Ubiquitylation of voltage-gated sodium channels.

Ion channel proteins are regulated by different types of posttranslational modifications. The focus of this review is the regulation of voltage-gated sodium channels (Navs) upon their ubiquitylation. The amiloride-sensitive epithelial sodium channel (ENaC) was the first ion channel shown to be regulated upon ubiquitylation. This modification results from the binding of ubiquitin ligase from the Nedd4 family to a protein-protein interaction domain, known as the PY motif, in the ENaC subunits. Many of the Navs have similar PY motifs, which have been demonstrated to be targets of Nedd4-dependent ubiquitylation, tagging them for internalization from the cell surface. The role of Nedd4-dependent regulation of the Nav membrane density in physiology and disease remains poorly understood. Two recent studies have provided evidence that Nedd4-2 is downregulated in dorsal root ganglion (DRG) neurons in both rat and mouse models of nerve injury-induced neuropathic pain. Using two different mouse models, one with a specific knockout of Nedd4-2 in sensory neurons and another where Nedd4-2 was overexpressed with the use of viral vectors, it was demonstrated that the neuropathy-linked neuronal hyperexcitability was the result of Nav1.7 and Nav1.8 overexpression due to Nedd4-2 downregulation. These studies provided the first in vivo evidence of the role of Nedd4-2-dependent regulation of Nav channels in a disease state. This ubiquitylation pathway may be involved in the development of symptoms and diseases linked to Nav-dependent hyperexcitability, such as pain, cardiac arrhythmias, epilepsy, migraine, and myotonias.

Acute muscular sarcocystosis: an international investigation among ill travelers returning from tioman island, malaysia, 2011-2012.

BACKGROUND Through 2 international traveler-focused surveillance networks (GeoSentinel and TropNet), we identified and investigated a large outbreak of acute muscular sarcocystosis (AMS), a rarely reported zoonosis caused by a protozoan parasite of the genus Sarcocystis, associated with travel to Tioman Island, Malaysia, during 2011-2012. METHODS Clinicians reporting patients with suspected AMS to GeoSentinel submitted demographic, clinical, itinerary, and exposure data. We defined a probable case as travel to Tioman Island after 1 March 2011, eosinophilia (>5%), clinical or laboratory-supported myositis, and negative trichinellosis serology. Case confirmation required histologic observation of sarcocysts or isolation of Sarcocystis species DNA from muscle biopsy. RESULTS Sixty-eight patients met the case definition (62 probable and 6 confirmed). All but 2 resided in Europe; all were tourists and traveled mostly during the summer months. The most frequent symptoms reported were myalgia (100%), fatigue (91%), fever (82%), headache (59%), and arthralgia (29%); onset clustered during 2 distinct periods: "early" during the second and "late" during the sixth week after departure from the island. Blood eosinophilia and elevated serum creatinine phosphokinase (CPK) levels were observed beginning during the fifth week after departure. Sarcocystis nesbitti DNA was recovered from 1 muscle biopsy. CONCLUSIONS Clinicians evaluating travelers returning ill from Malaysia with myalgia, with or without fever, should consider AMS, noting the apparent biphasic aspect of the disease, the later onset of elevated CPK and eosinophilia, and the possibility for relapses. The exact source of infection among travelers to Tioman Island remains unclear but needs to be determined to prevent future illnesses.

Oral hygiene products, medications and drugs - hidden aetiological factors for dental erosion.

Acidic or EDTA-containing oral hygiene products and acidic medicines have the potential to soften dental hard tissues. The low pH of oral care products increases the chemical stability of some fluoride compounds and favours the incorporation of fluoride ions in the lattice of hydroxyapatite and the precipitation of calcium fluoride on the tooth surface. This layer has some protective effect against an erosive attack. However, when the pH is too low or when no fluoride is present these protecting effects are replaced by direct softening of the tooth surface. Oral dryness can occur as a consequence of medication such as tranquilizers, antihistamines, antiemetics and antiparkinsonian medicaments or of salivary gland dysfunction. Above all, patients should be aware of the potential demineralization effects of oral hygiene products with low pH. Acetyl salicylic acid taken regularly in the form of multiple chewable tablets or in the form of headache powder, as well as chewing hydrochloric acids tablets for the treatment of stomach disorders, can cause erosion. There is most probably no direct association between asthmatic drugs and erosion on the population level. Consumers and health professionals should be aware of the potential of tooth damage not only by oral hygiene products and salivary substitutes but also by chewable and effervescent tablets. Several paediatric medications show a direct erosive potential in vitro. Clinical proof of the occurrence of erosion after use of these medicaments is still lacking. However, regular and prolonged use of these medicaments might bear the risk of causing erosion. Additionally, it can be assumed that patients suffering from xerostomia should be aware of the potential effects of oral hygiene products with low pH and high titratable acidity.

Radiological findings of sexual intercourse related emergency department admissions: a first overview

OBJECTIVES Sexuality is an essential aspect of human function, well-being and quality of life. Many people have sex without complications. However, there are some people who need to seek emergency medical help for related health problems. The aim of this study was to present a first overview of patients who received a radiological examination related to sexual intercourse based emergency department admission. METHODS Our centralized electronic patient record database was reviewed for patients who had been admitted to our emergency department with an emergency after sexual intercourse between 2000 and 2011. The database was scanned for the standardized key words 'sexual intercourse' or 'coitus' retrospectively. For all patients identified in the electronic patient record database the radiological examinations were searched for manually in our Radiology Information System, and reviewed by three independent radiologists. RESULTS One hundred and twenty nine out of 445 (29,0%) patients received a radiological examination after immediate emergency department admission related to sexual intercourse. Fifty two out of 129 (40.3%) patients had positive radiological findings while 77 (59.7%) did not. Eighty point seven percent (n = 42) of the radiological findings were a sexual intercourse-associated pathology and 19.2% (n = 10) were considered to be incidental findings. Age and male sex positively correlated with radiological imaging workup (p<0.001, respectively p<0.037). The most common sexual intercourse-associated pathology was headache attributed to cerebrovascular insult (n = 21, 40.3%) followed by epididymitis (n = 7, 16.6%) and obstructive uropathy (n = 5, 11.6%). Of the patients with headache attributed to non-traumatic intracranial hemorrhage, subarachnoid hemorrhage (n = 14, 66.6%) was the most common, followed by intracerebral bleeding (n = 4, 19.0%) and one subdural hemorrhage. CONCLUSIONS Pathological findings are manifold. Cerebral imaging is the most common type of radiological imaging performed. Further prospective and standardized studies should be performed to better evaluate the significance of radiological imaging in this patient collective with the aim to gain better knowledge on what patients profit from what type of radiological imaging when presenting with a sexual intercourse related emergency. ADVANCES IN KNOWLEDGE The present study provides a first overview on radiological findings of sexual intercourse related emergency department admissions.

Percutaneous closure of patent foramen ovale: safe and effective but underutilized.

With three recently published randomized trials on patent foramen ovale (PFO) closure, the concept of PFO closure to reduce recurrent strokes has been proven; however, PFO closure is currently only considered for secondary prevention. Given the potential devastating consequences of a PFO-related event, we advocate screening for and closure of a PFO for primary prevention in high-risk populations. Such populations include patients who are suffering from a disease that is associated with PFO (e.g., migraine) or patients with high-risk hobbies/professions (e.g., weight-lifters, frequent-flyers, and deep sea divers). Looking at young people with a remaining average life expectancy of 50 years, we have to close 2.4 PFOs to prevent one stroke. This should support a more proactive attitude toward PFO screening and closure.

Low-dosage clomiphene reduces premature ovulation rates and increases transfer rates in natural-cycle IVF

Natural-cycle IVF has been suggested as an alternative IVF treatment. However, efficacy is limited due to high premature ovulation rates, resulting in low transfer rates. This study investigates whether low dosages of clomiphene citrate reduce premature ovulation rate and increase transfer rate. Of 112 women included (aged 35.2 ± 4.5 years) 108 underwent one natural-cycle IVF cycle with human chorionic gonadotrophin (HCG) to induce ovulation and 103 underwent one natural-cycle IVF cycle with 25 mg/day clomiphene from about day 7 until HCG administration. Before retrieval, 1.2 monitoring consultations per cycle were required. Clomiphene reduced premature ovulation rate, from 27.8% without to 6.8% with clomiphene (P < 0.001) and increased transfer rate from 39.8% to 54.4% (P = 0.039). Clinical pregnancy rates without and with clomiphene were 27.9% versus 25.0% per transfer and 11.1% versus 13.6% per initiated cycle. Use of clomiphene resulted in mild hot flushes and headache in 5% of patients. Nausea and persisting ovarian cyst formation was not observed. In conclusion, clomiphene citrate led to very few side effects, required 1.2 monitoring consultations, significantly reduced premature ovulation rate and significantly increased transfer rate per initiated cycle, an effect which was not age dependent.

Management of spontaneous intracranial hypotension - Transorbital ultrasound as discriminator.

OBJECTIVE Spontaneous intracranial hypotension (SIH) is most commonly caused by cerebrospinal fluid (CSF) leakage. Therefore, we hypothesised that patients with orthostatic headache (OH) would show decreased optic nerve sheath diameter (ONSD) during changes from supine to upright position. METHODS Transorbital B-mode ultrasound was performed employing a high-frequency transducer for ONSD measurements in the supine and upright positions. Absolute values and changes of ONSD from supine to upright were assessed. Ultrasound was performed in 39 SIH patients, 18 with OH and 21 without OH, and in 39 age-matched control subjects. The control group comprised 20 patients admitted for back surgery without headache or any orthostatic symptoms, and 19 healthy controls. RESULTS In supine position, mean ONSD (±SD) was similar in patients with (5.38±0.91 mm) or without OH (5.48±0.89 mm; p=0.921). However, in upright position, mean ONSD was different between patients with (4.84±0.99 mm) and without OH (5.53±0.99 mm; p=0.044). Furthermore, the change in ONSD from supine to upright position was significantly greater in SIH patients with OH (-0.53±0.34 mm) than in SIH patients without OH (0.05±0.41 mm; p≤0.001) or in control subjects (0.01±0.38 mm; p≤0.001; area under the curve: 0.874 in receiver operating characteristics analysis). CONCLUSIONS Symptomatic patients with SIH showed a significant decrease of ONSD, as assessed by ultrasound, when changing from the supine to the upright position. Ultrasound assessment of the ONSD in two positions may be a novel, non-invasive tool for the diagnosis and follow-up of SIH and for elucidating the pathophysiology of SIH.

Contrast agents and ionization with respect to safety for patients and doctors

In hemodialysis patients, radiographic imaging with iodinated contrast medium (ICM) application plays a central role in the diagnosis and/or follow-up of disease-related conditions. Therefore, safety aspects concerning ICM administration and radiation exposure have a great impact on this group of patients. Current hardware and software improvements including the design and synthesis of modern contrast compounds allow the use of very small amounts of ICM in concert with low radiation exposure. Undesirable ICM side effects are divided into type A (predictable reactions such as heat feeling, headache, and contrast-induced acute kidney injury, for example) and type B (nonpredictable or hypersensitivity) reactions; this chapter deals with the latter. The first onset cannot be prevented. To prevent hypersensitivity upon reexposure of ICM, an allergological workup is recommended. If this is not possible and ICM is necessary, the patient should receive a premedication (H1 antihistamine with or without corticosteroids). Current imaging hardware and software improvements (e.g. such as additional filtration of the X-ray beam) allow the use of very small amount of ICM and small X-ray doses. Proper communication among the team involved in the treatment of a patient may allow to apply imaging protocols and efficient imaging strategies limiting radiation exposure to a minimum. Practical recommendations will guide the reader how to use radiation and ICM efficiently to improve both patient and staff safety.

Death after Sexual Intercourse

Sexuality is an essential aspect of quality of life. Nevertheless, sexual intercourse is physically challenging and leads to distinct changes in blood pressure, heart, and respiratory rate that may lead to vital complications. We present a case report of a 22-year-old female suffering from subarachnoid hemorrhage after sexual intercourse. The patient was immediately transported to hospital by emergency medical services and, after diagnosis, transferred to a tertiary hospital with neurosurgical expertise but died within 24 hours. After postcoital headaches, subarachnoid hemorrhage is the second most common cause of neurological complications of sexual intercourse and therefore patients admitted to an emergency department with headache after sexual intercourse should always be carefully evaluated by cerebral imaging.

Telomerase Inhibitor Imetelstat in Patients with Essential Thrombocythemia.

BACKGROUND Imetelstat, a 13-mer oligonucleotide that is covalently modified with lipid extensions, competitively inhibits telomerase enzymatic activity. It has been shown to inhibit megakaryocytic proliferation in vitro in cells obtained from patients with essential thrombocythemia. In this phase 2 study, we investigated whether imetelstat could elicit hematologic and molecular responses in patients with essential thrombocythemia who had not had a response to or who had had unacceptable side effects from prior therapies. METHODS A total of 18 patients in two sequential cohorts received an initial dose of 7.5 or 9.4 mg of imetelstat per kilogram of body weight intravenously once a week until attainment of a platelet count of approximately 250,000 to 300,000 per cubic millimeter. The primary end point was the best hematologic response. RESULTS Imetelstat induced hematologic responses in all 18 patients, and 16 patients (89%) had a complete hematologic response. At the time of the primary analysis, 10 patients were still receiving treatment, with a median follow-up of 17 months (range, 7 to 32 [ongoing]). Molecular responses were seen in 7 of 8 patients who were positive for the JAK2 V617F mutation (88%; 95% confidence interval, 47 to 100). CALR and MPL mutant allele burdens were also reduced by 15 to 66%. The most common adverse events during treatment were mild to moderate in severity; neutropenia of grade 3 or higher occurred in 4 of the 18 patients (22%) and anemia, headache, and syncope of grade 3 or higher each occurred in 2 patients (11%). All the patients had at least one abnormal liver-function value; all persistent elevations were grade 1 or 2 in severity. CONCLUSIONS Rapid and durable hematologic and molecular responses were observed in patients with essential thrombocythemia who received imetelstat. (Funded by Geron; ClinicalTrials.gov number, NCT01243073.).

Safety, pharmacokinetics, and antiretroviral activity of multiple doses of ibalizumab (formerly TNX-355), an anti-CD4 monoclonal antibody in HIV-1 infected adults

Context: Despite tremendous strides in HIV treatment over the past decade, resistance remains a major problem. A growing number of patients develop resistance and require new therapies to suppress viral replication. ^ Objective: To assess the safety of multiple administrations of the anti-CD4 receptor (anti-CD4) monoclonal antibody ibalizumab given as intravenous (IV) infusions, in three dosage regimens, in subjects infected with human immunodeficiency virus (HIV-1). ^ Design: Phase 1, multi-center, open-label, randomized clinical trial comparing the safety, pharmacokinetics and antiviral activity of three dosages of ibalizumab. ^ Setting: Six clinical trial sites in the United States. ^ Participants: A total of twenty-two HIV-positive patients on no anti-retroviral therapy or a stable failing regimen. ^ Intervention: Randomized to one of two treatment groups in Arms A and B followed by non-randomized enrollment in Arm C. Patients randomized to Arm A received 10 mg/kg of ibalizumab every 7 days, for a total of 10 doses; patients randomized to Arm B received a total of six doses of ibalizumab; a single loading dose of 10 mg/kg on Day 1 followed by five maintenance doses of 6 mg/kg every 14 days, starting at Week 1. Patients assigned to Arm C received 25 mg/kg of ibalizumab every 14 days for a total of 5 doses. All patients were followed for safety for an additional 7 to 8 weeks. ^ Main Outcome Measures: Clinical and laboratory assessments of safety and tolerability of multiple administrations of ibalizumab in HIV-infected patients. Secondary measures of efficacy include HIV-1 RNA (viral load) measurements. ^ Results: 21 patients were treatment-experienced and 1 was naïve to HIV therapy. Six patients were failing despite therapy and 15 were on no current HIV treatment. Mean baseline viral load (4.78 log 10; range 3.7-5.9) and CD4+ cell counts (332/μL; range 89-494) were similar across cohorts. Mean peak decreases in viral load from baseline of 0.99 log10(1.11 log10, and 0.96 log 10 occurred by Wk 2 in Cohorts A, B and C, respectively. Viral loads decreased by >1.0 log10 in 64%; 4 patients viral loads were suppressed to < 400 copies/mL. Viral loads returned towards baseline by Week 9 with reduced susceptibility to ibalizumab. CD4+ cell counts rose transiently and returned toward baseline. Maximum median elevations above BL in CD4+ cell counts for Cohorts A, B and C were +257, +198 and +103 cells/μL, respectively and occurred within 3 Wks in 16 of 22 subjects. The half-life of ibalizumab was 3-3.5 days and elimination was characteristic of capacity-limited kinetics. Administration of ibalizumab was well tolerated. Four serious adverse events were reported during the study. None of these events were related to study drug. Headache, nausea and cough were the most frequently reported treatment emergent adverse events and there were no laboratory abnormalities related to study drug. ^ Conclusions: Ibalizumab administered either weekly or bi-weekly was safe, well tolerated, and demonstrated antiviral activity. Further studies with ibalizumab in combination with standard antiretroviral treatments are warranted.^

Complications of misoprostol and other abortion induction methods in the developing world: A systematic review

OBJECTIVE: To systematically review published literature to examine the complications associated with the use of misoprostol and compare these complications to those associated with other forms of abortion induction. ^ DATA SOURCES: Studies were identified through searches of medical literature databases including Medline (Ovid), PubMed (NLM), LILACS, sciELO, and AIM (AFRO), and review of references of relevant articles. ^ STUDY SELECTION AND METHODS: A descriptive systematic review that included studies reported in English and published before December 2012. Eligibility criteria included: misoprostol (with or without other methods) and any other method of abortion in a developing country, as well as quantitative data on the complication of each method. The following is information extracted from each study: author/year, country/city, study design/study sample, age range, setting of data collection, sample size, the method of abortion induction, the number of cases for each method, and the percentage of complications with each method. RESULTS: A total of 4 studies were identified (all in Latin America) describing post-abortion complications of misoprostol and other methods in countries where abortion is generally considered unsafe and/or illegal. The four studies reported on a range of complications including: bleeding, infection, incomplete abortion, intense pelvic pain, uterine perforation, headache, diarrhea, nausea, mechanical lesions, and systemic collapse. The most prevalent complications of misoprostol-induced abortion reported were: bleeding (7-82%), incomplete abortion (33-70%), and infection (0.8-67%). The prevalence of these complications reported from other abortion methods include: bleeding (16-25%), incomplete abortion (15-82%), and infection (13-50%). ^ CONCLUSION: The literature identified by this systematic review is inadequate for determining the complications of misoprostol used in unsafe settings. Abortion is considered an illicit behavior in these countries, therefore making it difficult to investigate the details needed to conduct a study on abortion complications. Given the differences between the reviewed studies as well as a variety of study limitations, it is not possible to draw firm conclusions about the rates of specific-abortion related complications.^

INTERVENÇÕES FISIOTERAPÊUTICAS NUM CONTEXTO LÚDICO JUNTO A CRIANÇAS COM DOENÇAS RESPIRATÓRIAS CRÔNICAS

Verifica-se hoje em dia o aumento da incidência de problemas pulmonares que ocasiona internações hospitalares infantis com maior freqüência. Este projeto baseia-se na visão biopsicossocial da Psicologia da Saúde e leva em conta a valorização de atividades do cotidiano da criança, como o brincar, para sua recuperação. Tem por objetivo principal investigar se a utilização de técnicas interventivas lúdicas em fisioterapia contribui para a melhora dos níveis de oxigenação de crianças asmáticas e por objetivos específicos traçar um breve perfil clínico da criança que procura o Ambulatório de Alergia e Imunologia da Faculdade de Medicina do ABC e verificar a adesão da criança com problemas respiratórios a uma intervenção fisioterapêutica lúdica da criança. A análise qualitativa da intervenção lúdica registra grande envolvimento e participação prazerosa das crianças e ampla aceitação dos pais. Estes resultados sugerem que novas pesquisas sejam realizadas a respeito de intervenções lúdicas em fisioterapia. Utiliza-se de método avaliativo-interventivo quase-experimental. Seus participantes são 58 crianças de ambos os sexos com idade de quatro a 11 anos com as patologias de asma brônquica, bronquite e rinite alérgica, sem a presença da crise. Desenvolve-se por meio de sessão única com cada paciente, com avaliação antes e após da intervenção fisioterápica lúdica por meio das aferições dos sinais vitais, (PA, FC, FR,T°C, incluindo oximetria de pulso e PFE) técnicas de aquecimento, alongamento torácico, fortalecimento abdominal e expansão torácica. Realiza análise qualitativa da responsividade das crianças às técnicas interventivas empregadas no contexto lúdico. Os resultados a respeito do perfil clinico indicam maior incidência de Asma, com 44 casos (75,8620 %), para 11 casos de Rinite (18,9655 %) e apenas três de Bronquite (5,1724 %). Os dados relativos a PA, FC, FR,T°C e ao PFE mostram-se dentro da normalidade. Este estudo não constata diferença significativa em relação ao nível de saturação de O2 após a intervenção lúdica. Quanto à adesão, 55,2 % dos participantes aderiram, sendo que a não adesão deu-se por motivos particulares alegados pelos responsáveis ou indisposição da criança, de dor de cabeça, sonolência e/ou vômito. A análise qualitativa da intervenção lúdica registra grande envolvimento e participação prazerosa das crianças e ampla aceitação dos pais. Estes resultados sugerem que novas pesquisas sejam realizadas a respeito de intervenções lúdicas em fisioterapia.(AU)

INTERVENÇÕES FISIOTERAPÊUTICAS NUM CONTEXTO LÚDICO JUNTO A CRIANÇAS COM DOENÇAS RESPIRATÓRIAS CRÔNICAS

Verifica-se hoje em dia o aumento da incidência de problemas pulmonares que ocasiona internações hospitalares infantis com maior freqüência. Este projeto baseia-se na visão biopsicossocial da Psicologia da Saúde e leva em conta a valorização de atividades do cotidiano da criança, como o brincar, para sua recuperação. Tem por objetivo principal investigar se a utilização de técnicas interventivas lúdicas em fisioterapia contribui para a melhora dos níveis de oxigenação de crianças asmáticas e por objetivos específicos traçar um breve perfil clínico da criança que procura o Ambulatório de Alergia e Imunologia da Faculdade de Medicina do ABC e verificar a adesão da criança com problemas respiratórios a uma intervenção fisioterapêutica lúdica da criança. A análise qualitativa da intervenção lúdica registra grande envolvimento e participação prazerosa das crianças e ampla aceitação dos pais. Estes resultados sugerem que novas pesquisas sejam realizadas a respeito de intervenções lúdicas em fisioterapia. Utiliza-se de método avaliativo-interventivo quase-experimental. Seus participantes são 58 crianças de ambos os sexos com idade de quatro a 11 anos com as patologias de asma brônquica, bronquite e rinite alérgica, sem a presença da crise. Desenvolve-se por meio de sessão única com cada paciente, com avaliação antes e após da intervenção fisioterápica lúdica por meio das aferições dos sinais vitais, (PA, FC, FR,T°C, incluindo oximetria de pulso e PFE) técnicas de aquecimento, alongamento torácico, fortalecimento abdominal e expansão torácica. Realiza análise qualitativa da responsividade das crianças às técnicas interventivas empregadas no contexto lúdico. Os resultados a respeito do perfil clinico indicam maior incidência de Asma, com 44 casos (75,8620 %), para 11 casos de Rinite (18,9655 %) e apenas três de Bronquite (5,1724 %). Os dados relativos a PA, FC, FR,T°C e ao PFE mostram-se dentro da normalidade. Este estudo não constata diferença significativa em relação ao nível de saturação de O2 após a intervenção lúdica. Quanto à adesão, 55,2 % dos participantes aderiram, sendo que a não adesão deu-se por motivos particulares alegados pelos responsáveis ou indisposição da criança, de dor de cabeça, sonolência e/ou vômito. A análise qualitativa da intervenção lúdica registra grande envolvimento e participação prazerosa das crianças e ampla aceitação dos pais. Estes resultados sugerem que novas pesquisas sejam realizadas a respeito de intervenções lúdicas em fisioterapia.(AU)

Ablation of P/Q-type Ca2+ channel currents, altered synaptic transmission, and progressive ataxia in mice lacking the α1A-subunit

The Ca2+ channel α1A-subunit is a voltage-gated, pore-forming membrane protein positioned at the intersection of two important lines of research: one exploring the diversity of Ca2+ channels and their physiological roles, and the other pursuing mechanisms of ataxia, dystonia, epilepsy, and migraine. α1A-Subunits are thought to support both P- and Q-type Ca2+ channel currents, but the most direct test, a null mutant, has not been described, nor is it known which changes in neurotransmission might arise from elimination of the predominant Ca2+ delivery system at excitatory nerve terminals. We generated α1A-deficient mice (α1A−/−) and found that they developed a rapidly progressive neurological deficit with specific characteristics of ataxia and dystonia before dying ≈3–4 weeks after birth. P-type currents in Purkinje neurons and P- and Q-type currents in cerebellar granule cells were eliminated completely whereas other Ca2+ channel types, including those involved in triggering transmitter release, also underwent concomitant changes in density. Synaptic transmission in α1A−/− hippocampal slices persisted despite the lack of P/Q-type channels but showed enhanced reliance on N-type and R-type Ca2+ entry. The α1A−/− mice provide a starting point for unraveling neuropathological mechanisms of human diseases generated by mutations in α1A.