Pharmacological treatment of alcoholism

1. Pharmacological treatments are effective as part of a treatment plan that includes substantial education, psychological therapy and social support. This paper reviews recent literature on animal models of and treatment for alcohol abuse under seven categories: agents to block craving or reduce alcohol intake, agents to induce aversion to alcohol, agents to treat acute alcohol withdrawal, agents to treat protracted alcohol withdrawal, agents to diminish drinking by treating associated psychiatric pathology, agents to decrease drinking by treating associated drug abuse, and agents to induce sobriety in intoxicated individuals. 2. The benzodiazepines provide safe and effective treatment for detoxification, although current research focuses on finding drugs with a smaller likelihood of dependence. As yet, there are no drugs that effectively reverse the intoxicating effects of alcohol. 3. Currently, only two major groups of drugs that are relatively safe have shown any effect at reducing alcohol consumption: aversives such as disulfiram, and opioid antagonists such as naltrexone. 4. Finally, it is important to customize therapy for each patient rather than putting everyone through a standard treatment plan, especially in regards to the use of antidepressant or antipsychotic medications. Tailoring the program to the patient's needs dramatically improves the outcome of therapy and reduces the risk of adverse effects.     

Comparison of the performance of normal individuals and survivors of traumatic brain injury on repeat administrations of the Wisconsin Card Sorting Test

Despite convincing evidence that T cells are critical for both cellular and humoral immunity against haemoprotozoan parasites, the difficulty of performing meaningful experiments in cattle that would define the role of T cells in immunity to Babesia spp. has impeded research in this area. However, experiments performed ex vivo with immune T cells can reflect in-vivo events, and provide valuable insight into the nature of immunogenic proteins and the responding lymphocytes. The progress made towards identification of the immunogenic proteins and epitopes that stimulate anamnestic CD4+ type-1 (interferon-gamma-producing) T-cell responses in cattle immune to challenge with Babesia bovis or B. bigemina is the subject of the present review.     

Clinical and ocular histopathological findings in a patient with normal-pressure glaucoma

OBJECTIVE: To study the histopathological changes of eyes from a patient with normal-pressure glaucoma whose clinical and laboratory findings were well documented. METHODS: Postmortem histopathological findings in a patient with normal-pressure glaucoma who had monoclonal gammopathy and serum immunoreactivity to retinal proteins were examined in comparison with those of an age-matched control subject. Clinicopathological correlations to laboratory findings were examined. RESULTS: Clinical and histopathological findings of the patient, including cavernous degeneration of optic nerve and characteristic optic nerve cupping, were similar to those in patients with glaucoma who had high intraocular pressure. In addition, we found immunoglobulin G and immonuglobulin. A deposition in the ganglion cells, inner and outer nuclear layers of the retina, and evidence of apoptotic retinal cell death using terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling technique. CONCLUSIONS: Serum antibodies to retinal proteins and retinal immunoglobulin deposition constitute novel findings in a patient with normal-pressure glaucoma and may contribute to better understanding of the mechanisms underlying glaucomatous optic neuropathy in this disorder.     

Calcipotriol inhibits the proliferation of hyperproliferative CD29 positive keratinocytes in psoriatic epidermis in the absence of an effect on the function and number of antigen-presenting cells

The aim of this study was to elucidate some of the possible mechanisms of action of the vitamin D analogue calcipotriol in vivo. Calcipotriol is finding increasing use in the treatment of psoriasis, but the primary target cell in vivo has not yet been identified. We treated psoriatic patients and healthy volunteers with calcipotriol and placebo ointment for 4 and 7 days, and obtained epidermal cell suspensions from treated areas. Epidermal cells were cocultured with autologous T cells, isolated from peripheral blood, in the absence or the presence of a classical antigen or a superantigen. In both psoriatic and normal skin, calcipotriol treatment did not alter the capacity of epidermal antigen-presenting cells to stimulate the proliferation of autologous T cells, either in the absence or in the presence of exogenous antigen. Epidermal cell suspensions were analysed further by staining for infiltrating leucocytes (CD45+) and Langerhans cells (CD1a+). Flow cytometric analysis showed that calcipotriol did not alter the number of CD45+ cells or Langerhans cells in psoriatic skin. These results indicate that calcipotriol does not alter either the number of the function of epidermal antigen-presenting cells in psoriatic epidermis. In contrast, we found that calcipotriol significantly inhibited the proliferation of epidermal cells isolated from psoriatic skin after in vivo treatment, as determined by propidium iodide staining and flow cytometry. More specifically, we stained for CD29+ keratinocytes and found an even more significant reduction in proliferative capacity. This cell type contains the population of hyperproliferative keratinocytes in psoriatic epidermis. In conclusion, calcipotriol seems to act via an inhibitory effect on hyperproliferative basal keratinocytes of psoriatic epidermis, rather than via an effect on infiltrating leucocytes, including antigen-presenting cells.     

Malignant schwannoma of the parapharyngeal space

We present a case of malignant schwannoma (MS) of the parapharyngeal space which completely encircled the internal carotid artery in close proximity to the skull base and required resection of the internal carotid artery along with the excision of the tumour. There have been three previous case reports in the literature of malignant schwannoma of the parapharyngeal space of which one case was associated with neurofibromatosis. Our patient did not exhibit any feature of neurofibromatosis.     

The pharmacokinetics of poliosm

Functional features of type Br?nemark implants are compared with those of type IMZ implants. The problem of determining optimal stiffness characteristics of type IMZ implants has been solved by means of linear programming. The conclusion was made on considerable improvement in distribution of loads when type IMZ osseointegrated implants are used as supporting elements in the denture.     

Catalytic activation of extracellular signal-regulated kinases induces cyclin D1 expression in primary tracheal myocytes

We have demonstrated that extracellular signal-regulated kinases (ERKs) and cyclin D1 are required for bovine tracheal myocyte DNA synthesis. We hypothesized that catalytic activation by ERKs may regulate cyclin D1 expression in these cells. To test this hypothesis, we examined the effects of two inhibitors of ERKs and two reagents that increase the level of activated ERKs on cyclin D1 protein abundance and promoter activity. ERK activity was inhibited either by PD98059, a synthetic inhibitor of mitogen-activated protein kinase (MAPK)/ERK kinase (MEK), the upstream signaling intermediate required and sufficient for ERK activation, or by transient transfection with a dominant-negative mutant of MEK1 (MEK-2A). The level of activated ERKs was increased by transient transfection with either a constitutively active form of MEK1 (MEK-2E) or wild-type ERK2 (MAPKwt). Cyclin D1 expression was assessed either by immunoblot or cotransfection with the full-length cyclin D1 promoter subcloned into a luciferase reporter. We found that pretreatment of bovine tracheal myocytes with PD98059 significantly attenuated platelet- derived growth factor (PDGF)-induced cyclin D1 protein abundance. Furthermore, transfection with MEK-2A reduced PDGF-induced cyclin D1 promoter activity. Finally, transfection with either MEK-2E or MAPKwt induced cyclin D1 promoter activity in the absence of growth factor treatment. We conclude that catalytic activation of ERKs regulates cyclin D1 expression in airway smooth-muscle cells.     

Effect of intravesical capsaicin and vehicle on bladder integrity control and spinal cord injured rats

PURPOSE: To determine the acute effect of intravesical capsaicin on bladder mucosal integrity in normal and spinal cord injured (SCI) rats. MATERIALS AND METHODS: Intravesical reagents were instilled in 5 groups of age and weight matched female rats: 1) control + normal saline solution (NSS), 2) control + ethanol (EtOH), 3) control + capsaicin/EtOH, 4) SCI + NSS, 5) SCI + capsaicin/EtOH. Intravesical instillations were performed 4 weeks after a standard T10 SCI. Intravesical capsaicin (1 mM.) was dissolved in 30% EtOH/NSS. The animals (n = 3 each group) were sacrificed at 30 minutes, 24 hours, 72 hours, and 7 days after intravesical instillation. Whole bladders were harvested, fixed in 10% buffered formalin, and paraffin embedded. Tissue blocks were blind coded and sectioned (5 microns thickness) for histopathological analysis. All sections were initially stained with hematoxylin and eosin (H & E). Specific staining for mucin carbohydrate moieties included periodic acid-Schiff (PAS) and alcian blue. Also, immunohistochemical staining for GP51 (a urinary glycoprotein) was performed. RESULTS: Control and SCI rats exhibited similar bladder mucosal histology by H & E and mucin specific stains. Instillation of saline demonstrated no effect on bladder histology, whereas instillation of intravesical capsaicin induced a profound acute effect of thinning of the epithelium, submucosal edema, and diminished presence of GP51. EtOH produced similar pathological findings, but to a lesser degree than capsaicin. Intravesical capsaicin demonstrated a similar effect in both control and SCI animals. The peak effect was seen after 30 minutes and continued for 24 hours. Partial recovery was noted after 72 hours and complete recovery was evident by 1 week. CONCLUSIONS: The control and SCI rats demonstrated a histologically similar mucosa and glycosaminoglycan layer. The effect of saline instillation on the mucosa was negligible. Intravesical capsaicin dissolved in 30% ethanol/NSS had a profound effect on the bladder urothelium submucosa that was more pronounced than that seen with the ethanol vehicle alone in normal animals.     

Immunocytochemical colocalization of specific immunoglobulin A with sendai virus protein in infected polarized epithelium

Thrombocytopenia is often the dose-limiting toxicity for radionuclide therapy. Prediction of platelet counts after therapy is important for treatment planning. Simple prediction methods based on linear correlation between radiation dose and blood count nadir have been insufficient because they have not considered time, because of the complicated hierarchical structure of the hematopoietic system in which platelets are not directly injured by low dose rate radiation and because of changing radiation dose rates to marrow with time. This study addresses these problems using a cell kinetics model. METHODS: The model consists of compartments for progenitor cells, megakaryocytes, platelets and stromal cells. A linear quadratic formula was used for progenitor cell survival. Stromal cells were described by a model based on a maximum likelihood estimate for cellular damage, repair and proliferation. Reported values for murine cellular turnover rates and radiosensitivity of progenitor cells were used in the model calculations. Experimental mice received 4 Gy of external beam radiation for tumor implantation and 12.4-23.3 MBq 67Cu-2-iminothiolane-BAT-Lym-1 (BAT = 6-[p-(bromoacetamido) benzyl]-1,4,8,11-tetra-azacyclotetradecane-N,N',N',N'-tetraacet ic acid) 19-30 days later. Blood counts were measured three times each week. RESULTS: The model predicted the severity of thrombocytopenia, and the time of the nadir corresponded to measured values in mice. For a dose of 14.2 MBq 67Cu-2-iminothiolane-BAT-Lym-1 that induced a platelet nadir of 20% of baseline (Grade II), the model predicted that at least 20 days were needed before a second 14.2-MBq injection if a subsequent nadir of <10% of baseline (Grade IV) was to be avoided. CONCLUSION: The nadir and duration of thrombocytopenia predicted by the model were similar to those observed in the mice. Predicted information could be useful for planning the dose and timing of fractionated radionuclide therapy. This model provides a stepping stone for future development of a predictive model for patients.