Lithium for acute mania.

BACKGROUND: Bipolar disorder is a common condition associated with high morbidity; developing efficacious, safe treatments is therefore essential. Lithium is an effective maintenance treatment for bipolar disorder. It acts as mood stabiliser and reduces the risk of suicide. However, evidence assessing the efficacy of lithium in the treatment of acute mania is less robust. Current evidence-based guidelines cite multiple anti-dopaminergic and mood-stabilising agents as initial treatments: more definite evidence is needed to decide if lithium should be the first-line therapy. OBJECTIVES: 1. To assess the effects of lithium in comparison with placebo or other active treatment in alleviating the acute symptoms of a manic or mixed episode in people with bipolar disorder.2. To review the acceptability and tolerability of treatment with lithium in comparison with placebo or other active treatments in alleviating the acute symptoms of a manic or mixed episode in people with bipolar disorder. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Controlled Trials Register, CENTRAL, MEDLINE, Embase, and PsycINFO. We also searched the World Health Organization trials portal (ICTRP) and ClinicalTrials.gov. We checked the reference lists of all included studies and relevant systematic reviews. We have incorporated studies from searches to 18 May 2018 into the current analyses. SELECTION CRITERIA: Prospective randomised controlled studies comparing lithium with placebo or alternative drug treatment in treatment of acute mania. We included anyone with bipolar disorder, male and female, of any age. DATA COLLECTION AND ANALYSIS: At least two review authors independently extracted data and assessed methodological quality. We used odds ratios (ORs) to analyse binary efficacy outcomes, and mean differences (MDs) or standardised mean differences (SMDs) for continuously distributed outcomes. We used a fixed-effect model unless heterogeneity was moderate or substantial, in which case we used a random-effects model. We used Review Manager 5 to analyse data. We assessed the certainty of evidence for individual outcomes using the GRADE approach. MAIN RESULTS: We found 36 randomised controlled studies comparing lithium with placebo, one of 12 drugs, or electroconvulsive therapy for treatment of acute mania. Studies included male and female participants (n = 4220), of all ages, who all fitted criteria for a manic episode within the context of a diagnosis of bipolar disorder.Risk of bias was variable; 12 studies had a high risk of bias in one domain and 27 gave inadequate information on randomisation leading to an 'unclear' rating for selection bias.Lithium versus placeboHigh-certainty evidence found that lithium was an effective treatment for acute mania and was more effective than placebo at inducing a response (OR 2.13, 95% confidence interval (CI) 1.73 to 2.63; participants = 1707; studies = 6; I2 = 16%; high-certainty evidence), or remission (OR 2.16, 95% CI 1.73 to 2.69; participants = 1597; studies = 5; I2 = 21%; high-certainty evidence).Lithium was more likely than placebo to cause tremor (OR 3.25, 95% CI 2.10 to 5.04; participants = 1241; studies = 6; I2 = 0%; high-certainty evidence), and somnolence (OR 2.28, 95% CI 1.46 to 3.58; participants = 1351; studies = 7; I2 = 0%; high-certainty evidence).There was insufficient evidence to determine the effect of lithium for all-cause dropouts (OR 0.76; 95% CI 0.46 to 1.25; participants = 1353; studies = 7; I2 = 75%; moderate-certainty evidence), and weight gain (OR 1.48, 95% CI 0.56 to 3.92; participants = 735, studies = 3; I2= 51%; moderate-certainty evidence).Lithium versus antipsychotics or mood stabilisersFor the outcome of inducing a response, there was only very low-certainty evidence regarding lithium compared to haloperidol (MD -2.40, 95% CI -6.31 to 1.50; participants = 80; studies = 3; I2 = 95%), quetiapine (OR 0.66, 95% CI 0.28 to 1.55; participants = 335; studies = 2; I2 = 71%), and carbamazepine (SMD 0.21, 95% CI -0.18 to 0.60; participants = 102; studies = 3; I2 = 0%).Lithium was probably less likely to induce a response than olanzapine (OR 0.44, 95% CI 0.20 to 0.94; participants = 180; studies = 2; I2 = 0%; moderate-certainty evidence).Lithium may be less likely to induce a response than risperidone (MD 7.28, 95% CI 5.22 to 9.34; participants = 241; studies = 3; I2 = 49%; low-certainty evidence).There was no evidence of a difference between lithium and valproate (OR 1.22, 95% CI 0.87 to 1.70; participants = 607; studies = 5; I2 = 22%; moderate-certainty evidence).There was moderate-certainty evidence that lithium was more effective than topiramate at treating acute mania (OR 2.28, 95% CI 1.63 to 3.20; participants = 660; studies = 1).Data on adverse events for these comparisons contained too few studies to provide high-certainty evidence. AUTHORS' CONCLUSIONS: This systematic review indicates that lithium is more effective than placebo as a treatment for acute mania but increases the risk for somnolence and tremor. Limited evidence suggests little or no difference between lithium and other mood stabilisers (valproate, carbamazepine) or antipsychotics (risperidone, quetiapine, haloperidol). Olanzapine may be an exception, as it is probably slightly more effective than lithium. There is uncertain evidence that risperidone may also be more effective than lithium. Lithium is probably more effective at treating acute mania than topiramate. When compared to placebo, lithium was more likely to cause adverse events. However, when compared to other drugs, too few studies provided data on adverse effects to provide high-certainty evidence. More, rigorously designed, large-scale studies are needed to definitively conclude if lithium is superior to other interventions in treating acute mania.

Safety evaluation of orally administered afoxolaner and milbemycin oxime in eight-week-old dogs.

The safety profile of afoxolaner (an isoxazoline molecule) when combined with milbemycin oxime (a macrocyclic lactone) was evaluated according to the regulatory requirements when administered six times orally in a soft chewable formulation at a dose of at least 1×, 3×, or 5× the maximum exposure dose in 8-week-old Beagle dogs. Thirty-two healthy puppies (16 males and 16 females) were enrolled and allocated randomly to one of four treatment groups. Three doses were administered at 28-day intervals (Days 0, 28, and 56), followed by three additional doses administered with 14-day intervals (Days 84, 98, and 112). The study ended on Day 126. Treatment groups were as follows: Group 1: untreated, sham-dosed control; Group 2: afoxolaner/milbemycin oxime chews administered at a dose of at least 5 and 1 mg/kg, respectively (1×); Group 3: afoxolaner/milbemycin oxime chews administered at a dose of at least 15 and 3 mg/kg, respectively (3); and Group 4: afoxolaner/milbemycin oxime chews administered at a dose of at least 25 and 5 mg/kg, respectively (5×). All dogs were examined for general health twice a day beginning on Day -14. Physical examinations, and blood collections for clinical pathology analysis and afoxolaner and milbemycin oxime plasma concentrations, were performed throughout the study. No afoxolaner/milbemycin oxime treatment-related changes were observed in growth, physical variables, clinical pathology variables, or tissues examined histologically. No clinically relevant or statistically significant health abnormalities related to the administration of afoxolaner/milbemycin oxime were observed. No signs of macrocyclic lactone sensitivity were observed at any time during the study. Vomiting and diarrhea were observed sporadically across all groups including the controls. Based upon the results of this study, afoxolaner/milbemycin oxime soft chewables were shown to be safe when administered repeatedly at up to 5× the maximum exposure dose in dogs as young as 8 weeks of age.

Integrative veterinary medical education and consensus guidelines for an integrative veterinary medicine curriculum within veterinary colleges.

Integrative veterinary medicine (IVM) describes the combination of complementary and alternative therapies with conventional care and is guided by the best available evidence. Veterinarians frequently encounter questions about complementary and alternative veterinary medicine (CAVM) in practice, and the general public has demonstrated increased interest in these areas for both human and animal health. Consequently, veterinary students should receive adequate exposure to the principles, theories, and current knowledge supporting or refuting such techniques. A proposed curriculum guideline would broadly introduce students to the objective evaluation of new veterinary treatments while increasing their preparation for responding to questions about IVM in clinical practice. Such a course should be evidence-based, unbiased, and unaffiliated with any particular CAVM advocacy or training group. All IVM courses require routine updating as new information becomes available. Controversies regarding IVM and CAVM must be addressed within the course and throughout the entire curriculum. Instructional honesty regarding the uncertainties in this emerging field is critical. Increased training of future veterinary professionals in IVM may produce an openness to new ideas that characterizes the scientific method and a willingness to pursue and incorporate evidence-based medicine in clinical practice with all therapies, including those presently regarded as integrative, complementary, or alternative.

A kinetic study of histopathological changes in the subcutis of cats injected with non-adjuvanted and adjuvanted multi-component vaccines.

The aim of this study was to investigate the subcutaneous tissue response to administration of a single dose of multi-component vaccine in the cat. Three groups of 15 cats were injected with one of three vaccine products with saline as a negative control. Cats in group A received non-adjuvanted vaccine; cats in group B received vaccine with a lipid-based adjuvant; whilst those in group C were vaccinated with a product adjuvanted with an alum-Quil A mixture. The vaccine and saline injection sites were sampled on days 7, 21 and 62 post-vaccination. Biopsies of these vaccine sites were examined qualitatively and scored semi-quantitatively for a series of parameters related to aspects of the inflammatory and tissue repair responses. These data were analysed statistically, including by principal component analysis. At all three time points of the experiment, there was significantly less inflammation associated with administration of non-adjuvanted vaccine (p=0.000). Although there was evidence of tissue repair by day 62 in all groups, those cats receiving adjuvanted vaccines had evidence of residual adjuvant material accumulated within macrophages at this late time point. The severity of tissue reactions may vary significantly in response to vaccines which include adjuvants or are non-adjuvanted.

Inhalation developmental toxicity and reproduction studies with cyclohexane.

The reproductive and developmental toxicity of cyclohexane was assessed in a two-generation reproduction study with Crl:CD BR rats and in developmental toxicity studies with Crl:CD BR rats and Hra:(NZW)SPF rabbits. The animals were exposed whole-body to atmospheric concentrations of 0, 500, 2000, or 7000 ppm cyclohexane. In the two-generation reproduction study, parental effects included statistically significantly lower mean body weight, overall mean body weight gain, and overall mean food efficiency for P1 and F1 females of the 7000 ppm level and statistically significantly lower mean body weight for F1 males of that level. Adult rats exposed to 2000 ppm cyclohexane and above exhibited a transient diminished or absent response to a sound stimulus while in the chambers during exposure. Mean pup weight was statistically significantly lower than control from lactation day 7 throughout the remainder of the 25-day lactation period for both F1 and F2 7000 ppm litters. Changes observed at 500 ppm were either considered not to be compound related or not adverse. Therefore, the systemic-toxicity no-observed-effect level (NOEL) was 500 ppm and the reproductive NOEL was 2000 ppm. The reproductive NOEL was based solely on the decreased pup weights in both the F1 and F2 generations observed at 7000 ppm. In the developmental toxicity studies, only the rats showed evidence of maternal toxicity. For rats in the 7000 ppm group, statistically significant reductions were observed in overall maternal body weight gain and overall maternal food consumption for the treatment period. Rats exposed to 2000 ppm cyclohexane and above again exhibited a transient diminished or absent response to a sound stimulus while in the chambers during exposure. Therefore, for rats, the maternal no-observed-effect level (NOEL) was 500 ppm. In the rabbit developmental toxicity study, no compound-related maternal effects were observed at concentration levels of 7000 ppm and below. Therefore, the maternal NOEL for rabbits was 7000 ppm. No compound-related evidence of developmental toxicity was observed at any test concentration in either species. Therefore, the developmental NOEL for both species was 7000 ppm, the highest concentration tested.

Malignant angioendotheliomatosis with retinal detachments in a dog.

A Golden Retriever with bilateral conjunctival hyperemia, chemosis, and blepharospasm was determined to have malignant angioendotheliomatosis, which is an uncommon neoplastic disorder of dogs and human beings. It was believed to be of endothelial origin, but evidence in human beings indicates a lymphoid origin. The histogenesis of the disease in the dog was confirmed to be of lymphoid origin by use of a canine lymphoma-specific immunoperoxidase assay. The prognosis for malignant angioendotheliomatosis in dogs is poor, but with early diagnosis, the condition is potentially manageable.

Use of a bovine hemoglobin preparation in the treatment of cyclic ovarian hemorrhage in a miniature horse.

Anemia that was secondary to ovarian hemorrhage in a 4-year-old miniature horse mare was treated prior to laparotomy with polymerized ultrapurified bovine hemoglobin (PUBH). Two previous whole-blood transfusions had resulted in acute transfusion reaction, and a suitable blood donor could not be found among 9 horses, necessitating use of the blood substitute. Subsequent blood typing revealed the mare to be Aa-negative, with allo-antibodies against Aa in serum. Serious adverse reactions were not observed after infusion of PUBH, and the mare recovered. Although the safety and efficacy of using PUBH in horses has not been established, PUBH may prove to be an excellent alternative to whole-blood transfusions, when indicated.

Ocular lymphangiosarcoma in a cow.

Ocular lymphangiosarcoma was diagnosed in a Holstein cow with a progressively enlarging limbal mass. The cow was treated by exenteration. The cow survived for 2 years without clinical signs of recurrence. Lymphangiosarcoma is a vascular neoplasm that rarely has been reported in domestic animals. In other species, it has a high rate of metastasis and is associated with poor long-term survival.

Clinical and clinicopathologic findings in two foals infected with Bacillus piliformis.

Bacillus piliformis infection (Tyzzer's disease) in foals is rarely observed clinically because of the peracute course of the disease. Clinical and clinicopathologic findings as well as information on therapeutic attempts in two foals are described. Clinicopathologic abnormalities common to both cases included leukopenia, hyperfibrinogenemia, metabolic acidosis, and hypoglycemia. Treatment was unsuccessful in both cases.

Disseminated hemangiosarcoma in a horse.

A 6.5-year-old horse with a history of exercise-induced pulmonary hemorrhage was admitted because of acute onset of epistaxis, dyspnea, high respiratory rate, pale mucous membranes, and dark feces. There was no clinical or laboratory evidence of a bleeding disorder, and the horse's anemia was considered to be secondary to pulmonary hemorrhage. The cause of the hemorrhage was not found on thoracic sonograms or from cytologic examination of transtracheal aspirates. Despite supportive care, the horse's health deteriorated, and it was euthanatized. Necropsy revealed blood in the thoracic and peritoneal cavities and reddish black masses in many tissues. Histologic examination confirmed a diagnosis of hemangiosarcoma. Hemangiosarcoma is a rare tumor in horses; however, as this case demonstrates, it can cause pulmonary hemorrhage and respiratory distress and may be difficult to diagnose before death.

Equine juvenile mandibular ossifying fibroma.

Benign proliferative fibro-osseous lesions of the rostral mandible in six young horses are classified as equine juvenile mandibular ossifying fibroma. Histologically there is a characteristic abrupt transition from subgingival fibroblastic stroma to a zone of proliferating osteoblasts that form irregular spicules of osteoid. The layer of proliferating osteoblasts blends with a deeper zone of bony trabeculae rimmed by osteoblasts and separated by intertrabecular spaces of moderate cellular density. Incomplete surgical excision resulted in local recurrence, while rostral mandibulectomies resulted in no recurrence. The predilection for the rostral mandible of young horses coupled with the similar clinical, radiographic, and histological characteristics supports the classification of this lesion as a distinct entity.

Multicentric papillary cystadenoma in the udder of a cow.

A mammary gland neoplasm was identified at necropsy in a 9-year-old ovariectomized Holstein cow with a 1-year history of an enlarged left hindquarter. A sterile serous secretion was expressed from the quarter. The cow developed Corynebacterium pyogenes infection in the quarter one year later and died of secondary complications. The left hindquarter was found to contain multiple cysts. The histologic diagnosis was multicentric papillary cystadenoma.

Ciliated protozoa in the colonic wall of horses.

Ciliated protozoa of several morphological types were found in the colonic tissue of 8 horses, mostly immature Standardbreds. Most of the protozoa observed appeared similar to those normally found as commensals in the equine large intestinal lumen. In all cases, organisms were located in the lamina propria; organisms were also found in the submucosa of 2 horses. The association of colonic disease with the presence of intramural ciliates was unclear.

Omental fibrosarcoma in a horse.

A 13-year-old Thoroughbred mare had a 2-week history of weight loss and intermittent fever. Examination of abdominal and pleural fluid revealed peritonitis and pleuritis. Ultrasonography of the ventral abdominal midline revealed an intra-abdominal mass. Exploratory celiotomy was performed, but the mass was not surgically excisable. The mare was euthanatized and necropsied. Histologically, the mass was determined to be a fibrosarcoma of omental origin.

Pleuroscopic diagnosis of gastroesophageal squamous cell carcinoma in a horse.

A 15-year-old Quarter Horse gelding was examined because of chronic intermittent colic of 40 days' duration. The clinical signs included acute onset of depression, ptyalism, abdominal splinting, and rolling within an hour of eating. An intramural mass of the esophagus was identified during esophagoscopy. A large soft-tissue density surrounding the distal portion of the esophagus, creating a stricture, was identified on an esophagogram. With the horse slightly sedated, pleuroscopy was performed, allowing direct visualization and biopsy of the mass. The histopathologic diagnosis was squamous cell carcinoma.

Metastasis of a well-differentiated liposarcoma in a dog and a note on nomenclature of fatty tumours.

A slow-growing mass in the left thigh of a 7-year-old spayed female fox terrier dog was originally diagnosed as an infiltrative lipoma by surgical biopsy. Necropsy findings one year later revealed multiple masses made up of well-differentiated adipocytes in the spleen, liver, lungs and a lymph node. The final histopathological diagnosis of these masses and, in retrospect, for the initial leg mass was well-differentiated liposarcoma. This case illustrates some of the confusion in current nomenclature of fatty tumours. Tumours made up of well-differentiated adipose cells which show no tendency toward invasion of surrounding tissue should be designated lipomas. We suggest that fatty tumours characterized by local tissue invasion and/or metastasis should be classified as liposarcomas. Liposarcomas may be further subdivided into well-differentiated and poorly-differentiated types.

Chronic granulomatous bowel disease in three sibling horses.

Chronic granulomatous bowel disease was diagnosed in 3 sibling Standardbred horses. Clinical signs included weight loss, loose feces, and decreased appetite in the terminal stage of the disease. Abnormal laboratory findings included hypoproteinemia and low xylose absorption. Necropsy revealed granulomatous inflammation of the intestines, mesenteric lymph nodes, and liver. Eosinophilic infiltration of the granulomatous lesions was a prominent finding in one horse. A causative agent was not detected by special histochemical staining or bacteriologic culturing.

Pigeon herpesvirus: inclusion body hepatitis in a free-ranging pigeon.

An adult male pigeon (Columba livia) was presented to the Wildlife Service at the University of Pennsylvania School of Veterinary Medicine for depression, cachexia, and diarrhea. Five days after the initial presentation, the bird died and was necropsied. Gross lesions included opaque air sacs and multiple 1-mm yellow-white foci on the epicardial surface of the heart. Histopathologic lesions included a pericarditis, epicarditis, and multifocal hepatic necrosis accompanied by eosinophilic inclusion bodies. Ultrastructural examination of the hepatic inclusions revealed viral particles consistent with a herpesvirus. The gross, light microscopic, and electron microscopic findings are consistent with pigeon herpesvirus infection.