Alterations in cholinergic and non-cholinergic neurotransmitter receptor densities in transgenic Tg2576 mouse brain with beta-amyloid plaque pathology.

Cholinergic deficits in Alzheimer's disease are accompanied by a number of alterations in other transmitter systems including glutamate, noradrenaline and serotonin, suggesting the involvement also of other neurotransmitter systems in the pathogenesis of the disease. To address the question whether beta-amyloid may contribute to these deficits, brain tissue from transgenic Tg2576 mice with Alzheimer plaque pathology at ages of 5 (still no significant plaque load) and 17 months (moderate to high cortical beta-amyloid plaque load) were examined for a number of cholinergic and non-cholinergic markers. Transgenic mice with no significant plaque load demonstrated reduced hemicholinium-3 (HCh-3) binding to choline uptake sites in anterior brain regions as compared to non-transgenic littermates, while in aged transgenic mice with high number of plaque deposits decreased HCh-3 binding levels were accompanied by increased vesicular acetylcholine transporter binding in selected cortical brain regions. In aged transgenic mice GABA(A), NMDA, AMPA, kainate, and beta-adrenergic as well 5-HT(1A)- and 5-HT(2A)-receptor binding levels were hardly affected, whereas alpha(1)- and alpha(2)-adrenoceptor binding was increased in selected cerebral cortical regions as compared to non-transgenic littermates. The development of changes in both cholinergic and non-cholinergic markers in transgenic Tg2576 mouse brain already before the onset of progressive plaque deposition provides in vivo evidence of a modulatory role of soluble beta-amyloid on cortical neurotransmission and may be referred to the deficits in learning and memory observed in these mice also before significant plaque load.     

Structural models for the protein family characterized by gamete surface protein Pfs230 of Plasmodium falciparum

Ps230 is the largest representative of a 10-member family of proteins found in all Plasmodium species. The family is defined by partially conserved, cysteine-rich double domains that are approximately 350 aa in length and have one to three predicted disulfide bridges in each half. In Plasmodium falciparum, the most dangerous human malaria, Pf12 is the smallest member of the family, comprising just one double domain. Pfs230, with 7 double domains, and Pfs48/45 and Pfs47, with 1.5 double domains each, are found on the gamete surfaces and are thus potential candidates for a transmission-blocking vaccine. Fold prediction analyses of the double domains in Pfs230 reveal structural resemblance to SAG1 (surface antigen 1), a surface protein with a double beta-sandwich structure from another apicomplexan parasite, Toxoplasma gondii. Template-directed modeling onto SAG1 clearly establishes the structural link between SAG1 and Pfs230 and produces positions for the cysteines that accord with the disulfide-bonding arrangement predicted for the Pfs230 family in earlier work. A highly clustered region of polymorphisms within the second double domain in Pfs230 maps to one side of the sandwich surface. This observation suggests that this region may be functional and reinforces the validity of these molecular models for the core domains of the Pfs230 family of proteins.     

Heavy chain diseases

Heavy chain diseases (HCDs) are rare B-cell lymphoplasma-cell proliferative disorders characterized by production of truncated monoclonal immunoglobulin heavy chains without associated light chains. HCDs involving the three main immunoglobulin classes have been described; alpha-HCD is the most common and has the most uniform presentation, gamma- and mu-HCDs have variable clinical presentations and histopathologic features. HCDs can be thought of as variant types of non-Hodgkin lymphoma: alpha-HCD presents as an extranodal marginal-zone lymphoma of mucosa-associated lymph-node tissue, gamma-HCD as lymphoplasmacytoid non-Hodgkin lymphoma, and mu-HCD as small lymphocytic non-Hodgkin lymphoma or chronic lymphocytic leukemia. Diagnosis of HCD requires documentation of a deleted immunoglobulin heavy chain without a bound light chain in the serum or urine. Prognosis is variable, and no standardized effective treatment programs are available except for alpha-HCD, which in its early stage may respond to antibiotics.     

Primary localized amyloidosis of the bladder: experience with dimethyl sulfoxide therapy

PURPOSE: We present our long-term experience with intravesical dimethyl sulfoxide (DMSO) for primary localized amyloidosis of the bladder. MATERIALS AND METHODS: The study included 4 males and 2 females 28 to 68 years old (mean age 54) at diagnosis of biopsy proven primary localized amyloidosis involving the bladder diffusely or extensively in 1 locale. All patients had normal upper urinary tracts. They continued to be symptomatic (hematuria in 3, irritative voiding symptoms in 1, and hematuria and irritative voiding symptoms in 2) despite conventional transurethral destructive therapy. Every 2 weeks they received 30-minute instillations of 50 ml. 50% DMSO intravesically for 3 months (patient 1), 6 months (1) and 1 year (4). RESULTS: Therapy failed at 3 and 6 months in 2 patients of whom 1 with a contracted bladder underwent cystectomy and another was stabilized for 1 year with laser therapy. In the remaining 4 patients who were followed for 6 years disease stabilized for 2 to 6 years (mean 3.5) but 3 later required additional therapy including repeat DMSO in 1 and laser therapy in 2. CONCLUSIONS: Diffuse or locally extensive bladder involvement by primary localized amyloidosis usually fails to respond to conventional transurethral destructive surgical procedures. Collectively, our experience and the literature suggest that intravesical DMSO can be a bladder saving measure and help resolve ureterovesical obstruction in some patients. High recurrence rate mandates lifelong cystoscopic surveillance.     

Who makes the diagnosis? The role of clinical skills and diagnostic test results

RATIONALE, AIMS AND OBJECTIVES: Advances in medicine have led to a multitude of diagnostic tests. The contribution of the clinical skills of the general internist in the context of all these advances is unknown. Our objective was to assess the relative contributions of clinical skills and diagnostic test results in arriving at a final diagnosis. METHODS: Records were retrospectively reviewed from 248 consecutive patients admitted to a general internal medicine hospital service during a 3-month period in 2000. All diagnostic evaluations that yielded the final diagnosis were recorded along with the date and time they were performed. Diagnostic credit was given to the evaluation that yielded the diagnosis at the earliest point in time. RESULTS: All cases had a firm diagnosis by 3 months after hospitalization. Of the 248 patients, 246 received a final diagnosis during hospitalization. The diagnoses were made by use of the clinical judgement of the general internist in 50.4% of the cases, a radiologic study in 31.7%, a blood test or culture result in 9.4%, biopsy findings in 3.3% and various other diagnostic studies (endoscopy, echocardiography, electromyography and electroencephalography) in 5.2%. Clinicians provided the correct diagnosis significantly more often than radiologic studies (P = 0.0015), which was the next most useful type of diagnostic evaluation. CONCLUSION: Although technology has become increasingly available in clinical practice, clinical expertise and skills are still important factors with respect to making correct, timely diagnoses in hospitalized patients.     

Pulmonary abnormalities in inflammatory bowel disease

Extraintestinal manifestations of inflammatory bowel disease (IBD) is a common clinical problem affecting up to half of all IBD patients; pulmonary disease, however, ranks among less common extraintestinal manifestations of IBD. Pulmonary disease in patients with IBD is most frequently drug induced due to treatment with sulfasalazine or mesalamine leading to eosinophilic pneumonia and fibrosing alveolitis or due to treatment with methotrexate leading to pneumonitis. Recently, various opportunistic infections have been shown to be a further important cause of pulmonary abnormalities in those IBD patients who are treated with immunosuppressants such as anti TNF- monoclonal antibodies, methotrexate, azathioprine or calcineurin antagonists. In not drug related pulmonary disease a wide spectrum of disease entities ranging from small and large airway dysfunction to obstructive and interstitial lung disorders exist. Patients with lung disorders and inflammatory bowel disease should be evaluated for drug-induced lung disease and opportunistic infections prior to considering pulmonary disease as an extraintestinal manifestation of inflammatory bowel disease.