Successful eradication of methicillin-resistant Staphylococcus aureus (MRSA) intestinal carrier status in a healthcare worker--case report.

We describe bacteriophage therapy in the case of a healthcare worker whose gastrointestinal tract was colonized by methicillin-resistant Staphylococcus aureus (MRSA) with subsequent urinary tract infection caused by the same pathogen. Oral treatment with anti-MRSA phages resulted in eradication of the carrier status.

Ultrastructural study of mother and daughter muscle changes with mitochondrial encephalomyopathy.

We present the light and electron microscopy examinations of skeletal muscle biopsies from a 36-year-old mother and her 13-year-old daughter with mitochondrial encephalomyopathies. Clinical signs and symptoms suggesting mitochondrial disease, such as disseminated neurological symptoms, visual and hearing disturbances, mental disability, exercise intolerance, heart conduction disturbances, short stature, family history, were present in both patients. The mother's niece (8 years old) also died with progressive neurological disorder. CT showed cerebral and cerebellar atrophy in mother and multifocal subcortical atrophy in daughter. There was lactic acidosis in blood serum and cerebrospinal fluid in daughter. In the daughter's muscle a lot of fibres looked like ragged red fibres. Electron microscopic examination revealed the alterations of mitochondria in skeletal muscle of both patients that concerned the number, size, shape and the fine structural appearance of the mitochondria. The most characteristic mitochondrial abnormalities in daughter's muscles were paracrystalline inclusions in the intracristal space. In mother's muscles most of the mitochondria were markedly enlarged and they possessed aberrant configurations of cristae. The mitochondrial matrix contained sometimes spherical electron dense bodies different in size and vacuoles. Ring-shaped mitochondria were also observed. The most prominent ultrastructural feature, similarly as in daughter, was the occurrence of intramitochondrial highly ordered paracrystalline inclusions.

Preclinical models of Parkinson's disease.

Parkinson's disease is a neurodegenerative disease in which pigmented midbrain neurons progressively die producing a dopamine (DA) deficit in the striatum which manifests as an akinetic movement disorder. Experimentally induced striatal DA depletion in animals is a valid model of parkinsonism. The capacity of certain substances to damage catecholaminergic neurones has been used for a long time to produce DA deficiency in animals. This unit focuses on methods for inducing parkinsonism using the neurotoxins MPTP and 6-hydroxy dopamine and methods for evaluating the animals. Other models are briefly reviewed.

Convection-enhanced delivery of AAV vector in parkinsonian monkeys; in vivo detection of gene expression and restoration of dopaminergic function using pro-drug approach.

Using an approach that combines gene therapy with aromatic l-amino acid decarboxylase (AADC) gene and a pro-drug (l-dopa), dopamine, the neurotransmitter involved in Parkinson's disease, can be synthesized and regulated. Striatal neurons infected with the AADC gene by an adeno-associated viral vector can convert peripheral l-dopa to dopamine and may therefore provide a buffer for unmetabolized l-dopa. This approach to treating Parkinson's disease may reduce the need for l-dopa/carbidopa, thus providing a better clinical response with fewer side effects. In addition, the imbalance in dopamine production between the nigrostriatal and mesolimbic dopaminergic systems can be corrected by using AADC gene delivery to the striatum. We have also demonstrated that a fundamental obstacle in the gene therapy approach to the central nervous system, i.e., the ability to deliver viral vectors in sufficient quantities to the whole brain, can be overcome by using convection-enhanced delivery. Finally, this study demonstrates that positron emission tomography and the AADC tracer, 6-[(18)F]fluoro-l-m-tyrosine, can be used to monitor gene therapy in vivo. Our therapeutic approach has the potential to restore dopamine production, even late in the disease process, at levels that can be maintained during continued nigrostriatal degeneration.

MHC class II positive microglia and lymphocytic infiltration are present in the substantia nigra and striatum in mouse model of Parkinson's disease.

We have studied MHC class II antigen expression and lymphocytic infiltration during dopaminergic neurone degeneration produced by intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridine (MPTP). Microglial activation was observed in the striatum and in the substantia nigra (SN) in this model. We noticed a marked increase of MHC class II antigen expression on microglia and T-cell recruitment in these regions after MPTP treatment. B-lymphocytes were not observed. T-cell infiltration predominantly consisted of CD8+ cells at every time point but CD4+ cells were present too. More than a half of the observed lymphocytes showed strong staining of CD44 antigen. Our findings suggest a possible immune system involvement in the pathological process following MPTP intoxication.

The inflammatory reaction following 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine intoxication in mouse.

In degenerative disorders of the CNS an immune system involvement in the pathological process is postulated. The MPTP model of Parkinson's disease seem to be a good model for studying an inflammation following toxic neurodegeneration. In this model, microglial and astroglial reactions were previously found around impaired neurons. In the present work we showed an immune reaction, including lymphocytic infiltration of CD4+ and CD8+ T cells in the substantia nigra and striatum and elevated MHC class I and II antigens expression on microglia. Many activated lymphocytes were present, showing increased LFA-1 and CD44 antigen expression. We found also that ICAM-1 expression increased on the endothelium and appeared on microglia in the injured regions. Treatment with dexamethasone inhibited T-cell infiltration and MHC class II expression, lessened the glial reaction, and also diminished neuronal impairment. These findings suggest that an immune mechanism may contribute to the neuronal damage following MPTP administration.

Microglial and astrocytic involvement in a murine model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

We have studied the reaction of glial cells in mice treated with an intraperitoneal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a selective neurotoxin of dopaminergic nigrostriatal neurons. Signs of injury to the dopaminergic neurons started on the 1st day after MPTP administration and progressed up to the end of the observation time (21st day). A transient microglial reaction was demonstrated from the 1st until the 14th day in the substantia nigra (SN) and striatum. The cells showed an increase in number and changes in morphology. At the ultrastructural level, signs of phagocytosis and features indicating the secretion of biologically active substances were observed. Astrocytosis followed the microglial reaction by one day and was noticed until the end of the observation time. Interleukin-6 immunoreactivity was observed within microglia and astrocytes in the SN on days 2 and 3. There were no signs of depletion of dopaminergic cells or glial activation after the administration of MPTP simultaneously with pargyline, an inhibitor of monoamine oxidase-B that prevents MPTP neurotoxicity. Our study indicates that microglia and astrocytes are involved in the pathological process in the nigrostriatal system following MPTP administration. MPTP alone is not responsible for glial cell activation but its metabolite MPP+ and/or agents released by injured neurons may participate in this process.

Microglial reaction in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced Parkinson's disease mice model.

We studied the microglial reaction in mice using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced model for Parkinson's disease (PD). Microglial cells were identified by means of the Griffonia simplicifolia lectin (GSA-I-B4). Dopaminergic neurons were marked by tyrosine hydroxylase antibodies. Microglial activation was demonstrated by an increase in cellular number and changes of morphology (increased lectin staining, larger cell bodies and thicker processes) were seen in the substantia nigra from the 1st to the 14th day and in the striatum from the 1st to the 4th day after intoxication. Depletion of dopaminergic neurons was most pronounced 7 and 14 days following the treatment. The results suggest that microglial activation may be involved in the sequence of pathological changes that lead to dopaminergic neuronal damage after MPTP intoxication.

Cold water stress induced analgesia in unilateral inflammation of the hindpaw in hypertensive and normotensive rats.

Analgesia induced by cold water stress (CWS) was tested in the model of monolateral inflammation in spontaneously hypertensive (SHR), renal hypertensive (RHR) and normotensive Wistar (NR) and Wistar Kyoto (WKY) rats. Unilateral hind paw inflammation was induced by Freund's complete adjuvant (FCA). Four days after inoculation all tested rats exhibited profound analgesia following CWS in both inflamed and non-inflamed paws which reached a maximum immediately after CWS and returned to control values within 15 min. The activity of naloxone was tested both by systemic and local injection. Baseline pain thresholds of SHR rats were significantly higher than those of NR, WKY and RHR. Hyperalgesia following systemic intraperitoneal administration of naloxone applied ten minutes before CWS was higher in RHR and WKY than in NR and SHR. When administered directly into the inflamed paw, naloxone did not antagonize CWS-induced analgesia in RHR, in contrast to weak antagonism in NR, while more evident in SHR and WKY. Our results probably reflect biological and genetic variability of intrinsic opioid and inflammatory mechanisms in hypertension.