Onset Of Clinical Signs Research Articles

Antisense oligonucleotides extend survival of prion-infected mice.

Prion disease is a fatal, incurable neurodegenerative disease of humans and other mammals caused by conversion of cellular prion protein (PrPC) into a self-propagating neurotoxic conformer (prions; PrPSc). Strong genetic proofs of concept support lowering PrP expression as a therapeutic strategy. Antisense oligonucleotides (ASOs) can provide a practical route to lowering 1 target mRNA in the brain, but their development for prion disease has been hindered by 3 unresolved issues from prior work: uncertainty about mechanism of action, unclear potential for efficacy against established prion infection, and poor tolerability of drug delivery by osmotic pumps. Here, we test ASOs delivered by bolus intracerebroventricular injection to intracerebrally prion-infected WT mice. Prophylactic treatments given every 2–3 months extended survival times 61%–98%, and a single injection at 120 days after infection, near the onset of clinical signs, extended survival 55% (87 days). In contrast, a nontargeting control ASO was ineffective. Thus, PrP lowering is the mechanism of action of ASOs effective against prion disease in vivo, and infrequent — or even single — bolus injections of ASOs can slow prion neuropathogenesis and markedly extend survival, even when initiated near clinical signs. These findings should empower development of PrP-lowering therapy for prion disease.

Resection of urachal anomalies in dogs with recurrent lower urinary tract disease.

ObjectiveTo determine whether surgical removal of urachal anomalies improves the outcomes of dogs with recurrent lower urinary tract disease (LUTD) and bacterial urinary tract infection (BUTI).Study designRetrospective study.AnimalsThirty‐three dogs with urachal anomalies and recurrent LUTD or BUTI.MethodsMedical records of dogs with LUTD or BUTI and a diagnosis of urachal anomaly treated by partial cystectomy were reviewed. A minimum follow‐up of 9 months was required for inclusion.ResultsMedian age at onset of clinical signs was 12 months (range, 1 month to 10 years). Urachal anomalies were detected with histopathology in 20 of 28 (71%) dogs. At a median follow‐up of 22 months (range, 9‐114), 21 of 28 (64%) dogs were free of signs of LUTD. Nine (27%) dogs exhibited reduced signs of LUTD; in three (9%) dogs, no clinical improvement was observed. Among the 25 dogs with confirmed preoperative BUTI, 22 clinically improved with surgery.ConclusionPartial cystectomy reduced the long‐term severity of clinical signs and risk of recurrence of LUTD or BUTI in dogs with confirmed or suspected urachal anomalies.Clinical significancePartial cystectomy should be considered as an adjunct to the treatment of LUTD and BUTI in dogs.

Pasteurellosis Outbreak Due to Pasteurella multocida Type A in Rabbits (Oryctolagus cuniculus)

Background: Pasteurellosis is a common disease of cattle, pigs, and poultry, which rarely affects humans. In rabbits, the respiratory presentation of the disease is frequently reported. Clinical signs related to bronchopneumonia include sneezing, lung stertors, oculonasal discharge, dyspnea and cyanosis. Infection may lead to otitis, conjunctivitis, abscesses and sepsis. Furthermore, Pasteurella multocida infection may lead to sudden death without clinical manifestations. Reports of pasteurellosis in rabbits are scarce in Brazil. Therefore, the objective of this article is to describe an outbreak of pasteurellosis with high mortality in a rabbity in the State of Santa Catarina, Brazil.Cases: Two adult rabbits were submitted for necropsy at the Veterinary Pathology Laboratory of the Instituto Federal Catarinense - Campus Concórdia, within an interval of twenty days. Herd was represented by 40 animals, of which six fattening rabbits and three breeders died. Animals were kept in suspended cages with slatted floor. Clinical signs were represented by prostration, sneezing, and mucopurulent nasal discharge. In addition, wounds were observed in the distal portion of the limbs. Death occurred up to two days after the onset of clinical signs. Necropsies were performed and tissue samples were collected for histopathologic, immunohistochemical and microbiologic (bacterial culture and antibiogram) exams. At the necropsy, severe diffuse fibrinous exudate covering the pericardium sac, visceral and parietal pleural surfaces was noted, as well as multiple diaphragm adhesions. In addition, the lungs presented diffuse red coloration and showed multiple abscesses ranging from 0.3 to 1cm in diameter. The nasal sinus and the tracheal mucosa showed diffuse reddening (rabbits 1 and 2). Abscesses up to 2 cm in diameter were observed in the mammary glands (rabbit 1), heart and kidneys (rabbit 2). The urinary bladder was distended by cloudy urine and moderate amount of purulent exudate (rabbits 1 and 2). Histopathological evaluation revealed diffuse marked fibrinosuppurative pleuritis associated with severe multifocal suppurative bronchopneumonia (rabbits 1 and 2), as well as multifocal marked mastitis (rabbit 1), nephritis and myocarditis (rabbit 2). Also, intralesional bacterial aggregates and thrombosis were observed in both cases. Pasteurella multocida type A was isolated through bacterial culture, and antibiogram showed sensitivity to all tested antibiotics. Immunohistochemistry showed mild multifocal positive staining for P. multocida in the visceral pleura in both cases.Discussion: In the present case, P. multocida type A led to suppurative bronchopneumonia, pulmonary abscesses and fibrinosuppurative pleuritis in both rabbits. In addition, abscesses affecting the kidneys, heart and mammary glands were observed. These findings are typically seen in this condition in rabbits, and similar lesions may be noted in pigs. It is believed that nutritional, climatic and hierarchical changes may predispose to the development of the disease. In the present outbreak, the disease may have initially affected fattening rabbits, which are more exposed to stressful events, and then bacterial spread to breeders sharing the same facility may have occurred. Furthermore, contributing factors include concomitant bacterial infections, and the level of virulence of the bacterial strain involved in the outbreak. In the present study, the diagnosis of pasteurellosis in rabbits was based on the epidemiological, gross, histopathological, bacterial and immunohistochemical findings. It is believed that the present report will improve the understanding of the disease in rabbits in Brazil, since rare descriptions of the condition are currently available nationwide.

To treat or not to treat?

In a world of ever-increasing liability, the decision not to treat a patient comes less and less easily, even though both evidence-based medical and financial reasons may speak against treatment....

Generalised tetanus in a cat

This case report describes the presentation of a cat with generalised tetanus, which is uncommon in this species. The onset of clinical signs with focal limb rigidity occurred one week...

Spontaneous and experimental poisoning by Merremia macrocalyx (Convolvulaceae) in cattle

ABSTRACT: The aim of this work was to describe the epidemiological, clinical and pathological aspects of spontaneous poisoning by Merremia macrocalyx in cattle in the Pernambuco state, northeastern Brazil, and to experimentally replicate the poisoning by this plant. To determine the occurrence of poisonings, 30 farms were visited in six municipalities at the Forest Zone of Pernambuco. The plant was found in nine farms, in which history of plant poisoning in cattle, and occasionally in sheep were also reported. Three outbreaks of spontaneous poisonings in cattle were studied. To replicate the disease experimentally, two steers received a single dose of 60g/kg and two steers received 80g/kg of the fresh leaves of M. macrocalyx in the trough for spontaneous ingestion. Two steers were also used as a control group. The main clinical signs observed in spontaneous cases consisted of restlessness, bloat, polyuria, diarrhea, and death within 48 to 72 hours after the onset of clinical signs. Cattle experimentally poisoned presented similar clinical signs to those observed in spontaneous cases. Gross lesions consisted of dryness and impaction of the rumen, omasum and reticulum contents. Abomasal content was fluid, the mucosa was hyperemic, with swollen folds and multiple ulcers. Similar lesions were observed in duodenum mucosae. Histologically, lesions observed in the abomasum and duodenum mucosa consisted of necrosis, hemorrhage and inflammatory infiltration of neutrophils and lymphocytes. The wide distribution and palatability of this plant, associated with the high sensitivity of the bovine species verified in this experiment, highlight the importance of this plant in spontaneous cases of poisoning in cattle.

Pruritus and myoclonus following five consecutive doses of morphine administered through an epidural catheter in a dog

A 2-year, 10-month-old male entire whippet had an epidural catheter placed to provide postoperative analgesia following lateral thoracotomy. He received 0.1 mg/kg preservative free morphine every 12 hours via the...

Ghrelin as a Novel Pharmacological Treatment for Necrotizing Enterocolitis

Necrotizing enterocolitis (NEC) is the leading cause of mortality from gastrointestinal (GI) disease in preterm neonates. Its precise pathogenesis is unknown, but early stages of NEC are thought to be characterized by damage to the intestinal mucosa; while full intestinal necrosis and perforation occur during the later stages.The high‐frequency power spectra of heart rate variability (HF‐HRV) is a non‐invasive measure of vagal tone, our laboratory has shown that decreases in HF‐HRV may predict which neonates are at increased risk for NEC before the onset of clinical signs (Doheny et al. Neurogastroenterol. Motil., 2014). Furthermore, experimental NEC in newborn rat pups reduces HF‐HRV and increases NOS immunoreactivity in the myenteric neurons of the lower GI tract (Meister et al., Neurogastroenterol. Motil., 2018). Ghrelin is a GI hormone known to increase gastric motility via actions at several sites, including an excitation of dorsal vagal motoneurons upon brainstem microinjection, hence leading to an increase in vagal output to the GI tract.The aim of the present study was to test the hypotheses that ghrelin administration in a rodent model of NEC will: i) increase HF‐HRV values, and ii) restore the neurochemical phenotype of myenteric neurons of the lower GI tract.Newborn Sprague‐Dawley rats were randomly separated in the following groups: i) control, ii) mild NEC (<grade 2) induced via exposure to cold stress and hypoxia twice daily, and iii) mild NEC and anterior subdiaphragmatic vagotomy (grade >2). All groups underwent twice daily intraperitoneal injections of saline or ghrelin (0.05mg/kg) on postnatal days (PD)‐5 to PD‐10. Electrocardiogram recordings using bilateral electrodes to measure HF‐HRV were conducted on PD‐1, ‐5, and ‐10, prior to sacrifice on PD12. Upon sacrifice, GI tissues were collected to confirm NEC grade via H&E staining, and to assess the neurochemical phenotype of myenteric neurons through fluorescence immunohistochemistry.Mild NEC was confirmed via grade >2 histological examination; these pups did not display typical developmental increases in HF‐HRV. Ghrelin, but not saline, treatment reduced the NEC histological scale, increased HF‐HRV values and restored NOS‐immunoreactivity (NOS‐IR) in neurons of the myenteric plexus to levels similar to controls. Data are summarized in the Table below.Our data indicate that ghrelin administration in rodent model of NEC: i) decreased the histological severity of NEC, ii) increased HF‐HRV values, and iii) restored the neurochemical phenotype of myenteric neurons of the lower GI tract. We suggest that ghrelin may be a promising treatment to attenuate, or even reverse, the impaired HF‐HRV and altered neurochemical phenotype observed after NEC induction.Support or Funding InformationAmerican Physiological Society grant to C.R.B. & NIH grant DK99350 to R.A.T. & K.K.D.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

ATP13A2 missense variant in Australian Cattle Dogs with late onset neuronal ceroid lipofuscinosis

The neuronal ceroid lipofuscinoses (NCLs) are lysosomal storage disorders characterized by progressive neurodegeneration and declines in neurological functions. Pathogenic sequence variants in at least 13 genes underlie different forms of NCL, almost all of which are recessively inherited. To date 13 sequence variants in 8 canine orthologs of human NCL genes have been found to occur in 11 dog breeds in which they result in progressive neurological disorders similar to human NCLs. Canine NCLs can serve as models for preclinical evaluation of therapeutic interventions for these disorders. In most NCLs, the onset of neurological signs occurs in childhood, but some forms have adult onsets. Among these is CLN12 disease, also known as Kufor-Rakeb syndrome, PARK9, and spastic paraplegia78. These disorders result from variants in ATP13A2 which encodes a putative transmembrane ion transporter important for lysosomal function. Three Australian Cattle Dogs (a female and two of her offspring) were identified with a progressive neurological disorder with an onset of clinical signs at approximately 6 years of age. The affected dogs exhibited clinical courses and histopathology characteristic of the NCLs. Whole genome sequence analysis of one of these dogs revealed a homozygous c.1118C > T variant in ATP13A2 that predicts a nonconservative p.(Thr373Ile) amino acid substitution. All 3 affected dogs were homozygous for this variant, which was heterozygous in 42 of 394 unaffected Australian Cattle Dogs, the remainder of which were homozygous for the c.1118C allele. The high frequency of the mutant allele in this breed suggests that further screening for this variant should identify additional homozygous dogs and indicates that it would be advisable to perform such screening prior to breeding Australian Cattle Dogs.

FTY720 controls disease severity and attenuates sciatic nerve damage in chronic experimental autoimmune neuritis

BackgroundChronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune-mediated inflammatory disease of the peripheral nervous system characterized by a response directed against certain myelin proteins and for which therapies are limited. Previous studies have suggested a beneficial role of FTY720, a sphingosine 1-phosphate (S1P) receptor agonist, known to deplete lymphocytes from the peripheral blood by sequestering them into lymph nodes, in the treatment of experimental autoimmune neuritis (EAN). Therefore, we investigated whether FTY720 is also beneficial in chronic experimental autoimmune neuritis (c-EAN), a recently developed rat model mimicking human CIDP.Methodsc-EAN was induced in Lewis rats by immunization with S-palm P0(180–199) peptide. Rats were treated with FTY720 (1 mg/kg) or vehicle intraperitoneally once daily from the onset of clinical signs for 18 days; clinical signs were assessed daily until 60 days post-immunization (dpi). Electrophysiological and histological features were examined at different time points. We also evaluated the serum levels of different pro- and anti-inflammatory cytokines by ELISA or flow cytometry at 18, 40, and 60 dpi.ResultsOur data demonstrate that FTY720 decreased the severity and abolished the chronicity of the disease in c-EAN rats. Therapeutic FTY720 treatment reversed electrophysiological and histological anomalies, suggesting that myelinated fibers were subsequently preserved, it inhibited macrophage and IL-17+ cell infiltration in PNS, and it significantly reduced circulating pro-inflammatory cytokines.ConclusionsFTY720 treatment has beneficial effects on c-EAN, a new animal model mimicking human CIDP. We have shown that FTY720 is an effective immunomodulatory agent, improving the disease course of c-EAN, preserving the myelinated fibers, attenuating the axonal degeneration, and decreasing the number of infiltrated inflammatory cells in peripheral nerves. These data confirm the interest of testing FTY720 or molecules targeting S1P in human peripheral neuropathies.

Can Base Excess be Used for Prediction to Early Diagnosis of Neonatal Sepsis in Preterm Newborns?

BackgroundNeonatal sepsis remains an important and potentially life-threatening clinical syndrome and a major cause of neonatal mortality and morbidity. The aim of this study to investigate whether values of base excess before the onset of clinical signs and symptoms of sepsis indicate infection in the early diagnosis of neonatal sepsis.MethodsIn this study, a total of 118 infants were enrolled. The infants were classified into two groups: group 1 (sepsis, n=49) and group 2 (control, n=69). Blood gas analysis investigated for the screening of neonatal sepsis.ResultsA total of 49 newborns with neonatal sepsis and 69 healthy controls were enrolled. Comparison of markers of sepsis revealed C-reactive protein, interleukin-6 level to be significantly higher and pH, pCO2, HCO3, and base excess values to be significantly lower in newborns with sepsis compared healthy controls (p<0.01). The optimum cut-off value in the diagnosis of neonatal sepsis was found to be −5 mmol/L for base excess. Sensitivity, specificity, positive predictive value and negative predictive value of this base excess cut-off for neonatal sepsis were 75, 91, 86 and 84% respectively.ConclusionThis is the first study to determine the relationship between the decreased value of the base excess and early stage of neonatal sepsis. If the value of base excess <−5 mmol/L without an underlying another reason, may need close follow up of infants for neonatal sepsis and it may help early diagnosis.

Luteinizing hormone concentrations in healthy horses and horses with trigeminal-mediated headshaking over an 8-hour period.

BackgroundTrigeminal‐mediated headshaking results from a low threshold for firing of the trigeminal nerve. A seasonal component has been implicated in onset of clinical signs, which occur during the spring and summer months. Geldings are overrepresented in the affected population and hormonal differences as compared to a healthy control population of geldings might contribute to headshaking.Objective/HypothesisTo assess concentrations of luteinizing hormone (LH) over an 8‐hour period in gelded healthy controls and horses affected with headshaking. Our hypothesis was that geldings with seasonal headshaking would have higher concentrations of LH over an 8‐hour period compared to control horses during the summer when affected horses manifested headshaking.AnimalsTwelve geldings (6 controls and 6 affected).MethodsProspective controlled trial. Blood samples were drawn every 15 minutes over an 8‐hour time period during summer from all horses to measure circulating LH concentrations by using a radioimmunoassay for equine LH. All affected horses were actively affected by headshaking at the time of sample collection.ResultsNo statistically significant differences in LH concentrations were found throughout the study period in headshakers as compared to control horses. Time had no significant effect, but a slight decrease in LH concentrations was observed for all horses. The main limitation of the study was the low number of horses.Conclusions and Clinical ImportanceHorses affected with headshaking did not have significant differences in circulating LH during the late summer as compared to control horses.

Leukoencephalomalacia in horses associated with immature corn consumption

ABSTRACT: Horse leukoencephalomalacia (ELEM) is a disease caused by the ingestion of mycotoxins (fumonisins) produced by fungi of the genus Fusarium that infect corn and/or its byproducts. This disease has been described by ingestion of mature corn with humidity above 15% at temperatures below 20°C. The aim of this paper was to report an outbreak of leukoencephalomalacia in horses fed with immature corn. Two horses out of three showed neurological signs approximately seven days after eating immature corn in its reproductive phase (R2, milky grains). Corn was harvested and administered directly to the animals, with no storage. Deaths occurred approximately 24 hours after the onset of clinical signs. Grossly, there were multifocal dark red to brown areas in the white matter of the telencephalon and hyppocampus and thalamus. Histologically, there was edema and hemorrhage in several areas of the telencephalon white matter, which corresponded to dark red to brown areas observed in the macroscopy. There was also foci of malacia with presence of reactive astrocytes with abundant eosinophilic cytoplasm and inflammatory cells. Diffuse capillary wall degeneration and endothelial cell swelling were also observed. Two ppm of fumonisin were detected by immunoaffinity column method (VICAM) in the immature corn sample. The water activity in this cereal, when the grain is still milky, is 0.98 and can predispose it to growth of mycotoxin-producing fungi. In the present case, fumonisin was found in milky grains in the beginning of the reproductive phase (R2), which suggested that even immature corn may be infected by Fusarium spp. and should not be administered to horses.

Time to Diagnosis of Chronic Lymphocytic Leukemia in a Health System Setting

IntroductionChronic lymphocytic leukemia (CLL) is a low-grade malignancy that is generally indolent and often asymptomatic at presentation. While it can present with anemia, thrombocytopenia, progressive splenomegaly and adenopathy, it is usually diagnosed on routine laboratory studies with confirmatory flow cytometry. Complications of CLL include lack of appropriate immune response and surveillance, which may lead to more frequent infections and the development of second primary neoplasms, most commonly cutaneous malignancies. Prior studies have investigated the time to diagnose CLL from the onset of clinical signs and symptoms. One study looking at the Surveillance, Epidemiology, and End-Results (SEER) database found that the median time to diagnosis from the onset of signs or symptoms was approximately 63 days (1). While early diagnosis may not change the natural history of the disease, it may lead to earlier initiation of preventive strategies such as vaccinations and skin cancer screening. The purpose of this study is to investigate the time to diagnosis of patients with CLL from the onset of lymphocytosis meeting criteria for CLL to confirmatory flow cytometry and its correlation with patient characteristics within a rural health system. Methods A retrospective cohort analysis of patients with CLL who had an absolute lymphocyte count (ALC) greater than 5,000/microL and a flow cytometry was performed within the Geisinger Health System from 1997 to 2018. Patient age, sex, date of first lymphocytosis meeting diagnostic criteria, and date of flow cytometry was electronically extracted from the EMR. This data was then cross-referenced with the cancer registry database for accuracy of the diagnosis. To determine any difference between groups and the time from first ALC meeting criteria to confirmatory flow cytometry performed, the Wilcoxon Two-Sample Test was utilized. Associations between two continuous variables (age and time from first ALC meeting criteria to confirmatory flow cytometry performed, initial lymphocyte count and time from first ALC meeting criteria to confirmatory flow cytometry performed) were measured using the Pearson Correlation Coefficients. Results A total of 268 patients were identified. Univariate statistics are reported in Table 1. The median time from lymphocytosis to flow for our study was 7.5 days (IQR: 0 - 335) with a mean of 347 days (range: 0 - 5335 days). Just over half (53.8%) had a diagnosis within the first two weeks; however, greater than 20% were diagnosed after one year and just over 5% after five years (table 2). There was a positive correlation between age and time from lymphocytosis to flow (r=0.178, p=0.0034). Therefore, an increase in age at diagnosis was associated with an increase in time from initial lymphocytosis to flow. A weak negative correlation was seen between the degree of initial lymphocytosis and time from lymphocytosis to flow (r=-0.105, p=0.0867). Therefore, a lower lymphocyte count was associated with a slightly longer time to diagnosis. There was no significant difference between median time from lymphocytosis to flow in females (7 days IQR: 0 - 510) and males (8 days IQR: 0 - 271) with a p-value 0.4570. Conclusion This study demonstrates that there can be a broad range of time to diagnosis of CLL (figure 1). While gender did not play a significant role, increased age and lower initial lymphocyte value were associated with a delay in diagnosis. Larger studies are needed to include a more diverse population to confirm these predictive associations. Further data analyses are required to assess for co-morbidities and other characteristics in the identified at risk patient groups to help facilitate earlier diagnosis and appropriate preventative measures.

Prevalence of CD20+ cutaneous epitheliotropic T-cell lymphoma in dogs: a retrospective analysis of 24 cases (2011-2018) in the USA.

Limited information is known about the baseline frequency of canine CD20 positive (+ ) cutaneous epitheliotropic T-cell lymphoma. A single canine case report has been published. To characterize the baseline frequency of CD20+ staining in cases of canine cutaneous epitheliotropic T-cell lymphoma; to assess its values as a prognostic indicator. Skin biopsies from 24 client-owned animals diagnosed with cutaneous epitheliotropic lymphoma were assessed. A retrospective review of medical records from 2011 to 2018. Clinical histories and previous histological and immunohistochemical slides were collected from 24 dogs and additional immunohistochemical staining was performed as needed to assess cases of cutaneous epitheliotropic T-cell lymphoma for CD3, CD20, CD79a and PAX5 staining characteristics. Staining characteristics were assessed for their statistical relationship to median survival time. Overall median survival time was 189days following the onset of clinical signs and 99days following definitive diagnosis; 54% of cases had CD20+ staining. There was no statistically significant correlation between staining characteristics and median survival time from onset of signs (P=0.54) or from diagnosis (P=0.61). Canine cutaneous epitheliotropic lymphoma has a higher instance of CD20 positivity than documented previously. This indicates that CD20 staining may be unsuitable to differentiate T-cell and B-cell cutaneous epitheliotropic lymphoma. This also may have therapeutic implications with the advent of canine CD20 monoclonal antibody therapies.

The use of rotational thrombectomy in the treatment of arterial thrombosis

Rotation thrombectomy is a modern method of treating peripheral arterial disease. To date, there are no randomized studies regarding rotational thrombectomy. We want to share our own results in the treatment of patients with arterial thrombosis in the treatment of 8 patients with arteriosclerosis of the lower extremities, complicated by thrombosis using Rotarex. Patients noted the acute onset of the disease, but were referred to the clinic after 2 weeks since the onset of clinical signs of the disease. All patients underwent ultrasound examination, arteriography of the affected arterial segment. After treatment, all patients underwent control angiography. During the procedure, heparin and clopidogrel were administered. One patient had systemic lupus erythematosus. Patients had thrombosis of the femoro-popliteal arterial segments. All patients had a critical ischemia of the lower extremities. Men were 6, women — 2. 2 (25%) of patients had thrombosis of the stent of the superficial femoral artery. In 8 (100%) cases, rotational thrombectomy with rotary catheter was used. For the procedure, catheters with a diameter of 6F and a length of 110–135 cm were used. During the procedure, a catheter was performed from 3 to 5 passages in the affected segment. Duration of the procedure was 1.5–2 hours. In 6 (75%) cases, after the thrombectomy, ballooning of the affected segment was used with a balloon covered with polytaxel. In 8 (100%) patients, there was a clinical improvement. In 8 (100%) patients, control arteriography showed complete patency of the affected segments of the femoral and popliteal arteries. In 8 patients, ischemia was regressed. Cases of rethrombosis were not observed. Thus, rotation thrombectomy is a modern and effective method of treatment of arterial thrombosis of the femoral and popliteal segment.

Superior efficacy of HI-6 dimethanesulfonate over pralidoxime methylsulfate against Russian VX poisoning in cynomolgus monkeys (Macaca fascicularis)

Organophosphorus nerve agents still represent a serious risk to human health. In the French armed forces, the current emergency treatment against OP intoxications is a fully licensed wet-dry dual-chambered autoinjector (Ineurope ®), that contains pralidoxime methylsulfate (2-PAM) to reactivate inhibited acetylcholinesterase (AChE), atropine sulfate (AS) and avizafone chlorhydrate (AVZ). While this treatment is effective against several of the known nerve agents, it shows little efficacy against the Russian VX (VR), one of the most toxic compounds. HI-6 dimethanesulfonate (HI-6 DMS) is an oxime able to reactivate in vitro and in vivo VR-inhibited AChE. To confirm the superiority of HI-6 DMS towards 2-PAM prior to licensing, we compared the two 3-drug-combinations (HI-6 vs 2-PAM, 33 and 18 mg/kg respectively, equimolar doses; AS/AVZ 0.25/0.175 mg/kg respectively) in VR-poisoned cynomolgus macaques, the model required by the French drug regulatory agency. In parallel we performed HI-6 pharmacokinetics analysis using a one compartment model. A better efficacy of the HI-6 DMS combination was clearly observed: up to 5 LD50 of VR (i.m.), a single administration of the HI-6 DMS combination, shortly after the onset of clinical signs, prevented death of the four intoxicated animals. Conversely 2-PAM only prevented death in one out of three subjects exposed to the same amount of VR. As expected with V agents, reinhibition of blood AChE was observed but without any apparent impact on the clinical recovery of the animals. A single administration of the HI-6 DMS combination was still but partially effective at 15 LD50 of VR, allowing a 50% survival rate.

Pathological evaluation of thigh muscle, sciatic nerve, and spinal cord in downer cow syndrome with emphasis on the prognostic significance

To provide more reliable information for predicting prognosis of the downer cow syndrome and expand knowledge of the pathology of this disease, the thigh muscle, sciatic nerve, and spinal cord were investigated histopathologically. Eighteen Holstein-Friesian dairy cows varying in age from 2 to 13 years old (mean 6.3 years old), which presented with either anteparturient or postparturient onset of the downer cow condition, were culled because of poor prognosis. The duration of illness ranged from 1 to 19 days (mean 7.4 days). On histopathological examination, 4 (22%) of the 18 cows did not show any muscle lesions, but the others (78%) with disease duration of ≥ 3 days demonstrated bilateral or unilateral, widespread, obvious degenerative (necrotic) lesions in the thigh muscle. Sciatic nerve of 7 cows (39%) represented no significant lesions, whereas the nerve of the other 11 cows (61%) with disease duration of ≥ 3 days exhibited varying degrees of bilateral or unilateral degeneration of myelinated nerve fibers. This nerve fiber degeneration was identical to Wallerian-type changes of axons. Degenerative lesions in both the thigh muscle and sciatic nerve, which were thought to be extensive and severe to a sufficiently distinctive degree to develop clinical signs, could have occurred following disease duration of ≥ 3 days. Therefore, the possibility that time threshold for the development of the lesions in the thigh muscle and sciatic nerve was at least 3 days after the animals’ recumbency may be raised. Those 3 cows presenting with necrotic muscle lesions showed no lesions in the sciatic nerve, suggesting that, chronologically, the occurrence of sciatic nerve degeneration followed that of muscle lesion. Spinal cord had no significant lesions in 8 cows (44%), whereas in the other10 cows (56%), a minimal degree of axonal degeneration consistent with Wallerian-type degeneration was present in the spinal white matter. This nerve fiber degeneration was considered consistent with that previously documented in otherwise normal spinal cord in mature and aged domestic animals and was unlikely to have been implicated in the development of clinical signs in the present downer cows. With regard to the prevalence rate by lapse of time after the onset of clinical sign, there was no close relationship between the nerve fiber degeneration in the spinal cord and lesions of the thigh muscle and sciatic nerve.

Mutant huntingtin induces iron overload via up-regulating IRP1 in Huntington\u2019s disease

BackgroundIron accumulation in basal ganglia accompanies neuronal loss in Huntington’s disease (HD) patients and mouse disease models. Disruption of HD brain iron homeostasis occurs before the onset of clinical signs. Therefore, investigating the mechanism of iron accumulation is essential to understanding its role in disease pathogenesis.MethodsN171-82Q HD transgenic mice brain iron was detected by using Diaminobenzidine-enhanced Perls’ stain. Iron homeostatic proteins including iron response protein 1 (IRP1), transferrin (Tf), ferritin and transferrin receptor (TfR) were determined by using western blotting and immunohistochemistry, and their relative expression levels of RNA were measured by RT-PCR in both N171-82Q HD transgenic mice and HEK293 cells expressing N-terminal of huntingtin.ResultsIron was increased in striatum and cortex of N171-82Q HD transgenic mice. Analysis of iron homeostatic proteins revealed increased expression of IRP1, Tf, ferritin and TfR in N171-82Q mice striatum and cortex. The same results were obtained in HEK293 cells expressing N-terminal of mutant huntingtin containing 160 CAG repeats.ConclusionWe conclude that mutant huntingtin may cause abnormal iron homeostatic pathways by increasing IRP1 expression in Huntington’s disease, suggesting potential therapeutic target.

The inflammatory response and neuronal injury in Streptococcus suis meningitis

BackgroundMany of the currently used models of bacterial meningitis have limitations due to direct inoculation of pathogens into the cerebrospinal fluid or brain and a relatively insensitive assessment of long-term sequelae. The present study evaluates the utility of a Streptococcus (S.) suis intranasal infection model for the investigation of experimental therapies in meningitis.MethodsWe examined the brains of 10 piglets with S. suis meningitis as well as 14 control piglets by histology, immunohistochemistry and in-situ tailing for morphological alterations in the hippocampal dentate gyrus and microglial activation in the neocortex.ResultsIn piglets with meningitis, the density of apoptotic neurons was significantly higher than in control piglets. Moreover, scoring of microglial morphology revealed a significant activation of these cells during meningitis. The slight increase in the density of dividing cells, young neurons and microglia observed in piglets suffering from meningitis was not statistically significant, probably because of the short time frame between onset of clinical signs and organ sampling.ConclusionsThe morphological changes found during S. suis meningitis are in accordance with abnormalities in other animal models and human autopsy cases. Therefore, the pig should be considered as a model for evaluating effects of experimental therapeutic approaches on neurological function in bacterial meningitis.