Targeting acute ischemic stroke with a calcium-sensitive opener of maxi-K potassium channels.

During ischemic stroke, neurons at risk are exposed to pathologically high levels of intracellular calcium (Ca++), initiating a fatal biochemical cascade. To protect these neurons, we have developed openers of large-conductance, Ca++-activated (maxi-K or BK) potassium channels, thereby augmenting an endogenous mechanism for regulating Ca++ entry and membrane potential. The novel fluoro-oxindoles BMS-204352 and racemic compound 1 are potent, effective and uniquely Ca++-sensitive openers of maxi-K channels. In rat models of permanent large-vessel stroke, BMS-204352 provided significant levels of cortical neuroprotection when administered two hours after the onset of occlusion, but had no effects on blood pressure or cerebral blood flow. This novel approach may restrict Ca++ entry in neurons at risk while having minimal side effects.

Hereditary syndactyly in Angus cattle.

Twenty-five syndactylous Angus cattle, characterized pathologically, were reported from 16 herds in 10 states from 1979 to 1994. Twenty-one (84%) had all 4 legs syndactylous, 3 (12%) had 3 legs syndactylous, and 1 (4%) had 2 legs syndactylous. All syndactylous cattle walked with considerable difficulty. Hooves of aged animals became curled and bent laterally or medially. Affected hooves had the appearance of a truncated cone, the base of which was located at the coronary band. Most hooves were fused completely with no indication of dual anlage. An occasional hoof had a distal notch, and other hooves had a dorsally located groove indicating dual embryonic origin. Lateral dewclaws were enlarged in most cases. Radiographs and dissections of limbs of 19 animals revealed a consistent pattern of fusion in most affected calves. Lesions included 1 or more of the following: disappearance of the large metacarpal and metatarsal intertrochlear notches, horizontal fusion of 1 or more carpals and tarsals, fusion of proximal sesamoids, 1 distal sesamoid, and fusion of paired phalanges. Evidence of a genetic cause consisted of 11 syndactylous calves among 70 offspring of 4 3/4 sib families, 8 preterm syndactylous fetuses among 148 preterm fetuses and 13 calves in progenies of 19 animals tested for possible heterozygosity, and 5 syndactylous calves from matings of an Angus syndactylous bull with 1 Angus and 4 Holstein syndactylous cows. Data were consistent with recessive inheritance at a single locus. Angus cattle with sydactytly had a larger number of affected limbs than did syndactylous Holsteins and their Angus crosses, suggesting existence of 2 recessive alleles. The allele of Holsteins (syH) appeared to influence phenotypic expression in a dominant pattern over the Angus allele (syA). Both syA and syH alleles acted as recessives to the normal SY allele. Phenotypic effects on limb development were most dramatic in calves with the syA/syA genotype.

1-Phenyl-3-(aminomethyl)pyrroles as potential antipsychotic agents. Synthesis and dopamine receptor binding.

A series of 1-phenyl-3-(aminomethyl)pyrroles were prepared in two steps from aniline and their affinities for D2, D3, and D4 dopamine receptor subtypes determined. A 15-fold selectivity for cloned human D4 receptors over cloned African Green monkey D2 receptors was observed with 1-(2-pyridyl)-4-[[3-(1-phenylpyrrolyl)]methyl]piperazine.

2-Phenyl-4-(aminomethyl)imidazoles as potential antipsychotic agents. Synthesis and dopamine D2 receptor binding.

A series of 2-phenyl-4-(aminomethyl)imidazoles were designed as conformationally restricted analogs of the dopamine D2 selective benzamide antipsychotics. The title compounds were synthesized and tested for blockade of [3H]YM-09151 binding in cloned African green monkey dopamine D2 receptor preparations. The binding affinity data thus obtained were compared against that of the benzamides and a previously described series of 2-phenyl-5-(aminomethyl)-pyrroles.

Experimental allergic encephalomyelitis. T cell trafficking to the central nervous system in a resistant Thy-1 congenic mouse strain.

BACKGROUND: The understanding of recognition events that underlie the migration of antigen-specific T cells to a target organ during immune-mediated damage will be integral to the therapy of a number of human conditions of proven or suspected autoimmune etiology. In experimental allergic encephalomyelitis (EAE), the laboratory model of the human demyelinating disease, multiple sclerosis, previous studies have concentrated on susceptible strains and have shown that myelin-specific T cells play an early, key role in central nervous system (CNS), lesion formation. Not known in this model is whether in EAE-resistant strains, similar antigen-specific T cells possess the ability to recognize CNS endothelium and infiltrate the CNS. EXPERIMENTAL DESIGN: Myelin basic protein (MBP)-responsive T cells derived from mice of the C57BL/6 strain (bearing the Thy-1.2 allele) were adoptively transferred to the Thy-1.1 congenic strain C57BL/Ka. Some recipients were given a subsequent challenge with MBP in adjuvant, a protocol recently shown to break resistance in this strain and cause EAE. On the basis of the difference in Thy-1 allele, T cell trafficking was followed in this EAE-resistant congenic strain following the different sensitization protocols. RESULTS: In C57BL/Ka mice receiving adoptively transferred C57BL/6 cells followed by MBP challenge, donor MBP-responsive Thy-1.2+ lymphocytes were detected by immunocytochemistry in the Thy-1.1 host CNS and also in peripheral lymphoid organs. In mice given MBP-sensitized cells without additional antigen challenge, although Thy-1.2+ cells were found in the spleen and lymph nodes, similar cells could not be found in the CNS, and animals displayed neither clinical nor pathologic signs of EAE. Donor T lymphocytes appeared in the host CNS with clinical onset, 10 to 14 days after challenge. When mice went into remission, Thy-1.2+ lymphocytes could not be found in the CNS, but were still present in peripheral lymphoid organs up to 3 months after challenge. From the total number of infiltrating cells, T cell receptor-alpha beta+ cells constituted 27% in perivascular cuffs, 15% in meninges, and 13% in the parenchymal infiltrates in the spinal cord. Thy-1.2+ cells contributed up to about 40% of total T cell receptor-alpha beta+ lymphocytes. Approximately 60% of all infiltrating T cells expressed L3T4 (helper/inducer), whereas 18% expressed Lyt-2 (suppressor/cytotoxic). The majority of infiltrating cells were memory and activated cells expressing on their surface Pgp-1 and CD 25. Immunostaining for cytokines showed that the majority of infiltrating cells belonged to the TH1 subset and contained interferon-gamma and tumor necrosis factor-alpha, while a minority were positive for interleukin-4. CONCLUSIONS: These results suggest that: (a) T lymphocytes from an EAE-resistant strain of mouse are capable of homing to the CNS; (b) T lymphocytes from an EAE-resistant strain express phenotypic characteristics, activation, memory, and cytokine profiles similar to infiltrating cells derived from susceptible strains; and (c) the presence of donor T cells in the recipient CNS correlates with clinical and histopathologic signs of EAE.

Heritability and diagnosis of congenital abnormalities in food animals.

The heritability and diagnosis of congenital abnormalities in food animals have been reviewed from the viewpoint of practitioners, clinicians, and researchers. At least 632 putative mutant genes have been cataloged and listed according to the principal body system affected and mode of inheritance (see Tables 1 and 2). Implications of recent advances in genetic methodology are noted.

Rectovaginal constriction in Jersey cattle: genetics and breed dynamics.

Data from farmer-owned herds and from experimental matings supported monofactorial recessive inheritance of rectovaginal constriction in US Jersey cattle. Kempthorne's population genetics model of a recessive trait involving only male selection was extended to include mutation and converted to selection of females only. Computer analyses with that model estimate slow decline in the frequency of the gene for rectovaginal constriction. Practical dynamics of the disorder in a breed registering 50,000 females and 2,000 males annually are given for current conditions and after 500 generations of selection.

Multicentric reticulohistiocytosis: response to alkylating agents in six patients.

STUDY OBJECTIVE: To determine the efficacy of alkylating agents in multicentric reticulohistiocytosis. DESIGN: Open consecutive case series. SETTING: Tertiary-care referral clinic. PATIENTS: Six patients with skin-biopsy-proven multicentric reticulohistiocytosis. All had skin nodules and polyarthritis. INTERVENTION: Five patients received cyclophosphamide (dose range, 1.25 to 2.2 mg/kg body weight) and one patient received chlorambucil (0.1 mg/kg). Therapy was administered from 6 to 24 months. MEASUREMENTS AND MAIN RESULTS: In five patients treated with cyclophosphamide a response was seen within 4 months. Four patients eventually had a complete remission and one had almost a complete remission. The four patients in complete remission had cyclophosphamide therapy discontinued after 6, 12, 16, and 18 months. Three of the four patients remained in complete remission off therapy at 6, 6, and 22 months, whereas one had a recurrence after 6 months. The one patient given chlorambucil went into a complete remission and stopped treatment after 12 months. He remained in complete remission 32 months after stopping medication. CONCLUSION: Our experience with patients with aggressive multicentric reticulohistiocytosis shows that alkylation therapy is warranted. We conclude that a response to an alkylating agent may be expected. Whether after treatment for 6 to 18 months most patients may be able to discontinue the drug and remain in remission has yet to be shown. The rarity of multicentric reticulohistiocytosis precludes the possibility of a double-blind study.

Inheritance of microphthalmia with coloboma in the Australian shepherd dog.

Microphthalmia with coloboma behaves as an incompletely penetrant recessive trait in the merle Australian Shepherd dog. Microphthalmia and related anomalies occurred more often in merle dogs with predominate white than in merles with limited white hair coat. The study did not establish a genetic relationship between the amount of merling and microphthalmia. The inheritance of merling behaved as a dominant trait, but fewer non-merles occurred than were expected. Variations in white spotting were satisfactorily explained by several hypotheses involving 2 or 3 alleles at the S locus. Each requires some or all homozygous merles to be largely white and 1 or more of the S alleles to exhibit some extent of dominance over other alleles in the series.

Relapsing polychondritis with glomerulonephritis. Improvement with prednisone and cyclophosphamide.

A 32-year-old man presented with relapsing polychondritis (RP) and microhematuria. A renal biopsy specimen disclosed focal segmental glomerulonephritis with occasional crescents. Immunofluorescent and electron micrographic studies suggested immune complex--mediated glomerular injury. Initially, life-threatening upper airway obstruction responded to high-dose corticosteroid therapy. Subsequently, progressive renal insufficiency and proteinuria caused by increasingly active glomerulonephritis were treated by adding cyclophosphamide, with sustained improvement. This case supports the concept that RP is an immunologically mediated disease and suggests that a regimen of prednisone and cyclophosphamide warrants consideration for use in cases of RP with glomerulonephritis.

Giant cell (cranial) arteritis: a clinical review.

Giant cell arteritis is a disease of the elderly which is more common than previously recognized. It is important to be aware of this condition because treatment effectively relieves symptoms and prevents serious complications. The disease is suggested when an elderly patient complains of constitutional symptoms, headache, jaw claudication, or the musculoskeletal manifestations of polymyalgia rheumatica. Abnormalities in temporal arteries or other cranial arteries, or evidence of large vessel involvement may be detected by physical examination. A markedly elevated sedimentation rate in association with other clinical features of the disease strongly suggests giant cell arteritis, but a biopsy should be performed to confirm the diagnosis. Corticosteroid therapy should be started promptly in high doses in order to prevent blindness. Prolonged treatment with lower dose corticosteroids is generally necessary for up to 1 to 2 years, and sometimes longer, for continued symptomatic relief. Long-term follow-up of treated patients has demonstrated no detectable effect on survivorship.

Comparison of three immunoassays for immune complexes in rheumatoid arthritis.

Three widely used radioassays that depend on different principles for the measurement of circulating immune complexes (CIC) in biologic fluids are the monoclonal rheumatoid factor (mRF), Raji cell, and C1q binding tests. A comparison of the ability of these methods to measure immune complex-like material in 71 sera and 30 synovial fluids of 91 patients with rheumatoid arthritis (RA) was carried out by a group working in adjacent laboratories in a single institution. The highest number of abnormal levels in the seropositive group was detected by the C1q binding assay (91%). Levels of CIC by the mRF and Raji cell tests were elevated in 81% and 76% of the patients, respectively. The closest correlation was between the Raji and mRF tests (r = 0.44 and P = 0.002) although one depends on complement fixation and one does not. Though significant correlations between the levels of CIC determined by the C1q test and either the mRF (P = 0.2) or Raji cell (P = 0.3) assay were not found in this group, 59% of the samples had elevated levels by all three tests. The frequency of CIC in the sera of patients with seronegative RA was much lower, with the C1q test again giving the highest number of abnormal results (29% versus 16% and 12% for the Raji and mRF tests). In view of the technical problems associated with these tests, particularly lack of a uniform reliable standard, it is likely that all three tests measure the same material in most RA sera and that some of the differences observed are related to inherent variability in the tests themselves rather than intrinsic differences among the CIC detected in these samples.

Left atrial myxoma simulating peripheral vasculitis.

Left atrial myxoma remains a diagnostic challenge clinically. A brief review of previously reported cases and their individualistic clinical and laboratory features are described. The present case report documents an unusual clinical presentation, initially directing attention to the central nervous system as well as to the peripheral arterial system. Histologic evidence of peripheral arterial myxomatous emboli, associated with vasculitis but without other confirmatory immunologic evidence of collagen vascular disease, had predated for 14 months the subsequent echocardiographic diagnosis of left artrial myxoma. These findings further emphasize the importance of recognizing the enigmatic and variable clinical presentation of left atrial myxoma.

Temporal arteritis: a 25-year epidemiologic, clinical, and pathologic study.

Among the population of Olmsted County, Minnesota, 42 patients with temporal arteritis were identified during a 25-year period. The average annual incidence per 100 000 population aged 50 and older rose from 5.1 in 1950-1959 to 17.4 in 1970-1974. The prevalence of patients with a history of the diagnosis of temporal arteritis on 1 January 1975 was 133 per 100 000 population aged 50 and older. All patients received corticosteroid therapy for a range of 1 to 77 months (median, 7 months). Relapses in 10 of 11 patients were associated with corticosteroid reduction. The majority of patients recovered fully and were followed off corticosteroids for 10 months to 19 years (median, 5 years). Temporal arteritis had no significant effect on survival. Vertebral compression fractures and myopathy were the most serious complications of therapy. The presence of giant cells in biopsies was in part related to the number of sections examined, and their presence had no apparent influence on the clinical course.