Caenorhabditis elegans RAC1/ced-10 mutants as a new animal model to study very early stages of Parkinson's disease.

Patients with Parkinson's disease (PD) display non-motor symptoms arising prior to the appearance of motor signs and before a clear diagnosis. Motor and non-motor symptoms correlate with progressive deposition of the protein alpha-synuclein (Asyn) both within and outside of the central nervous system, and its accumulation parallels neurodegeneration. The genome of Caenorhabditis elegans does not encode a homolog of Asyn, thus rendering this nematode an invaluable system with which to investigate PD-related mechanisms in the absence of interference from endogenous Asyn aggregation. CED-10 is the nematode homolog of human RAC1, a small GTPase needed to maintain the function and survival of dopaminergic neurons against human Asyn-induced toxicity in C. elegans. Here, we introduce C. elegans RAC1/ced-10 mutants as a predictive tool to investigate early PD symptoms before neurodegeneration occurs. Deep phenotyping of these animals reveals that, early in development, they displayed altered defecation cycles, GABAergic abnormalities and an increased oxidation index. Moreover, they exhibited altered lipid metabolism evidenced by the accumulation of lipid droplets. Lipidomic fingerprinting indicates that phosphatidylcholine and sphingomyelin, but not phosphatidylethanolamine or phosphatidylserine, were elevated in RAC1/ced-10 mutant nematodes. These collective characteristics reflect the non-motor dysfunction, GABAergic neurotransmission defects, upregulation of stress response mechanisms, and metabolic changes associated with early-onset PD. Thus, we put forward an easy-to-manipulate preclinical animal model to deepen our understanding of early-stage PD and accelerate the translational path for therapeutic target discovery.

Clinical efficacy of clodronic acid in horses diagnosed with navicular syndrome: A field study using objective and subjective lameness evaluation.

Navicular syndrome, a common cause of equine forelimb lameness, is associated with pathological changes in the navicular bone. Consequently, administration of bisphosphonates (BPs) has been advocated in order to modify the rate of bone turnover. The present study aimed to assess the clinical efficacy of intramuscularly administered clodronic acid for the treatment of 11 horses with clinical and radiographic findings compatible with navicular syndrome. Magnetic resonance imaging was performed in 5 of the 11 horses. The animals were treated with an intramuscular dose of clodronic acid of 765 mg/horse, administered over three separate injection sites. Before and at 7, 30 and 90 days after treatment, horses were subjected to lameness and accelerometric evaluations. A clinical improvement was observed in 6 of the 11 horses. These 6 horses showed a mean reduction of two degrees in lameness score. Accelerometry in these horses revealed increased velocity, stride length, stride regularity and dorsoventral displacement of the gravity of centre together with a reduction in stride frequency, suggesting a gait improvement. This study demonstrates that intramuscular clodronic acid can be useful for lameness reduction in some horses with navicular syndrome.

Azacitidine improves outcome in higher-risk MDS patients with chromosome 7 abnormalities: a retrospective comparison of GESMD and GFM registries.

Treatment with azacitidine (AZA) has been suggested to be of benefit for higher-risk myelodysplastic syndrome (HR-MDS) patients with chromosome 7 abnormalities (Abn 7). This retrospective study of 235 HR-MDS patients with Abn 7 treated with AZA (n = 115) versus best supportive care (BSC; n = 120), assessed AZA treatment as a time-varying variable in multivariable analysis. A Cox Regression model with time-interaction terms of overall survival (OS) at different time points confirmed that, while chromosome 7 cytogenetic categories (complex karyotype [CK] versus non-CK) and International Prognostic Scoring System risk (high versus intermediate-2) retained poor prognosis over time, AZA treatment had a favourable impact on OS during the first 3 years of treatment compared to BSC (Hazard ratio [HR] 0·5 P < 0·001 at 1 year, 0·7 P = 0·019 at 2 years; 0·73 P = 0·029 at 3 years). This benefit was present in all chromosome 7 categories, but tended to be greater in patients with CK (risk reduction of 82%, 68% and 53% at 1, 3 and 6 months in CK patients; 79% at 1 month in non-CK patients, P < 0·05 for all). AZA also significantly improved progression-free survival (P < 0·01). This study confirms a time-dependent benefit of AZA on outcome in patients with HR-MDS and cytogenetic abnormalities involving chromosome 7, especially for those with CK.

A Probabilistic Model for Cushing's Syndrome Screening in At-Risk Populations: A Prospective Multicenter Study.

CONTEXT: Cushing's syndrome (CS) is challenging to diagnose. Increased prevalence of CS in specific patient populations has been reported, but routine screening for CS remains questionable. To decrease the diagnostic delay and improve disease outcomes, simple new screening methods for CS in at-risk populations are needed. OBJECTIVE: To develop and validate a simple scoring system to predict CS based on clinical signs and an easy-to-use biochemical test. DESIGN: Observational, prospective, multicenter. SETTING: Referral hospital. PATIENTS: A cohort of 353 patients attending endocrinology units for outpatient visits. INTERVENTIONS: All patients were evaluated with late-night salivary cortisol (LNSC) and a low-dose dexamethasone suppression test for CS. MAIN OUTCOME MEASURES: Diagnosis or exclusion of CS. RESULTS: Twenty-six cases of CS were diagnosed in the cohort. A risk scoring system was developed by logistic regression analysis, and cutoff values were derived from a receiver operating characteristic curve. This risk score included clinical signs and symptoms (muscular atrophy, osteoporosis, and dorsocervical fat pad) and LNSC levels. The estimated area under the receiver operating characteristic curve was 0.93, with a sensitivity of 96.2% and specificity of 82.9%. CONCLUSIONS: We developed a risk score to predict CS in an at-risk population. This score may help to identify at-risk patients in non-endocrinological settings such as primary care, but external validation is warranted.

Better prognosis for patients with del(7q) than for patients with monosomy 7 in myelodysplastic syndrome.

BACKGROUND: Abnormalities involving chromosome 7 are frequent in myelodysplastic syndrome (MDS) and suggest a poor prognosis. METHODS: The authors examined the hypothesis that the clinical features and survival associated with isolated deletion (del) of part of the long arm of chromosome 7 (7q) in MDS are different from those associated with isolated monosomy 7 (complete loss of chromosome 7). In total, 133 patients with a diagnosis of de novo MDS (according to the World Health Organization [WHO] classification) and chromosome 7 abnormalities in the Spanish MDS Registry were evaluated retrospectively. Four karyotypic groups were identified: isolated del(7q) (n = 29), isolated monosomy 7 (n = 27), del(7q) with additional abnormalities (n = 24), and monosomy 7 with additional abnormalities (n = 53). RESULTS: Isolated del(7q) was more frequent in patients with less advanced MDS according to the WHO classification or the International Prognostic Scoring System. In addition, isolated del(7q) was associated with fewer blasts in bone marrow than other cytogenetics groups. Survival was significantly superior in patients with isolated del(7) than in those with isolated monosomy 7, del(7q) with additional abnormalities, or monosomy 7 with additional abnormalities. On multivariate analysis, age, the percentage of blasts in bone marrow, and other chromosome 7 abnormalities apart from isolated del(7q) were identified as independent risk factors for survival. CONCLUSIONS: The current results demonstrated that patients who had MDS with isolated del(7q) had some distinct clinical-pathologic characteristics as well as better survival than patients who had MDS with isolated monosomy 7.

Histological and biomechanical effects of palatal sclerotherapy in the horse using sodium tetradecyl sulfate.

Palatal sclerotherapy using sodium tetradecyl sulfate has been suggested as a treatment for dorsal displacement of the soft palate in young Standardbred horses. The present study evaluated histological and biomechanical changes in the equine soft palate following trans-endoscopic treatment with a low dose of this compound. Two horses were euthanased and examined at 2 weeks and at 1, 2, 4 and 6 months post-sclerotherapy, while two further horses served as untreated controls. The technique was easily performed in all cases without major complications. On histological examination there was no evidence of palatal necrosis, inflammation or fibrosis in any of the treated or control animals. There was no variation in the density of palatal connective tissue between individuals, and on biomechanical assessment no significant difference in the stiffness of the palatal tissue was found between treated and control horses at any time. The lower dose of sodium tetradecyl sulfate used in this study relative to previous reports, might explain the absence of tissue alterations. This method of sclerotherapy did not alter the morphology or biomechanical properties of normal equine soft palates.

A surgical approach to the lateral compartment of the equine guttural pouch in the standing horse: modification of the forgotten "Garm technique".

The objective of this study was to evaluate the feasibility, efficacy and complications following lavage and drainage of the lateral compartment (LC) of the equine guttural pouch (GP) using a modified Garm's technique (MGT). In an ex vivo study (study 1), six cadaver heads were examined to assess the anatomical limits of the surgical approach and whether vital structures might be damaged. This was followed by an in vivo study (study 2) in which a lavage/drainage tube was placed for 3 days into each LC of four standing horses using the MGT. In both studies, the procedure offered direct access into the LC and indirect access into the medial compartments of the GP. In study 1, the MGT provided a rostroventral point of access allowing drainage of the LC, with no obvious iatrogenic damage. In study 2, the MGT permitted lavage of the entire GP in three healthy horses and one horse with mild GP empyema. The only major complication was development of emphysema of the lateral wall of one LC, with secondary collapse of the mucous membrane. The time for secondary wound healing was 12-14 days. The MGT can be performed safely in standing horses and may be of value in providing access for lavage and drainage in horses with mild GP empyema.

Seudoquistogastrostomia espontánea: manejo selectivo del seudoquiste agudo pancreático / Spontaneous pseudocystogastrostomy: selective management of acute pancreatic pseudocyst

Antecedentes: En nuestro medio el seudoquiste agudo de páncreas se presenta luego de pancreatitis aguda severa o trauma pancreático. El diagnóstico Inicial se realiza por ecografía, tomografía computada y, con menor frecuencia, por la clínica. El tratamiento puede ser quirúrgico o mimmoinvasivo. Objetivos: Presentar un paciente con un voluminoso seudoquiste agudo de páncreas que tuvo una resolución espontánea. Material y Métodos: Paciente de sexo masculino, de 71 años, con episodio de pancreatitis aguda severa, complicada con necrosis pancreática infectada, que requirió necrosectomias en etapas y colecistectomia; después, desarrolló un seudoquiste agudo de páncreas de 20 cm. de diámetro. La complejidad de la patología y la repercusión en el estado general del enfermo postergó el tratamiento del seudoquiste, que en su evolución natural se drenó espontáneamente al estómago, sin complicaciones ni recidiva de la lesión. Conclusión: Los seudoquistes agudos de páncreas mayores de 6 cm. que persisten más allá de las 12 semanas habitualmente son tratados quirúrgicamente. Algunos casos, como el enfermo reportado, podrían ser manejados en forma no operatoria con un seguimiento adecuado.

Background: In our medium, acute pancreatic pseudocyst occur after severe acute pancreatitis or pancreatic trauma. The initial diagnosis is made by ultrasound examination, computed axial tomography and less frequently, by clinical assessment. Treatment may be either surgical or minimal invasive. Objectives: To present a patient with a large acute pancreatic pseudocyst which had a spontaneous resolution. Material and methods: The patient was a 71-years-old male who had an attack of severe acute pancreatitis necrosis requiring serial necrosectomies and cholecystectomy; he then developed a 20 cm acute pancreatic pseudocyst. The severity of the disease and its implication on the patien´s general condition delayed treatment on the pseudocyst, which in its natural course, spontaneously drained into the stomach with no complications or relapses. Conclusion: Acute pancreatic cysts larger than 6 cm persisting for more than 12 weeks are usually surgically treated. Some cases, as the one reported below, could be managed by non-surgical means with adequate follow-up.

Seudoquistogastrostomia espontánea: manejo selectivo del seudoquiste agudo pancreático / Spontaneous pseudocystogastrostomy: selective management of acute pancreatic pseudocyst

Antecedentes: En nuestro medio el seudoquiste agudo de páncreas se presenta luego de pancreatitis aguda severa o trauma pancreático. El diagnóstico Inicial se realiza por ecografía, tomografía computada y, con menor frecuencia, por la clínica. El tratamiento puede ser quirúrgico o mimmoinvasivo. Objetivos: Presentar un paciente con un voluminoso seudoquiste agudo de páncreas que tuvo una resolución espontánea. Material y Métodos: Paciente de sexo masculino, de 71 años, con episodio de pancreatitis aguda severa, complicada con necrosis pancreática infectada, que requirió necrosectomias en etapas y colecistectomia; después, desarrolló un seudoquiste agudo de páncreas de 20 cm. de diámetro. La complejidad de la patología y la repercusión en el estado general del enfermo postergó el tratamiento del seudoquiste, que en su evolución natural se drenó espontáneamente al estómago, sin complicaciones ni recidiva de la lesión. Conclusión: Los seudoquistes agudos de páncreas mayores de 6 cm. que persisten más allá de las 12 semanas habitualmente son tratados quirúrgicamente. Algunos casos, como el enfermo reportado, podrían ser manejados en forma no operatoria con un seguimiento adecuado.(AU)

Background: In our medium, acute pancreatic pseudocyst occur after severe acute pancreatitis or pancreatic trauma. The initial diagnosis is made by ultrasound examination, computed axial tomography and less frequently, by clinical assessment. Treatment may be either surgical or minimal invasive. Objectives: To present a patient with a large acute pancreatic pseudocyst which had a spontaneous resolution. Material and methods: The patient was a 71-years-old male who had an attack of severe acute pancreatitis necrosis requiring serial necrosectomies and cholecystectomy; he then developed a 20 cm acute pancreatic pseudocyst. The severity of the disease and its implication on the patien´s general condition delayed treatment on the pseudocyst, which in its natural course, spontaneously drained into the stomach with no complications or relapses. Conclusion: Acute pancreatic cysts larger than 6 cm persisting for more than 12 weeks are usually surgically treated. Some cases, as the one reported below, could be managed by non-surgical means with adequate follow-up.(AU)

Vasospasm after use of a tourniquet: another cause of postoperative limb ischemia?

IMPLICATIONS: Two previously reported causes of postoperative limb ischemia after use of a tourniquet, compartment syndrome and arterial thromboembolism, require aggressive and invasive management. We report another probable cause that can be managed nonsurgically: vasospasm.