Oxidative DNA damage in reconstituting T cells is associated with relapse and inferior survival after allo-SCT.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the only curative treatment option for a number of hematologic malignancies. Its therapeutic potential relies on the potency of donor T cells to eliminate residual malignant cells, the so-called graft-versus-leukemia (GVL) effect. Disease relapse remains the most frequent treatment failure and is associated with poor outcome. Therefore, it is inevitable to decipher mechanisms that weaken GVL. In recent years, studies of tumor biology have revealed that metabolic remodeling of the micromilieu can critically regulate immune responses. Accumulation of reactive oxygen species leads to a metabolic condition known as oxidative stress, which can severely hamper T cells. Currently, only a few studies, mainly using preclinical models, have demonstrated the occurrence of oxidative stress after allo-SCTs. Therefore, we sought to investigate oxidative stress in a well-characterized group of patients who underwent allo-SCT and its impact on reconstituting T cells. We identified high concentrations of serum 8-hydroxydeoxyguanosine (8-OHdG) as an established biomarker for oxidative stress. 8-OHdG is one of the major products of DNA oxidation, which is normally rapidly removed. After allo-SCT, T cells accumulated oxidative DNA damage. High cellular 8-OHdG content (8-OHdGhi) was associated not only with signs of enhanced T-cell activation but also premature exhaustion. The inability of 8-OHdGhi T cells to efficiently target malignant cells or produce cytotoxic granzyme B and interferon gamma was associated with a significantly increased relapse risk and a shorter overall survival. Taken together, our novel findings could give reason to focus on bolstering DNA repair in reconstituting T cells as a means to improve GVL efficacy.

Setaria tundra in a roe deer (Capreolus capreolus) in the Donau-Ries district of Bavaria, Germany.

INTRODUCTION: Setaria tundra is known as a common parasite of sylvatic ungulates in Northern latitudes. Although mostly considered of low pathogenicity, severe disease outbreaks and remarkable economic losses have been observed in reindeer (Rangifer tarandus tarandus). Host density and climatic factors are major drivers of the expansion of Setaria spp. facilitating their development and spread. Five adult specimens of S. tundra were retrieved from a male roe deer in Bavaria, Germany. Deoxyribonucleic acid (DNA) barcoding confirmed morphological identification. Cyclooxygenase 1 gene sequences showed 98,73-99,68 % similarity to sequences of other S. tundra specimens found in deer (Cervidae) and mosquitoes (Culicidae). The results raise awareness for the presence of S. tundra in a hitherto unkown endemic region and represent a starting point for broader investigations to understand the biology and distribution of this parasite in roe deer as well as other potential definitive hosts.

INTRODUCTION: Setaria toundra est connu comme un parasite commun des ongulés sylvatiques aux latitudes septentrionales. Bien que généralement considéré comme faiblement pathogène, de graves épidémies et des pertes économiques significatives ont été observées chez le renne (Rangifer tarandus tarandus). La densité d'hôtes et les facteurs climatiques sont les principaux moteurs de l'expansion de Setaria spp., facilitant leur développement et leur diffusion. Cinq spécimens adultes de S. toundra ont été récupérés sur un chevreuil mâle en Bavière, en Allemagne. Le séquençage de l'acide désoxyribonucléique (ADN) a confirmé l'identification morphologique. Les séquences du gène de la cyclooxygénase 1 ont montré une similarité de 98,73 à 99,68 % avec les séquences d'autres spécimens de S. toundra trouvés chez les cerfs (Cervidae) et les moustiques (Culicidae). Les résultats sensibilisent à la présence de S. toundra dans une région endémique jusqu'alors inconnue et représentent un point de départ pour des investigations plus larges pour comprendre la biologie et la distribution de ce parasite chez le chevreuil ainsi que d'autres hôtes définitifs potentiels.

Prevalence of disorders in preweaned dairy calves from 731 dairies in Germany: A cross-sectional study.

The objective of this cross-sectional study was to determine the prevalence of disorders in preweaned calves in 3 regions in Germany, exemplary for structural diversity in dairy farming. A farm visit was performed on a single occasion on 731 dairy farms in the northern, eastern, and southern regions of Germany between December 2016 and July 2019. Farms differed in herd size, geographical location, and management. In the northern region, the farms had a median of 90 milking cows and were often run as full-time family businesses, partly with external workers. The eastern region tended to have larger farms (a median of 251 milking cows), which were often large-scale agricultural enterprises with employees. In the southern region, the farms had a median of 39 milking cows and were often traditional family businesses, some of these being part-time businesses. Clinical examinations were performed on 14,164 preweaned dairy calves (median 12 calves per farm) by trained veterinarians. A complete data set was available for 13,656 calves. Almost half (42.0%) of the evaluated calves were classified as being affected by at least 1 of the common calf disorders. Omphalitis (O, 20.9%; n = 2,876) and diarrhea (D, 18.5%; n = 2,670) were the most frequently recorded diagnoses, whereas respiratory diseases (RD) were observed to a lesser extent (8.7%; n = 1,100). A striking feature was the fact that 7.1% (n = 987) of the calves were affected by more than 1 disorder at the same time (multimorbidity, M). The following combinations of disorders were frequently observed: O and D (n = 596), O and RD (n = 164), and D and RD (n = 140). Disorders such as O and D, as well as M, were predominantly observed in calves aged 2 wk. A gradual increase in the frequency of RD was observed with age. For all disorders except RD, male calves were more often affected than females. Omphalitis was predominantly diagnosed in the summer months, whereas RD, D, and M were more common in the fall. We detected several statistically significant differences in the prevalence of clinical signs and disorders in preweaned dairy calves between the 3 exemplary regions. The prevalence of RD was higher in the south (10.8%) than in the north (8.2%) and east (7.4%). In the north (33.2%), O was observed more frequently than in the other regions (east: 18.9%; south: 10.5%), whereas D was found less frequently in the north (13.8%) than in the east (21.6%) and south (20.0%).

CD137 (4-1BB) stimulation leads to metabolic and functional reprogramming of human monocytes/macrophages enhancing their tumoricidal activity.

Immunotherapies have heralded a new era in the cancer treatment. In addition to checkpoint inhibitors, agonistic antibodies against co-stimulatory immune receptors hold the potential to invoke efficient antitumor immunity. Targeting CD137 has gained momentum based on its ability to drive NK- and T-cell-based responses. CD137-engaging mAbs have already entered clinical trials for different types of tumors showing promising results. Despite the efforts to translate CD137-mediated immunotherapy into clinical practice, little remains known regarding the role of CD137 in human monocytes/macrophages.We found CD137 being expressed on monocytes of healthy controls and at even higher levels in patients with multiple myeloma or CLL. CD137HI(GH) monocytes displayed a distinct phenotypic, transcriptomic, and metabolic profile. They possessed an increased phagocytic capacity enabling superior antibody-dependent phagocytosis (ADPC) of multiple myeloma and lymphoma cells that were treated with anti-CD38 or anti-CD20 mAbs. Triggering CD137 promoted both metabolic and tumoricidal activity in an extracellular signal-regulated kinase (ERK)-dependent fashion. In addition, we observed a phenotypic, transcriptomic, and functional skewing towards a M1-like phenotype.Overall, we introduce CD137 as a positive immune checkpoint on human monocytes/macrophages, which can have therapeutic implications especially in view of synergistic effects when combining CD137 agonists with tumor-targeting antibodies.

Malignant Cutaneous Peripheral Nerve Sheath Tumour with Rhabdomyosarcomatous Differentiation (Triton Tumour) in a Domestic Cat.

Divergent differentiation is encountered frequently within human malignant peripheral nerve sheath tumours (MPNSTs). The new component is often a rhabdomyosarcoma, but in animals this specific form of divergent differentiation within MPNSTs has only been reported once (in a dog). Incisional wedge biopsy of a locally extensive, ventral abdominal wall mass, which extended from the dermis to the subcutis, from a 12-year-old female domestic shorthaired cat, was performed. The tissue was examined with routine haematoxylin and eosin staining and immunohistochemical methods. A malignant neoplasm with spindle and polygonal cell components and progression towards a rhabdomyosarcomatous phenotype was observed. Both neoplastic cell populations exhibited strong expression of vimentin and there was multifocal expression of S100 and desmin. There was strong cytoplasmic labelling for α-sarcomeric actin and muscle actin and weak labelling for myoglobin within the cells positive for desmin. There was multifocal positive nuclear labelling for myogenin. Glial fibrillary acidic protein, α-smooth muscle actin, microphthalmia-associated transcription factor and melanoma antigen recognized by T cells were not expressed. Microscopical features, aided by immunohistochemistry, identified a MPNST with progression towards a rhabdomyosarcomatous phenotype, a so-called 'triton tumour'. A Schwann cell component could account for the divergent patterns of growth, given the plasticity of the neural crest. Nerve sheath tumours have been reported in the skin and subcutis of cats and are a differential diagnosis of feline cutaneous spindle cell neoplasms.

Clinicopathologic Features and Magnetic Resonance Imaging Findings in 24 Cats With Histopathologically Confirmed Neurologic Feline Infectious Peritonitis.

BACKGROUND: Feline infectious peritonitis (FIP) is the most common infectious central nervous system (CNS) disease in the cat and is invariably fatal. Improved means of antemortem diagnosis is required to facilitate clinical decision making. Information regarding the magnetic resonance imaging (MRI) findings of neurologic FIP currently is limited, resulting in the need for better descriptions to optimize its use as a diagnostic tool. OBJECTIVE: To describe the clinicopathologic features and MRI findings in cases of confirmed neurologic FIP. ANIMALS: Twenty-four client-owned cats with histopathologic confirmation of neurologic FIP. METHODS: Archived records from 5 institutions were retrospectively reviewed to identify cases with confirmed neurologic FIP that had undergone antemortem MRI of the CNS. Signalment, clinicopathologic, MRI, and histopathologic findings were evaluated. RESULTS: Three distinct clinical syndromes were identified: T3-L3 myelopathy (3), central vestibular syndrome (7), and multifocal CNS disease (14). Magnetic resonance imaging abnormalities were detected in all cases, including meningeal contrast enhancement (22), ependymal contrast enhancement (20), ventriculomegaly (20), syringomyelia (17), and foramen magnum herniation (14). Cerebrospinal fluid was analysed in 11 cases; all demonstrated a marked increase in total protein concentration and total nucleated cell count. All 24 cats were euthanized with a median survival time of 14 days (range, 2-115) from onset of clinical signs. Histopathologic analysis identified perivascular pyogranulomatous infiltrates, lymphoplasmacytic infiltrates, or both affecting the leptomeninges (16), choroid plexuses (16), and periventricular parenchyma (13). CONCLUSIONS AND CLINICAL IMPORTANCE: Magnetic resonance imaging is a sensitive means of detecting neurologic FIP, particularly in combination with a compatible signalment, clinical presentation, and CSF analysis.

Retrospective evaluation of COX-2 expression, histological and clinical factors as prognostic indicators in dogs with renal cell carcinomas undergoing nephrectomy.

Limited veterinary literature is available regarding prognostic markers for canine renal cell carcinoma (CRCC). We retrospectively evaluated COX-2 expression, histological and clinical features associated with prognosis of CRCC. Sixty-four cases post-nephrectomy were included, 54 had histopathological assessment and 30 had COX-2 immunostaining performed. Eight dogs (13%) had metastatic disease at initial diagnosis. Twenty-seven dogs (42%) received adjuvant therapy after nephrectomy. On univariate analysis, COX-2 expression, mitotic index (MI), histologic type, vascular invasion, neoplastic invasiveness and metastasis at diagnosis were significantly associated with overall median survival time (MST). COX-2 score (COX-2 score > 3 MST 420 days versus 1176 days if COX-2 score <3; P = 0.011) and MI (MI > 30 MST 120 days versus 540 days for MI < 30; P = 0.003) were the only variables associated with CRCC outcome on multivariate analysis. The addition of MI and COX-2 immunostaining to standard histopathological evaluation would help predicting outcome in CRCC patients.

Existence of bovine neonatal pancytopenia before the year 2005? Retrospective evaluation of 215 cases of haemorrhagic diathesis in cattle.

Haemorrhagic diathesis (HD) in cattle is a relatively rare syndrome that can have many different causes. With the occurrence of bovine neonatal pancytopenia (BNP) in 2007, the number of cases of HD in cattle has increased. This led to an enhanced interest in diseases presenting with bleeding disorders. The possible causes of HD in cattle, the clinical findings, and the course of various diseases are described and evaluated. Furthermore, we determined whether cases of BNP occurred before the introduction of the vaccine Pregsure BVD since its widespread use was associated with the syndrome. Records of 215 cases of HD in cattle that had been referred to the Clinic for Ruminants with Ambulatory and Herd Health Services at the Centre for Clinical Veterinary Medicine, Ludwig Maximilian University, Munich, between 1982 and 2014 were evaluated. The two most commonly diagnosed diseases were BNP (n = 95) and septicaemia (n = 35), with fatality rates of 82% and 66%, respectively. In 27 (13%) cases, no clear cause for the HD could be designated. Statistically significant differences were found with regard to the course of the various disorders and the clinical findings. A receiver operating characteristic analysis of thrombocyte counts of affected animals at the time of arrival at the clinic did not provide any predictive information on disease outcome. Two cases of HD occurred before the introduction of Pregsure BVD (1989, 1991). In both cases, clinical, haematological, and pathological findings were identical to BNP. The cause of HD in these two cases could not be determined retrospectively.

WITHDRAWN: Clinical Signs, Neuroanatomical Distribution and Histopathological Characterisation of Meningoencephalitis in Wild Red Foxes (Vulpes vulpes) Associated with a Novel fox Circovirus.

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

Experimental analysis of the mechanical behavior of the viscoelastic porcine pancreas and preliminary case study on the human pancreas.

The aim of this article is to study the mechanical properties of the pancreas. Up to now, the mechanical properties of the pancreas are not sufficiently characterized. The possibility of intraoperative mechanical testing of pathological pancreata will allow the classification of pancreatic diseases in the future. The application of mechanical parameters instead of the intraoperative frozen section analysis shortens waiting times in the operating room. This study proves the general applicability of shear rheology for the determination of the mechanical properties of pancreas and the assessment of graft quality for transplantation. Porcine and human pancreas samples were examined ex vivo and a nonlinear viscoelastic behavior was observed. Pancreas was found to be more viscous than liver but both abdominal organs showed a similar flow behavior. The shear deformation dependence of healthy human pancreas was similar to porcine pancreas. An increase in the post-mortem time led to an increase in the complex modulus for a post-mortem time up to 8.5 days. Histological investigations showed that an increased amount of collagen coincides with the stiffening of the pancreatic tissue.

[Nasal, pulmonary, and abomasal aspergillosis (Aspergillus fumigatus) in a calf]. / Nasale, pulmonale und abomasale Aspergillose (Aspergillus fumigatus) bei einem Kalb.

This study presents a case of nasal aspergillosis in a 17-days old calf (German Fleckvieh): it had been admitted moribund to the Clinic for Ruminants of the University of Munich, and died after a short time. Pathologically, the calf was diagnosed with purulent-necrotizing rhinitis, necrotizing pneumonia, and diphtheroid-necrotizing abomasitis. Histologically, fungal elements were found in all the localizations mentioned before, and mycologically, Aspergillus fumigatus was cultured from nasal cavity. Pathogenesis is discussed.

[Squamous cell carcinomas of the ear: factors of gravity and surgical treatment, about 30 cases]. / Carcinomes spinocellulaires de l'oreille : facteurs de gravité et traitement chirurgical, à propos de 30 cas.

INTRODUCTION: Squamous cell carcinomas (SCC) of the ear are known for their aggressiveness. The aim of this study was to investigate factors of gravity while freeing the therapeutic requirements. PATIENTS AND METHODS: This is a retrospective study of 28 patients (30 ears) operated for SCC. The characteristics of the lesion, the presence of metastasis, treatment modalities and histologic findings were collected. Local recurrences and metastasis are identified with a mean follow-up time of 37months (17-110months). RESULTS: The lesion size was less than 2cm in 19 cases (63.3%) and greater than or equal to 2cm in 11 cases (36.7%). Macroscopic resection margins were 5, 7 or 10mm. The resections were histologically incomplete in 4 cases (13%) requiring further surgery. Six cases had local recurrence (20%): three with pulmonary or lymph node metastases (10%) and one death (3.3%). In these 6 cases of recurrence, the surgical margins were 6.3mm on average, the initial lesion measured always greater than 2cm (100%). Three quarters of incomplete resections have recurrent despite a surgical revision in healthy margin. CONCLUSION: Our study confirms the data of literature, namely the pejorative character of a lesion greater than 2cm and incomplete resection. The HAS recommendations seem minimal regarding the ear. In case of injury by more than 2cm and with a proximal location on the ear pinna, only amputation of the ear allows satisfactory cancer control.

How preservation time changes the linear viscoelastic properties of porcine liver.

The preservation time of a liver graft is one of the crucial factors for the success of a liver transplantation. Grafts are kept in a preservation solution to delay cell destruction and cellular edema and to maximize organ function after transplantation. However, longer preservation times are not always avoidable. In this paper we focus on the mechanical changes of porcine liver with increasing preservation time, in order to establish an indicator for the quality of a liver graft dependent on preservation time. A time interval of 26 h was covered and the rheological properties of liver tissue studied using a stress-controlled rheometer. For samples of 1 h preservation time 0.8% strain was found as the limit of linear viscoelasticity. With increasing preservation time a decrease in the complex shear modulus as an indicator for stiffness was observed for the frequency range from 0.1 to 10 Hz. A simple fractional derivative representation of the Kelvin Voigt model was applied to gain further information about the changes of the mechanical properties of liver with increasing preservation time. Within the small shear rate interval of 0.0001-0.01 s⁻¹ the liver showed Newtonian-like flow behavior.

IV thrombolysis and statins.

OBJECTIVE: To examine whether prior statin use affects outcome and intracranial hemorrhage (ICH) rates in stroke patients receiving IV thrombolysis (IVT). METHODS: In a pooled observational study of 11 IVT databases, we compared outcomes between statin users and nonusers. Outcome measures were excellent 3-month outcome (modified Rankin scale 0-1) and ICH in 3 categories. We distinguished all ICHs (ICH(all)), symptomatic ICH based on the criteria of the ECASS-II trial (SICH(ECASS-II)), and symptomatic ICH based on the criteria of the National Institute of Neurological Disorders and Stroke (NINDS) trial (SICH(NINDS)). Unadjusted and adjusted odds ratios (OR) with 95% confidence intervals were calculated. RESULTS: Among 4,012 IVT-treated patients, 918 (22.9%) were statin users. They were older, more often male, and more frequently had hypertension, hypercholesterolemia, diabetes, coronary heart disease, and concomitant antithrombotic use compared with nonusers. Fewer statin users (35.5%) than nonusers (39.7%) reached an excellent 3-month outcome (OR(unadjusted) 0.84 [0.72-0.98], p = 0.02). After adjustment for age, gender, blood pressure, time to thrombolysis, and stroke severity, the association was no longer significant (0.89 [0.74-1.06], p = 0.20). ICH occurred by trend more often in statin users (ICH(all) 20.1% vs 17.4%; SICH(NINDS) 9.2% vs 7.5%; SICH(ECASS-II) 6.9% vs 5.1%). This difference was statistically significant only for SICH(ECASS-II) (OR = 1.38 [1.02-1.87]). After adjustment for age, gender, blood pressure, use of antithrombotics, and stroke severity, the OR(adjusted) for each category of ICH (ICH(all) 1.15 [0.93-1.41]; SICH(ECASS-II) 1.32 [0.94-1.85]; SICH(NINDS) 1.16 [0.87-1.56]) showed no difference between statin users and nonusers. CONCLUSION: In stroke patients receiving IVT, prior statin use was neither an independent predictor of functional outcome nor ICH. It may be considered as an indicator of baseline characteristics that are associated with a less favorable course.

[Sports-related carotid artery dissection]. / Karotisdissektionen nach Sport.

Sports-related carotid artery dissection are very rare and were described in different kinds of sports. We report on a 45-year old man who suffered bilateral brain infarctions caused by bilateral extracranial internal carotid artery dissection after excessive weight lifting in a gym. As possible trigger factors for the dissections we assumed the abrupt extension of the neck during weight lifting and the frequent Valsalva manoeuvers with massive rise in the pressure in the carotid artery system. The patient underwent angioplasty and stenting of the stenosis of right carotid artery, the primarily occluded left carotid artery recanalized spontaneously. Secondary prevention was established by platelet aggregation inhibitors. The patient recovered completely. The pathogenesis of sports-related dissections is multifactorial. In addition to sporting activities hereditary or acquired structural aberrations in the arterial walls could be discussed. Acute focal neurological symptoms after sport should always focus on carotid or vertebral artery dissection.

Analysis of adenovirus gene transfer into adult neural stem cells.

Adult neural stem cells (aNSCs) represent an attractive source for the production of specific types of neurons in degenerative CNS diseases and for the development of new regenerative gene therapies. However, the use of adult NSCs for transplantation and gene replacement strategies requires efficient gene expression in the cells. Due to the low pathogenicity of adenovirus (Ad) for humans, its large delivery capacity, and long-term transgene expression, Ad vectors are widely used. Here, we tested the potential of the Ad vector system to transduce adult NSCs. Analysis of Ad receptor expression in primary aNSCs revealed a complete lack of the coxsackie-adenovirus receptor and no or low expression of alphanu- and beta5-integrins, respectively, on mRNA and protein level. Consistently, transduction at different multiplicities of infection using an Ad vector expressing the enhanced green fluorescent protein (GFP) showed that adult NSCs are particularly resistant to Ad infection even at highest MOI (1000) in contrast to differentiated types of neural cells.

[Assessing deinstitutionalization of the nursing home area of a large state mental hospital from the point of view of patients and staff]. / Der Enthospitalisierungsprozess des psychiatrischen Heimbereichs eines ehemaligen Grosskrankenhauses aus Patienten- und Mitarbeitersicht.

OBJECTIVE: Within the deinstitutionalization process of a large psychiatric hospital, the development of two cohorts of patients with chronic schizophrenia is compared over a two-year period: patients living in the hospital's nursing-home area (n = 50) vs. patients already released to two social therapeutic hostels (n = 51). Results of the cohort study were compared with assessments of nurses working in the nursing home (n = 55), focusing on their subjective views of the deinstitutionalization process and its impact on their working conditions. METHODS: Patients are assessed through yearly home-visits in their place of residence. The instruments used measure several outcome parameters: psychopathology, social disabilities, subjective quality of life, and normative needs for care. Concurrent staff assessments were conducted using standardized survey instruments focusing on current working conditions and quality of teamwork. Nineteen nurses participated in qualitative interviews evaluating the deinstitutionalization process. RESULTS: For all measures, patients living in the nursing home show significantly worse outcomes. Furthermore, during the study period 34 % experienced a change in their living situation with which they were dissatisfied. Needs for care and the number of areas of "unmet" need increased significantly for this subgroup. Patients living in social therapeutic hostels demonstrate stable levels of psychopathological symptoms, social disabilities, and needs for care. Assessments indicating a deterioration in patients' subjective quality of life focus mainly on areas important for social contacts. Regarding "personal concerns" and "insecurity at work", ratings from nursing home staff were significantly worse than those of a reference group from several other health care institutions (n = 224). Staff showed a tendency to give higher ratings for their opportunities to participate in decisions, in contrast with the low ratings for chances to improve their knowledge in the workplace, a result which may indicate a lack of prospects. In general, staff faces the conundrum of being asked to adopt a new mental health care paradigm while organisational structures are being eliminated and insecurity about career opportunities is increasing. CONCLUSION: To adequately manage deinstitutionalization of care, all participating parties must be involved in the process as early as possible to clarify expectations and to demonstrate commitment to future opportunities in the new system.

Omega-3 fatty acids, homocysteine, and the increased risk of cardiovascular mortality in major depressive disorder.

Depression is associated with elevated rates of cardiovascular morbidity and mortality. This elevation seems to be due to a significantly increased risk of coronary artery disease and myocardial infarction and, once the ischemic heart disease is established, sudden cardiac death. Recent data suggest that the increased rates of cardiovascular disease in patients with depression may be the result of one or more still-unrecognized underlying physiological factors that predispose a patient to both depression and cardiovascular disease. Two possibly related factors that may have a causal relation with both depressive disorders and cardiovascular disease are an omega-3 fatty acid deficiency and elevated homocysteine levels. We present the available data connecting cardiovascular disease, depression, omega-3 fatty acids, and homocysteine. In addition, we suggest research strategies and some preliminary treatment recommendations that may reduce the increased risk of cardiovascular mortality in patients with major depressive disorder.

Inhibitory effects of omega-3 fatty acids on protein kinase C activity in vitro.

Preliminary clinical data indicate that omega-3 fatty acids may be effective mood stabilizers for patients with bipolar disorder. Both lithium and valproic acid are known to inhibit protein kinase C (PKC) activity after subchronic administration in cell culture and in vivo. The current study was undertaken to determine the effects of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on protein kinase C phosphotransferase activity in vitro. Various concentrations of DHA, EPA, and arachidonic acid (AA) were incubated with the catalytic domain of protein kinase C beta from rat brain. Protein kinase C activity was measured by quantifying incorporation of (32)P-PO(4) into a synthetic peptide substrate. Both DHA and EPA, as well as the combination of DHA and EPA, inhibited PKC activity at concentrations as low as 10 micromol l(-1). In contrast, arachidonic acid had no effect on PKC activity. Thus, PKC represents a potential site of action of omega-3 fatty acids in their effects on the treatment of bipolar disorder.