, we reviewed 287 papers describing patients with OD and MS. We also created a survey that was distributed directly to 162 patients through Facebook. Here, we compare the review of the cases described in the literature to the survey's responses. The review of the literature showed that: the patients with OD are diagnosed at a younger age; the prevalence of chondrosarcomas among patients with OD or MS was ~30%; in four patients, vascular anomalies were identified in internal organs only; and, the prevalence of cancer among patients with OD or MS was ~50%. With these data, health care providers will better understand the natural history, severity, and prognosis of these diseases and the prevalence of malignancies in these patients. Here, we recommend new guidelines for the care of patients with OD and MS.

Consensus on Neonatal Through Preadolescent Acne.

BACKGROUND: Acne vulgaris is the most common dermatological disorder. Pediatric acne may be a manifestation of the underlying pathology and can occur in the first weeks, months, or years of life. Acne in childhood can be categorized by age and pubertal status. OBJECTIVE: An expert panel of pediatric dermatologists and dermatologists developed a consensus paper on neonatal through preadolescent acne, providing information on differential diagnosis, prevention, treatment, and maintenance of the condition. METHODS: A systematic literature review explored present clinical guidelines, treatment options, and therapeutic approaches addressing neonatal through preadolescent acne. The information from the literature searches was used together with the panel’s expert opinion and experience to adopt consensus statements following established standards. RESULTS: The panel members reached unanimous consensus on seven statements addressing the various age categories of pediatric acne: neonatal acne: birth to ≤ 8 weeks; infantile acne: 8 weeks to ≤1 year; mid-childhood acne: 1 year to <7 years; preadolescent acne: ≥7 to 12 years; adolescent acne: ≥12 to 19 years or after menarche for girls. Health care providers treating children need to pay more attention to pediatric acne and should monitor the risk of endocrine-associated abnormalities, especially in mild-childhood acne. When prescribing acne treatment, newer medications approved for use in children older than nine years of age may offer a suitable option. CONCLUSION: The differential diagnosis of pediatric acne, as well as its treatment and maintenance, requires much more attention and consideration from health care providers treating children. J Drugs Dermatol. 2020;19(6):592-600. doi:10.36849/JDD.2020.5065.

Mycosis fungoides in pediatric patients: Clinical features, diagnostic challenges, and advances in therapeutic management.

Mycosis fungoides (MF) is the most common primary cutaneous lymphoma in pediatric patients. Given the indolent nature of MF, symptoms often present in childhood but may not be diagnosed as MF until adulthood. Delayed diagnosis is associated with poor long-term prognosis. Thus, increased clinician recognition and accurate diagnosis of early-stage MF in pediatric patients is critically important. In this review, we summarize the clinical features of the most common pediatric MF subtypes and highlight important differences between pediatric and adult MF. Moreover, we reviewed all pediatric MF case series published between 2008 and 2018 to analyze treatment modalities and identify emerging therapies. As treatment of pediatric MF is complex, selection of therapy varies significantly depending upon the specific clinical characteristics, disease severity, and patients' preferences.

Antibiotic sensitivity and clinical outcomes in staphylococcal scalded skin syndrome.

Staphylococcal scalded skin syndrome causes widespread skin denudation primarily in infants < 1 year old. Selection of empiric therapy is complicated by rising rates of antibiotic resistance in community-acquired staphylococcal infections. Consistent with a previous study, this retrospective review found that SSSS-associated isolates were more likely to be clindamycin-resistant and less likely to be methicillin-resistant compared to overall staphylococcal infections. We favor cephalosporins and penicillinase-resistant penicillins (eg, oxacillin) for empiric management of SSSS, with consideration of adding MRSA coverage in communities with high MRSA prevalence or failure to improve following several days of treatment.

Disseminated bullous impetigo and atopic dermatitis: Case series and literature review.

BACKGROUND: Bullous impetigo (BI) is a common skin infection of early childhood, resulting from desmoglein-1 cleavage by Staphylococcus aureus exfoliative toxins. Due to compromised barrier function and immune dysregulation, children with atopic dermatitis (AD) are at increased risk of cutaneous infections, yet no literature has been published on disseminated bullous impetigo (DBI) in children with atopic dermatitis (AD). We sought to explore the atopic phenotypes, antibiotic sensitivities, and treatment courses of children diagnosed with disseminated bullous impetigo at our institution. METHODS: We conducted a retrospective case series of 12 children diagnosed with disseminated bullous impetigo at Johns Hopkins from 12/2016 to 5/2017. RESULTS: Eleven children (92%) had severe AD. All children were initially misdiagnosed; the majority (67%) were misdiagnosed with AD flares, and other misdiagnoses included scabies, eczema herpeticum, ecthyma, varicella, and eczema coxsackium. All cultures were positive for methicillin-sensitive Staphylococcus aureus (MSSA). Three children (25%) had clindamycin-resistant strains of MSSA, and only one child was positive for both MSSA and methicillin-resistant S aureus. All children were treated with systemic antibiotics and experienced resolution of symptoms within 24-48 hours. CONCLUSIONS: This case series is the first of its kind exploring children with DBI with the atopic diathesis. Our results indicate that DBI is often misdiagnosed, and increased training is likely needed for pediatricians, emergency room physicians, and dermatologists. Earlier diagnosis of bullous impetigo may prevent dissemination and spare a patient treatment with systemic antibiotics. Given the high rate of clindamycin resistance observed in this series, we recommend cephalosporins to treat uncomplicated cases of DBI.

Retrospective case series of increased oral propranolol dosage for infantile hemangiomas.

BACKGROUND: Infantile hemangiomas (IH) are the most common benign tumor of infancy. Although oral propranolol is currently first-line therapy, optimal dosing for treatment of IH remains debated. We sought to identify hemangioma characteristics associated with poor response to standard dosing (2 mg/kg/d) and to assess the therapeutic benefit of higher dosing. METHODS: Retrospective chart review was conducted of 559 patients with IH seen at Johns Hopkins between 2008 and 2018, of whom 245 (44%) were treated with propranolol. Baseline characteristics were compared between patients who received increased propranolol dosing (≥2.5 mg/kg/d) and those who remained on standard dose (2 mg/kg/d). Changes in the Hemangioma Activity Score (HAS) during the increased dosage period were scored by two trained, blinded pediatric dermatologists. RESULTS: Of 245 patients, 204 (83%) received standard 2 mg/kg/d propranolol dosing while 41 (17%) received a higher dose of ≥2.5 mg/kg/d. The most common location of IH in both groups was the face. In the increased dosage group, 85.4% of IH were of mixed or deep morphology with a mean greatest diameter of 4.6 cm. IH requiring increased dosing received longer courses of propranolol (mean of 389 vs. 282 days, P < .001) and underwent higher rates of excision by plastic surgery (26.8% vs. 5.9%, P < .001). Mean change in HAS over the period with dosage ≥2.5 mg/kg/d was minimal (-0.70; P < .001). CONCLUSIONS: Most recalcitrant IH were located on the face, larger in diameter, and of mixed or deep morphology. Patients had little improvement in HAS score with increased propranolol dosing implemented late in the treatment course with over one-fourth ultimately receiving surgical excision.

Operative findings and surgical outcomes in patients undergoing Chiari 1 malformation decompression: relationship to the extent of tonsillar ectopia.

BACKGROUND: The diagnosis of Chiari 1 malformation is based on the extent of tonsillar ectopia. OBJECTIVE: To examine the relationship between the extent of tonsillar ectopia and the intra-operative findings and clinical outcome following Chiari decompression surgery. METHODS: Patients were divided into four groups depending on the position of the cerebellar tonsil (T): group 1: 0 < T < 3; group 2: 3 ≤ T ≤ 5; group 3: 5 < T ≤ 10; and group 4: T > 10. Intra-operative observations were recorded with regard to compression of the brain stem by posterior inferior cerebellar artery (pica), neuroma formation along the first cervical (C1), and accessory spinal nerves (XI), and pallor of the cerebellar tonsils. Brain stem auditory evoked potentials, (BAEP), were monitored in each case. One hundred sixty-eight patients accrued between 2009 and 2013 agreed to participate in an outcome study to determine the effectiveness of foramen magnum decompression. Findings across the four groups were compared using one-way ANOVA. Observed differences were further subjected to paired analysis. Intra-group comparisons were made using the paired t test. A P value less than 0.05 was considered statistically significant. RESULTS: There were 98 patients in group 1, 147 patients in group 2, 180 patients in group 3, and 63 patients in group 4. The mean extent of tonsillar ectopia was 0.4, 4.0, 7.1, and 14.3 mm in the four groups respectively. The prevalence of tonsillar pallor was greatest in group 4. Otherwise, there was no difference observed in the operative findings. A reduction of > 0.1 msec in the wave III-wave V latency of the BAEP was noted in all four groups with equal frequency. One hundred ten patients complied with at least 6 months follow-up. There was no difference in the prevalence of symptoms between the four groups at the time of initial evaluation and at 6 weeks and 6 months following surgery. There was a statistically significant reduction in the intensity of individual symptoms 6 months following surgery regardless of the extent of tonsil ectopia. CONCLUSION: Other than the finding of tonsillar pallor, there was no relationship between the extent of tonsillar ectopia and the intraoperative anatomical and physiological observations, nor was there any relationship to the likelihood of symptomatic improvement following surgery. These observations call into question the focus on the extent of tonsillar of ectopia in assessing the patient who presents with symptoms of the Chiari malformation.

The neural basis of motion sickness.

Although motion of the head and body has been suspected or known as the provocative cause for the production of motion sickness for centuries, it is only within the last 20 yr that the source of the signal generating motion sickness and its neural basis has been firmly established. Here, we briefly review the source of the conflicts that cause the body to generate the autonomic signs and symptoms that constitute motion sickness and provide a summary of the experimental data that have led to an understanding of how motion sickness is generated and can be controlled. Activity and structures that produce motion sickness include vestibular input through the semicircular canals, the otolith organs, and the velocity storage integrator in the vestibular nuclei. Velocity storage is produced through activity of vestibular-only (VO) neurons under control of neural structures in the nodulus of the vestibulo-cerebellum. Separate groups of nodular neurons sense orientation to gravity, roll/tilt, and translation, which provide strong inhibitory control of the VO neurons. Additionally, there are acetylcholinergic projections from the nodulus to the stomach, which along with other serotonergic inputs from the vestibular nuclei, could induce nausea and vomiting. Major inhibition is produced by the GABAB receptors, which modulate and suppress activity in the velocity storage integrator. Ingestion of the GABAB agonist baclofen causes suppression of motion sickness. Hopefully, a better understanding of the source of sensory conflict will lead to better ways to avoid and treat the autonomic signs and symptoms that constitute the syndrome.