Neuronal ceroid lipofuscinosis (NCL) is caused by the entire deletion of CLN8 in the Alpenländische Dachsbracke dog.

Neuronal ceroid lipofuscinoses (NCLs) are inherited lysosomal storage diseases that have been described in a variety of dog breeds, where they are caused by different mutations in different genes. However, the causative gene defect in the breed Alpenländische Dachsbracke remained unknown so far. Here we present two confirmed cases of NCL in Alpenländische Dachsbracke dogs from different litters of the same sire with a different dam harboring the same underlying novel mutation in the CLN8 gene. Case 1, a 2-year-old male Alpenländische Dachsbracke was presented with neurological signs including disorientation, character changes including anxiety states and aggressiveness, sudden blindness and reduction of food intake. Magnetic resonance imaging (MRI) scans showed cerebral atrophy with dilation of all cerebral ventricles, thinning of the intermediate mass of the thalamus and widening of the cerebral sulci. Postmortem examination of the central nervous system (CNS) showed neuronal loss in the cerebral cortex, cerebellum and spinal cord with massive intracellular deposits of ceroid pigment. Additional ceroid-lipofuscin deposits were observed in the enteric nervous system and in macrophages within spleen, lymph nodes and lung. Ultrastructural analyses confirmed NCL with the presence of osmiophilic membrane bounded lamellar-like structures. Case 2, a 1,5-year old female Alpenländische Dachsbracke was presented with progressive generalized forebrain disease including mental changes such as fearful reactions to various kinds of external stimuli and disorientation. The dog also displayed seizures, absence of menace reactions and negative cotton-ball test with normal pupillary light reactions. The clinical and post mortem examination yielded similar results in the brain as in Case 1. Whole genome sequencing of Case 1 and PCR results of both cases revealed a homozygous deletion encompassing the entire CLN8 gene as the most likely causative mutation for the NCL form observed in both cases. The deletion follows recessive inheritance since the dam and a healthy male littermate of Case 1 were tested as heterozygous carriers. This is the first detailed description of CLN8 gene associated NCL in Alpenländische Dachsbracke dogs and thus provides a novel canine CLN8 model for this lysosomal storage disease. The presence of ceroid lipofuscin in extracerebral tissues may help to confirm the diagnosis of NCL in vivo, especially in new dog breeds where the underlying mutation is not known.

Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes.

Reduced expression of the Gad1 gene-encoded 67-kDa protein isoform of glutamic acid decarboxylase (GAD67) is a hallmark of schizophrenia. GAD67 downregulation occurs in multiple interneuronal sub-populations, including the parvalbumin-positive (PVALB+) cells. To investigate the role of the PV-positive GABAergic interneurons in behavioral and molecular processes, we knocked down the Gad1 transcript using a microRNA engineered to target specifically Gad1 mRNA under the control of Pvalb bacterial artificial chromosome. Verification of construct expression was performed by immunohistochemistry. Follow-up electrophysiological studies revealed a significant reduction in γ-aminobutyric acid (GABA) release probability without alterations in postsynaptic membrane properties or changes in glutamatergic release probability in the prefrontal cortex pyramidal neurons. Behavioral characterization of our transgenic (Tg) mice uncovered that the Pvalb/Gad1 Tg mice have pronounced sensorimotor gating deficits, increased novelty-seeking and reduced fear extinction. Furthermore, NMDA (N-methyl-d-aspartate) receptor antagonism by ketamine had an opposing dose-dependent effect, suggesting that the differential dosage of ketamine might have divergent effects on behavioral processes. All behavioral studies were validated using a second cohort of animals. Our results suggest that reduction of GABAergic transmission from PVALB+ interneurons primarily impacts behavioral domains related to fear and novelty seeking and that these alterations might be related to the behavioral phenotype observed in schizophrenia.

Site-directed spin labeling of proteins for distance measurements in vitro and in cells.

Site-directed spin labeling (SDSL) in combination with electron paramagnetic resonance (EPR) spectroscopy allows studying the structure, dynamics, and interactions of proteins via distance measurements in the nanometer range. We here give an overview of available spin labels, the strategies for their introduction into proteins, and the associated potentials for protein structural studies in vitro and in the context of living cells.

Modulation of behavioral networks by selective interneuronal inactivation.

Gamma-aminobutyric acid (GABA)-ergic disturbances are hallmark features of schizophrenia and other neuropsychiatric disorders and encompass multiple interneuronal cell types. Using bacterial artificial chromosome-driven, miRNA silencing technology we generated transgenic mouse lines that suppress glutamic acid decarboxylase 1 (GAD1) in either cholecystokinin (CCK)- or neuropeptide Y (NPY)-expressing interneurons. In situ lipidomic and proteomic analyses on brain tissue sections revealed distinct, brain region-specific profiles in each transgenic line. Behavioral analyses revealed that suppression of GAD1 in CCK+ interneurons resulted in locomotor and olfactory sensory changes, whereas suppression in NPY+ interneurons affected anxiety-related behaviors and social interaction. Both transgenic mouse lines had altered sensitivity to amphetamine albeit in opposite directions. Together, these data argue that reduced GAD1 expression leads to altered molecular and behavioral profiles in a cell type-dependent manner, and that these subpopulations of interneurons are strong and opposing modulators of dopamine system function. Furthermore, our findings also support the hypothesis that neuronal networks are differentially controlled by diverse inhibitory subnetworks.

Metastasizing Esthesioneuroblastoma in a Dog.

A 7-year-old Afghan hound presented with a history of disorientation, loss of vision, and seizures. Magnetic resonance imaging helped identify a mass at the level of the main olfactory bulb that compressed and displaced adjacent tissues in the cribriform plate into the nasal cavity and nasopharynx. Bony structures were osteolytic. After removing almost 80% of the mass, the tumor recurred a few months later. Due to severe respiratory distress and subsequent to an ultrasound diagnosis of a liver tumor, the dog was euthanized. In addition to the nasal mass, a single nodule in the liver and multiple nodules in the lung were present. All masses had similar cell morphology and were diagnosed as metastasizing esthesioneuroblastoma. The neoplastic cells expressed neuron-specific enolase and chromogranin A, and a few cells within the nasal mass were positive for cytokeratin. This is the first description of a canine esthesioneuroblastoma with distant metastases.

Novel animal models for studying complex brain disorders: BAC-driven miRNA-mediated in vivo silencing of gene expression.

In schizophrenia, glutamic acid decarboxylase 1 (GAD1) disturbances are robust, consistently observed, cell-type specific and represent a core feature of the disease. In addition, neuropeptide Y (NPY), which is a phenotypic marker of a sub-population of GAD1-containing interneurons, has shown reduced expression in the prefrontal cortex in subjects with schizophrenia, suggesting that dysfunction of the NPY+ cortical interneuronal sub-population might be a core feature of this devastating disorder. However, modeling gene expression disturbances in schizophrenia in a cell type-specific manner has been extremely challenging. To more closely mimic these molecular and cellular human post-mortem findings, we generated a transgenic mouse in which we downregulated GAD1 mRNA expression specifically in NPY+ neurons. This novel, cell type-specific in vivo system for reducing gene expression uses a bacterial artificial chromosome (BAC) containing the NPY promoter-enhancer elements, the reporter molecule (eGFP) and a modified intron containing a synthetic microRNA (miRNA) targeted to GAD1. The animals of isogenic strains are generated rapidly, providing a new tool for better understanding the molecular disturbances in the GABAergic system observed in complex neuropsychiatric disorders such as schizophrenia. In the future, because of the small size of the silencing miRNAs combined with our BAC strategy, this method may be modified to allow generation of mice with simultaneous silencing of multiple genes in the same cells with a single construct, and production of splice-variant-specific knockdown animals.

[Intraoperative sonography for examination of intervertebral disk extrusion in the dog]. / Einsatz der intraoperativen Sonographie zur Untersuchung des Bandscheibenvorfalls beim Hund. Eine intraoperative Studie.

OBJECTIVE: It has been shown that the components of the vertebral canal (dura mater, pia mater, subarachnoid space, spinal cord parenchyma and central canal) can be visualized intraoperatively with the help of ultrasonography. This study was conducted to document the intraoperative sonographical findings of disc extrusion and to determine imaging criteria for the localisation of the extrusion and the consecutive changes of the spinal cord parenchyma. MATERIAL AND METHODS: 43 dogs of different breeds with a diagnosed disc extrusion were sonographically examined immediately after establishing the surgical decompression (hemilaminectomy, laminectomy, ventral slot) (examination 1) and again after removal of disc material (examination 2). RESULTS: In all 34 patients the extruded disc material could be imaged sonographically appearing as inhomogenous, hyperechoic areas of moderate echogenicity. There was a distal shadowing dependent on the grade of calcification in 53% of the patients in examination 1 and in 79% at examination 2. Furthermore, a tendency towards a central localisation of the disc prolapse (67.6% in examination 1 and 57.1% examination 2) was observed. Intraoperative identification of disc extrusion could be accomplished in 79% of the cases. Intraoperative haemorrhage highly significantly impaired the assessment of the spinal cord (p<0.0001). CONCLUSION: Intraoperative spinal ultrasonography using a linear probe with a frequency from 5 to 10 MHz is a valuable tool for the visualization of spinal structures. It provides information for intraspinal navigation and evaluation of the extent of spinal lesions as well as the state of decompression. Bleeding has a negative influence on the visualization of the spinal canal.

Exceptional Changes in Skeletal Anatomy under Domestication: The Case of Brachycephaly.

"Brachycephaly" is generally considered a phenotype in which the facial part of the head is pronouncedly shortened. While brachycephaly is characteristic for some domestic varieties and breeds (e.g., Bulldog, Persian cat, Niata cattle, Anglo-Nubian goat, Middle White pig), this phenotype can also be considered pathological. Despite the superficially similar appearance of "brachycephaly" in such varieties and breeds, closer examination reveals that "brachycephaly" includes a variety of different cranial modifications with likely different genetic and developmental underpinnings and related with specific breed histories. We review the various definitions and characteristics associated with brachycephaly in different domesticated species. We discern different types of brachycephaly ("bulldog-type," "katantognathic," and "allometric" brachycephaly) and discuss morphological conditions related to brachycephaly, including diseases (e.g., brachycephalic airway obstructive syndrome). Further, we examine the complex underlying genetic and developmental processes and the culturally and developmentally related reasons why brachycephalic varieties may or may not be prevalent in certain domesticated species. Knowledge on patterns and mechanisms associated with brachycephaly is relevant for domestication research, veterinary and human medicine, as well as evolutionary biology, and highlights the profound influence of artificial selection by humans on animal morphology, evolution, and welfare.

La braquicefalia generalmente se considera un fenotipo en el que el cráneo, específicamente el hocico, es notablemente acortado. Mientras que la braquicefalia es característica de algunas variedades domésticas y razas (p.e. Bulldog, gato persa, vaca ñata, cabra anglo nubiana, cerdo Middle White), también se puede interpretar como un fenotipo patológico. A pesar de que la braquicefalia tiene una apariencia semejante, por lo menos superficial, en estas variedades y razas, al examinarla más en detalle se descubre que la "braquicefalia" incluye una variedad de diferentes modificaciones del cráneo que probablemente tienen diferentes subyacentes genéticos y de desarrollo y que están relacionados con la historia de la raza. Revisamos las diferentes definiciones y propiedades relacionadas con la braquicefalia en varias especies domésticas. Describimos diferentes tipos de braquicefalia (tipo bulldog, "katantognático" y braquicefalia alométrica) y analizamos condiciones morfológicas relacionadas con la braquicefalia incluyendo enfermedades (p.e. síndrome obstructivo respiratorio). Además, examinamos los complejos procesos genéticos y de desarrollo subyacentes y los motivos culturales y de desarrollo por las que variedades braquicéfalas pueden ser más o menos prevalentes en ciertas especies domésticas. El conocimiento de patrones y mecanismos asociados a la braquicefalia son relevantes para la investigación sobre la domesticación, medicina veterinaria y humana, así como para la biología evolutiva y destaca la profunda influencia de la selección artificial sobre la morfología y bienestar de los animales y su evolución.

Cyclic adenosine monophosphate in brain areas: microwave irradiation as a means of tissue fixation.

Amounts of cyclic adenosine monophosphate in discrete regions of the brain were estimated after exposure of rats to microwave irradiation. Amounts were highest in the cerebellum and brainstem, intermediate in the hypothalamus and midbrain, and lowest in the hippocampus and cortex. Decapitation increased the concentration of cyclic adenosine monophosphate in all brain areas, although the increase in the cerebellum was three to four times greater than that in other areas. Microwave irradiation may provide a means of rapidly fixing brain tissue in situ while permitting easy dissection of the brain. In this way artifacts produced by decapitation can be eliminated, and concentrations of heat-stable compounds in the brain can be estimated under conditions which more closely approximate those in vivo.

Asian bull elephants: Flehmen-like responses to extractable components in female elephant estrous urine.

Flehmen-like responses (urine tests) are one of the characteristic behavioral reactions of male Asian elephants (Elephants maximus) to cow elephants in estrus. Components of the urine of estrous cow elephants were extracted with organic solvents and partially purified by chromatography and shown to evoke Flehmen-like responses when they were presented to adult bulls.

Universality class of replica symmetry breaking, scaling behavior, and the low-temperature fixed-point order function of the Sherrington-Kirkpatrick model.

A scaling theory of replica symmetry breaking (RSB) in the Sherrington-Kirkpatrick (SK) model is presented in the framework of critical phenomena for the scaling regime of large RSB orders kappa , small temperatures T , and small (homogeneous) magnetic fields H . We employ the pseudodynamical picture [R. Oppermann, M. J. Schmidt, and D. Sherrington, Phys. Rev. Lett. 98, 127201 (2007)], where two critical points CP1 and CP2 are associated with the order function's pseudodynamical limits lim_{a-->infinity}q(a)=1 and lim_{a-->0}q(a)=0 at (T=0 , H=0 , 1kappa=0) . CP1 - and CP2 -dominated contributions to the free energy functional F[q(a)] require an unconventional scaling hypothesis. We determine the scaling contributions in accordance with detailed numerical self-consistent solutions for up to 200 orders of RSB. Power laws, scaling functions, and crossover lines are obtained. CP1 -dominated behavior is found for the nonequilibrium susceptibility, which decays like chi_{1}=kappa;{-53}f_{1}(Tkappa;{-53}) , for the entropy, which obeys S(T=0) approximately chi_{1};{2} , and for the subclass of diverging parameters a_{i}=kappa;{53}f_{a_{i}}(Tkappa;{-53}) [describing Parisi box sizes m_{i}(T) identical witha_{i}(T)T ], with f_{1}(zeta) approximately zeta and f_{a_{i}}(zeta) approximately 1zeta for zeta-->infinity , while f(0) is finite. CP2 -dominated behavior, controlled by the magnetic field H while temperature is irrelevant, is retrieved in the plateau height (or width) of the order function q(a) according to q_{pl}(H)=kappa;{-1}f_{pl}(H;{23}kappa;{-1}) with f_{pl}mid R:(zeta)mid R:_{zeta-->infinity} approximately zeta and f_{pl}(0) finite. Divergent characteristic RSB orders kappa_{CP1}(T) approximately T;{-35} and kappa_{CP2}(H) approximately H;{-23} , respectively, describe the crossover from mean field SK- to RSB-critical behavior with rational-valued exponents extracted with high precision from our RSB data. The order function q(a) is obtained as a fixed-point function q(a) of RSB flow, in agreement with integrated fixed-point energy and susceptibility distributions.

The Relationship between Brachycephalic Head Features in Modern Persian Cats and Dysmorphologies of the Skull and Internal Hydrocephalus.

BACKGROUND: Cat breeders observed a frequent occurrence of internal hydrocephalus in Persian cats with extreme brachycephalic head morphology. OBJECTIVE: To investigate a possible relationship among the grade of brachycephaly, ventricular dilatation, and skull dysmorphologies in Persian cats. ANIMALS: 92 Persian-, 10 Domestic shorthair cats. METHODS: The grade of brachycephaly was determined on skull models based on CT datasets. Cranial measurements were examined with regard to a possible correlation with relative ventricular volume, and cranial capacity. Persians with high (peke-face Persians) and lower grades of brachycephaly (doll-face Persians) were investigated for the presence of skull dysmorphologies. RESULTS: The mean cranial index of the peke-face Persians (0.97 ± 0.14) was significantly higher than the mean cranial index of doll-face Persians (0.66 ± 0.04; P < 0.001). Peke-face Persians had a lower relative nasal bone length (0.15 ± 0.04) compared to doll-face (0.29 ± 0.08; P < 0.001). The endocranial volume was significantly lower in doll-face than peke-face Persians (89.6 ± 1.27% versus 91.76 ± 2.07%; P < 0.001). The cranial index was significantly correlated with this variable (Spearman's r: 0.7; P < 0.0001). Mean ventricle: Brain ratio of the peke-face group (0.159 ± 0.14) was significantly higher compared to doll-face Persians (0.015 ± 0.01; P < 0.001). CONCLUSION AND CLINICAL RELEVANCE: High grades of brachycephaly are also associated with malformations of the calvarial and facial bones as well as dental malformations. As these dysmorphologies can affect animal welfare, the selection for extreme forms of brachycephaly in Persian cats should be reconsidered.

[Central pattern generators in the spinal cord of the cat and their relevance in rehabilitation after spinal lesion]. / Zentrale Lokomotionsgeneratoren im Rückenmark der Katze und ihre Bedeutung bei der Rehabilitation nach spinalen Läsionen.

The ability of the spinal cord to recover after partial or complete transection, and even reinitiate motor function, was investigated in several studies in cats. It has been shown that even after a complete spinalisation at the level of T12/T13, the possibility of restoration of hind-limb function is good. Central pattern generators (CPGs), located in the spinal cord, play an important role in this situation. Although CPGs alone are unable to restore function, the combination of CPGs with targeted and consistent mobility training and, in some cases, hind-limb sensory stimulation is essential to improve function. These result in a reorganisation of the CPGs and neuronal networks in the spinal cord. The age of the animal at the time of injury and the extent and localisation of lesions, play a crucial role in recovery. A new focus of research is the influence of neurotransmitters/neuromodulators on spinal-cord regeneration. How and to what extent these factors support locomotor training remains for further clinical investigation.

Genetically encoded fluorophenylalanines enable insights into the recognition of lysine trimethylation by an epigenetic reader.

Fluorophenylalanines bearing 2-5 fluorine atoms at the phenyl ring have been genetically encoded by amber codon. Replacement of F59, a phenylalanine residue that is directly involved in interactions with trimethylated K9 of histone H3, in the Mpp8 chromodomain recombinantly with fluorophenylalanines significantly impairs the binding to a K9-trimethylated H3 peptide.

Individuals With Traumatic Brain Injury and Their Significant Others' Perceptions of Information Given About the Nature and Possible Consequences of Brain Injury: Analysis of a National Survey.

PURPOSE OF THE STUDY: An online survey was developed to assess how well individuals with brain injuries and family/friends of those with traumatic brain injury (TBI) (significant others) felt they were informed about the nature and consequences of brain injury. PARTICIPANTS: A total of 117 significant others completed the survey. They were primarily female (84.6%), white (94.9%), and well educated (81.2%). A total of 149 individuals with brain injuries completed the survey and again were primarily female (63.8%), white (88.2%), and well educated (82.9%). RESULTS: More than half of the significant other respondents indicated that they were not provided enough information about TBI (53.5%). Up to 53.8% of the respondents with TBI felt that they were not provided enough information, with 43% reporting dissatisfaction with services. Female survivors and those with mild brain injuries were significantly more likely to feel that they were not provided sufficient rehabilitation or information. Increased satisfaction with services was correlated with decreased time since injury (r = -0.165, p = .049). Qualitative analysis revealed key themes about prognostic information and the adequacy of discharge planning and resources. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: Given that more than half of all surveyed indicated that they were not well-informed about brain injury and its possible effects, it is evident that case managers and their teams need to be aware of and invested in their efforts to educate both individuals with brain injuries and their significant others (family and friends) about both the nature and consequences of brain injury. Specific recommendations for practice are included.

Effect of dehydroepiandrosterone sulfate on carnitine acetyl transferase activity and L-carnitine levels in oophorectomized rats.

Alteration in energy metabolism of postmenopausal women might be related to the reduction of dehydroepiandrosterone sulfate (DHEAS). DHEA and DHEAS decline with age, leveling at their nadir near menopause. DHEA and DHEAS modulate fatty acid metabolism by regulating carnitine acyltransferases and CoA. The purpose of this study was to determine whether dietary supplementation with DHEAS would also increase tissue L-carnitine levels, carnitine acetyltransferase (CAT) activity and mitochondrial respiration in oophorectomized rats. Plasma L-carnitine levels rose following oophorectomy in all groups (P < 0.0001). Supplementation with DHEAS was not associated with further elevation of plasma L-carnitine levels, but with increased hepatic total and free L-carnitine (P = 0.021 and P < 0.0001, respectively) and cardiac total L-carnitine concentrations (P = 0.045). In addition, DHEAS supplementation increased both hepatic and cardiac CAT activities (P < 0.0001 and P = 0.05 respectively). CAT activity positively correlated with the total and free carnitine levels in both liver and heart (r = 0.764, r = 0.785 and r = 0.700, r = 0.519, respectively). Liver mitochondrial respiratory control ratio, ADP:O ratio and oxygen uptake were similar in both control and supplemented groups. These results demonstrate that in oophorectomized rats, dietary DHEAS supplementation increases the liver and heart L-carnitine levels and CAT activities. In conclusion, DHEAS may modulate L-carnitine level and CAT activity in estrogen deficient rats. The potential role of DHEAS in the regulation of fatty acid oxidation in postmenopausal women is worthy of investigation.

Genetically Encoded Spin Labels for In Vitro and In-Cell EPR Studies of Native Proteins.

Electron paramagnetic resonance (EPR) spectroscopy in combination with site-directed spin labeling (SDSL) is a powerful approach to study the structure, dynamics, and interactions of proteins. The genetic encoding of the noncanonical amino acid spin-labeled lysine 1 (SLK-1) eliminates the need for any chemical labeling steps in SDSL-EPR studies and enables the investigation of native, endogenous proteins with minimal structural perturbation, and without the need to create unique reactive sites for chemical labeling. We report detailed experimental procedures for the efficient synthesis of SLK-1, the expression and purification of SLK-1-containing proteins under conditions that ensure maximal integrity of the nitroxide radical moiety, and procedures for intramolecular EPR distance measurements in proteins by double electron-electron resonance.

3H-amphetamine concentrations in the brains of young and aged rats: implications for assessment of drug effects in aged animals.

The distribution of amphetamine in the brain, liver, and fat of 3-month-old Wistar rats was compared to the distribution in 24-month-old rats. Animals were killed 20 or 65 min after IP administration of 2.5 mg/kg of 3H-amphetamine. Amphetamine levels in tissues were measured by homogenizing organs in acid and extracting radioactive amphetamine into toluene. Amounts were quantified by scintillation counting. Amphetamine concentrations were twice as high in the brains of the old rats as in young animals at both time points. The liver and fat of old rats also contained more amphetamine. These findings lead us to question the common practice in aging studies of administering compounds using total body weight as the reference point.

Further experience with division of the left renal vein.

The left renal vein (LRV) has numerous tributaries including, but not limited to, the inferior phrenic, suprarenal, and gonadal veins. The resultant potential for collateral LRV outflow through these tributaries in instances of LRV division is obvious. One of us has previously reported 10 such cases of LRV division (close to its confluence with the inferior vena cava and without reanastomosis) for the purpose of facilitating proximal abdominal aortic exposure for reconstructive procedures. One of the 10 patients had moderate renal insufficiency at follow-up. We present herein an additional 19 patients who underwent LRV division predominantly for aneurysmal disease of the abdominal aorta. Sixteen patients were available for follow-up. Three patients died in the intraoperative and early postoperative periods. Multivariate analysis of variance of preoperative, postoperative, and follow-up laboratory data--serum creatinine and BUN--showed no significant change in renal function as assessed.

Improvement of myocardial function in diabetic rats after treatment with L-carnitine.

The effects of L-carnitine administration on the severity of diabetes were investigated. Serum glucose, free fatty acids (FFA), triglycerides, and ketones from diabetic and normal rats injected for 2 weeks with 3 g/kg/d of either L-carnitine or saline were assayed. Hearts were analyzed for carnitine and long-chain acyl coenzyme A. L-carnitine treatment to diabetic rats significantly reduced serum glucose, FFA, triglycerides, and ketones. In nondiabetic rats, carnitine increased serum ketones while FFA and triglycerides were decreased. L-carnitine treatment to diabetic rats prevented a decrease in myocardial total carnitine content. Long-chain acyl carnitine increased while long-chain acyl coenzyme A decreased. In another experiment, L-carnitine administration (750 mg/kg/d for 14 days) significantly improved the recovery of cardiac output after 60, 90, and 120 minutes of ischemia in diabetic perfused hearts. These results suggest that L-carnitine therapy may reduce the severity of diabetes mellitus and improve myocardial performance.