Transgenic and Natural Mouse Models of Proteolipid Protein (PLP)-Related Dysmyelination and Demyelination

The X chromosome-linked PLP/DM-20 gene is the CNS myelin gene most frequently associated with mutations, resulting in dysmyelination in several species including man (Pelizaeus-Merzbacher disease, X-linked Spastic Paraplegia). The pathology of most PLP gene mutations is characterized by hypomyelination, glial cell proliferation, increased numbers of microglia, and premature oligodendrocyte death. In most mutants, residual myelin structures have an abnormal ultrastructure and periodicity. Surprisingly, transgenic mice which carry extra copies of the wild type PLP gene show dysmyelination, demonstrating that the PLP gene is dosage sensitive. Pathological changes of transgenic mice vary from the phenotype of natural mutants. Specifically, many Golgi saccules of oligodendrocytes are vacuolated and the cytoplasm contains autophagic vacuoles hinting at a perturbation in protein trafficking. In fact, upon transgenic overexpression PLP becomes a prominent peripheral myelin protein, whereas in normal Schwann cells PLP is restricted from entering the myelin compartment. Surprisingly, transgenic animals which overexpress PLP/DM-20 at a low level appear normal during early development, but later spontaneously demyelinate. The mechanisms underlying this demyelination phenotype is unknown but an immune-mediated process has been suggested. All attempts to correct the phenotype of natural PLP mutants, such as jimpy mice, with a wild type transgene have had little effects, indicating a dominant-negative effect of the mutant gene product. On the other hand, mice with a targeted disruption of the PLP/DM-20 gene have suprisingly minor clinical signs. This suggests that the lethal phenotype associated with the majority of PLP gene mutations is a complex combination of loss and gain-of-function effects of a mutant myelin protein.     

Investigation of Gamma-aminobutyric acid (GABA) A receptors genes and migraine susceptibility

Background  

Migraine is a neurological disorder characterized by recurrent attacks of severe headache, affecting around 12% of Caucasian populations. It is well known that migraine has a strong genetic component, although the number and type of genes involved is still unclear. Prior linkage studies have reported mapping of a migraine gene to chromosome Xq 24–28, a region containing a cluster of genes for GABA A receptors (GABRE, GABRA3, GABRQ), which are potential candidate genes for migraine. The GABA neurotransmitter has been implicated in migraine pathophysiology previously; however its exact role has not yet been established, although GABA receptors agonists have been the target of therapeutic developments. The aim of the present research is to investigate the role of the potential candidate genes reported on chromosome Xq 24–28 region in migraine susceptibility. In this study, we have focused on the subunit GABA A receptors type ε (GABRE) and type θ (GABRQ) genes and their involvement in migraine.     

Virological and serological diagnosis of cytomegalovirus infection in bone marrow allograft recipients

To detect cytomegalovirus (CMV) infections, a total of 1,074 cultures of urine, saliva, or blood were collected weekly from 43 consecutive patients undergoing allogeneic bone marrow transplantation. Twenty-three patients were seronegative before transplant and primary infection occurred in 2 (9%). Twenty patients were initially seropositive and recurrent infections occurred in 5 (25%). Three patients in the recurrent group had proven CMV pneumonitis; viraemia was detected in two recipients, while the third had CMV isolated only from bronchial lavage fluid. The serological response of the 43 patients was defined by testing 559 serial sera for specific IgG and IgM antibodies by radioimmunoassay. Passive acquisition of IgG antibodies from blood products was found in 78% of initially seronegative recipients. One patient with primary infection responded in a pattern typical of immunocompetent individuals with long-term production of specific IgG and transient production of specific IgM antibodies. The second patient also had a typical response, but this was delayed until several weeks after the start of virus excretion. In patients with recurrent infections, specific IgM production did not correlate with episodes of virus excretion. Three of five such patients failed to mount a specific IgM response, and these were the only patients in the study to develop CMV pneumonitis. We conclude that CMV infection in bone marrow recipients can only be diagnosed by detection of virus; therefore, the ability of these patients to mount humoral immune responses should not be relied upon for diagnostic purposes.     

Human cognitive function following binedaline (50 mg and 100 mg) and imipramine (75 mg): Results with a new battery on tests

Rats were made diazepam dependent by chronic treatment with daily injections of the drug, 20 mg/kg, IP, for 3 weeks. On abrupt termination of the drug, the animals showed withdrawal hyperactivity which was indicated by increased horizontal locomotion and vertical activity, and diarrhoea. The peak effect was seen 3 days after the withdrawal of diazepam. Effects of various alpha₂ agonists, clonidine, guanfacine and B-HT 920, were studied on the diazepam withdrawal phenomena. Clonidine (100 g/kg, IP) given twice a day at an interval of 12 h prevented both withdrawal-induced hyperactivity and diarrhoea. On the contrary, equimolar doses of guanfacine and B-HT 920 failed to reverse withdrawal-induced hyperactivity but attenuated the effect of diarrhoea. However, higher doses (500 g/kg, IP) of guanfacine and B-HT 920 given twice a day at 12-h intervals were found to be effective. Pretreatment with yohimbine (1.5 mg/kg, IP) reversed the protective effect of clonidine, indicating the involvement of alpha₂ receptors in the action of clonidine.     

Clinical Diagnostic Accuracy in the Management of Primary Stage 1 Cutaneous Malignant Melanoma in a Plastic Surgery Unit

In a retrospective review of 614 primary Stage I cutaneous malignant melanomata and 40 nonmelanoma lesions, the diagnostic accuracy(DA) for malignant melanoma was 86.2%. A positive preoperative clinical diagnosis of malignant melanoma was confirmed histologically in 564/604 (93.3%) of lesions. For 614 histologically proven malignant melanomata a correct pre-operative clinical diagnosis had been made in 564/614 (91.9%).An additional 172 patients were referred for wider excisional surgery within 3 months of a biopsy elsewhere. For the total 786 (614+172) patients, the incidence of biopsy of a clinicially unsuspected (but subsequently histologically proven) malignant melanoma prior to referral to the Plastic Surgery Unit was lowest for lesions of the head and neck (18.3%) and lower limb (19.0%), and highest (almost half of the patients) for lesions of the hands and fingers.Previous reports of the poor level of clinical diagnostic accuracy in cutaneous malignant melanoma have not been confirmed in the present study.

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Robotic-Assisted Total Knee Arthroplasty: An Assessment of Content,Quality, and Readability of Available Internet Resources

BackgroundThe use of robotic-assisted total knee arthroplasty (TKA) has significantly increased over the past decade. Internet content is largely unregulated and may contain inaccurate and/or misleading information about robotic TKA. Our goal was to assess the content, quality, and readability of online material regarding robotic-assisted TKA.MethodsWe conducted an internet search for the top 50 web sites from each of the 3 most popular search engines (Google, Yahoo, and Bing) using the search term robotic total knee replacement. Each web site was assessed for content, quality, and readability. Web site quality was assessed utilizing the QUality Evaluation Scoring Tool (QUEST). Readability was assessed utilizing the Simple Measure of Gobbledygook, Flesch-Kincaid Grade Level, and Flesch Reading Ease Formula scores.ResultsGeneral risks of TKA were discussed in 47.2%, while benefits were discussed in 98.6% of all web sites. Inaccurate claims occurred at a significantly higher rate in physician/community hospital sources compared to university/academic web sites (59% vs 28%, P = .045). Web sites from university/academic web sites had the highest QUEST scores, while physician/community hospital sources scored the lowest (16.1 vs 10.6, P = .01). Most web sites were written at a college reading level or higher.ConclusionPatients should be counseled on the largely unregulated nature of online information regarding robotic-assisted TKA. Physicians and hospitals should consider revising the readability of their online information to a more appropriate level in order to provide accurate, evidence-based information to allow the patient to make an informed consent decision.     

Discriminative-stimulus effects of azaspirodecanedione anxiolytics in baboons trained to discriminate beta-carboline-3-carboxylic acid ethyl ester or pentylenetetrazole

Baboons were trained to discriminate either pentylenetetrazole (PTZ) or beta-carboline-3-carboxylic acid ethyl ester (beta-CCE) from the no-drug condition. Both drugs specifically bind sites in the gamma-aminobutyric acid A (GABA(A)) receptor complex and decrease GABAergic transmission. beta-CCE occasioned drug-lever responding in baboons trained to discriminate PTZ and vice versa. Flumazenil, the benzodiazephine receptor antagonist, blocked beta-CCE, consistent with beta-CCE's receptor binding activity. The azaspirodecanedione anxiolytics buspirone and ipsapirone produced full generalization in all baboons; gepirone and tandospirone yielded full generalization in some baboons and partial in others. These anxiolytics are inactive in the GABA(A) complex and potently bind 5-HT(1A) sites. A specific 5-HT(1A) ligand, 8-hydroxy-2-(di-n-propylamino)tetralin, produced generalization similar to gepirone and tandospirone, which show the most specific 5-HT(1A) binding. The major azaspirodecanedione metabolite, 1-(2-pyrimidinyl)piperazine (an alpha(2)-adrenergic antagonist), occasioned the least drug-appropriate responding. Full generalization to buspirone and ipsapirone may have resulted from dopaminergic or alpha(1)-adrenergic activity combined with 5-HT(1A) activity. The molecular mechanism of the generalization profile for PTZ and beta-CCE shown by the present results is unclear. The data may reflect altered relationships between GABAergic and serotonergic transmission, and altered stimulus effects of the training drugs, in the context of chronically decreased GABAergic transmission.