Multifocal intraocular lenses

Since the publication of my last article in Current Opinion in Ophthalmology in 1991 (2:33-34), the use of multifocal intraocular lenses (IOLs) has not gained general acceptance among ophthalmologists. Despite this situation, major IOL companies have continued to invest in clinical trials of new designs. Recently, large optic multifocal lenses used mainly with extracapsular extraction provided good results, with 94% to 100% of best-corrected cases having distance correction of 20/40 vision or better; 77% to 100% similarly had J3 near vision or better, and approximately 52% to 63% of patients became eyeglass independent. Between 50% to 80% of eyes in which 20/40 vision or better was obtained and in which J2 or better resulted were unaided. However, all multifocal lens designs showed some reduction in contrast sensitivity compared with monofocal designs using Regan charts and Vistech 6500 tests. Contrast sensitivity loss was probably only significant when reading very small print or in low-contrast light. Small-incision surgery with phacoemulsification and more accurate IOL power calculations have made the goal of emmetropia more possible. Also, less eyeglass dependence with the use of multifocal IOLs is a more realistic expectation.     

Pharmacokinetic profile of Mitoguazone (MGBG) in patients with AIDS related non-Hodgkin's lymphoma

Summary Mitoguazone is a unique chemotherapeutic agent whose activity is believed to result primarily from the competitive inhibition of S-adenosyl-methionine decarboxylase leading to a disruption in polyamine biosynthesis. Initial clinical trials demonstrated that the dose-limiting toxicities (mucositis and myelosuppression) of Mitoguazone were both dose and schedule dependent. Early pharmacokinetic studies of Mitoguazone in man revealed a prolonged half-life. Concurrent with a recent Phase II trial of Mitoguazone in patients with AIDS related non-Hodgkin's lymphoma, the single dose pharmacokinetics of Mitoguazone were characterized. Twelve patients received 600 mg/m² of intravenous Mitoguazone over 30 minutes on an intermittent every 2 week schedule. Blood, urine, cerebrospinal fluid (CSF), pleural fluid and tissue samples were collected and analyzed by HPLC. Mitoguazone was cleared from the plasma triexponentially with a harmonic mean terminal half-life of 175 hours and a mean residence time of 192 hours. Peak plasma levels occurred immediately post-infusion, ranged from 6.47 to 42.8 g/ml, and remained (for an extended period) well above the reported concentration for inhibition of polyamine biosynthesis. Plasma clearance averaged 4.73 l/hr/m² with a relatively large apparent volume of distribution at steady-state of 1012 l/m² indicating tissue sequestration. Renal excretion of unchanged Mitoguazone accounted for an average of 15.8% of the dose within 48 to 72 hours post-administration. Detectable levels of drug were present in random voided samples eight days post-dose. Mitoguazone levels in CSF ranged from 22 to 186 ng/ml post-dose with CSF/plasma ratios ranging from 0.6% to 7%. The pleural fluid/plasma ratio was approximately 1. Tissue levels of Mitoguazone were highest in the liver followed by lymph node, spleen and the brain.     

Some characteristics of the ATP-induced histamine release from and permeabilization of rat mast cells

Extracellular adenosine 5-triphosphate (ATP) induced a characteristic, dose-dependent release of histamine and prostaglandin D₂ (PGD₂) from rat peritoneal mast cells. The process was relatively slow, non-cytotoxic, maximal at physiological pH and dependent on external calcium. Strontium and barium ions were able to substitute for calcium, although higher concentrations were required for maximal release. Cells stimulated in the absence of calcium progressively lost the ability to respond to subsequent reintroduction of the cation. The secretion of histamine induced by ATP was largely unaffected by the anti-asthmatic drugs disodium cromoglycate and nedocromil sodium but was inhibited by structurally related flavonoids and by cAMP-active drugs. Importantly, the non-hydrolysable guanosine 5-triphosphate (GTP) analogue, GTP--S, elicited a dose-dependent release of histamine when introduced into mast cells permeabilized with ATP in the absence of external calcium. ATP thus appears to be a useful cell permeabilizing tool with which to study the biochemical processes involved in mast cell activation.     

A comparison of digital subtraction angiography and noninvasive testing in the diagnosis of cerebrovascular disease

Among the 1,892 patients who underwent cerebrovascular digital subtraction angiography at our hospital over the past 18 months, there was a subgroup of 34 patients (65 carotid arteries) for whom noninvasive cerebrovascular test results and standard cerebral arteriograms were also available. These patients were reviewed retrospectively and the ability of both methods to detect hemodynamically significant lesions, defined as a greater than 50 percent reduction in the diameter of the carotid artery, was determined using the arteriograms as the "gold standard." Noninvasive cerebrovascular tests had a sensitivity of 81 percent, a specificity of 95 percent, a positive predictive value of 92 percent, a negative prediction value of 88 percent, and an overall accuracy of 89 percent. Digital subtraction angiography had a sensitivity of 84 percent, a specificity of 92 percent, a positive predictive value of 88 percent, a negative predictive value of 89 percent, and an overall accuracy of 89 percent. If the four cases of hemodynamically significant stenosis of the carotid siphon not detected by digital subtraction angiography had been considered as false-negatives, its sensitivity would have been reduced to 72 percent. In patients with hemispheric cerebral ischemia, we found noninvasive cerebrovascular tests neither necessary nor cost-effective. Digital subtraction angiography, on the other hand, often provided definitive diagnostic information in such patients if the intracranial circulation was well defined and the extracranial lesion corresponded to the patients' symptoms. Noninvasive cerebrovascular testing was the safest and most cost-effective technique for screening patients with asymptomatic bruits, atypical, nonhemispheric cerebral symptoms, and those who have undergone carotid endarterectomy. If the noninvasive cerebrovascular test result was positive or equivocal, digital subtraction angiography was performed to localize the responsible lesion and exclude carotid occlusion.     

Heavy metal and metallothionein concentrations in Atlantic Canadian seabirds

Seabird tissues, collected during the 1988 breeding season from colonies on the Atlantic coast of Canada, were analyzed for toxic metals—Cd, Hg and Pb—and 18 other trace elements. Metallothionein (MT) was measured in kidney, and kidneys and livers underwent histopathological examination. Levels of most essential trace elements appear to be closely regulated in seabird tissues; values were in good agreement with those previously reported in the published literature. Liver-Se concentrations in Leach's storm-petrels (Oceanodroma leucorhoa) (77.6+7.49 g/g dry weight) were much higher than values normally reported for freeliving birds and mammals. Cd levels varied greatly among individuals, but were always higher in kidney than in liver. Highest mean Cd concentrations (183+65 g/g dry weight) were in kidneys of the planktivorous Leach's storm-petrels from the Gulf of St. Lawrence. A few individuals of this species had values >300 g/g dry weight. Cd and metallothionein (MT) concentrations were positively correlated in kidneys of Leach's storm-petrels (r=0.692), Atlantic puffin (Fratercula arctica) (r=0.845) and herring gull (Larus argentatus) (r=0.866). Concentrations of total Hg varied greatly among species and individuals, but were consistently higher in liver than in kidney. Highest mean levels (21+28 g/g) were in livers of the piscivorous double-crested cormorant (Phalacrocorax auritus) from Saint John Harbour in the Bay of Fundy. Concentrations of Hg and Se were positively correlated (r=0.736) in livers of Leach's storm-petrel, but not in other species. Pb concentrations were consistently greatest in bone, with mean levels being highest in herring gulls from a colony in the Bay of Fundy (63+36 g/g). Histological examination of liver and kidney failed to reveal indications of tissue damage associated with elevated levels of heavy metals.     

Brain acetylcholinesterase activity in forest songbirds exposed to a new method of UULV fenitrothion spraying

Brain acetylcholinesterase (AChE) activity was measured in forest songbirds exposed to Ultra Ultra Low Volume (UULV) aerial spraying of fenitrothion in New Brunswick for spruce budworm control. Brain AChE activity was determined in 324 songbirds from the sprayed blocks and 47 from an unsprayed control area, and represented four species. In most cases, more than half of the individuals of any species sampled were diagnosed as exposed (20% inhibition) to the fenitrothion sprays and had a mean percent level of inhibition of 40% or greater, relative to mean control values. The proportion of birds with life-threatening levels of inhibition (50%) was usually less than 20%. The largest proportion of birds with life-threatening inhibition was found after the first 210 g AI/ha spray. The White-throated Sparrow had the highest proportion (25–55%) of individuals with life-threatening inhibition after all sprays. Brain AChE inhibition was greater in exposed birds collected after the first 210 g AI/ha spray than after the second one. Variation among species' responses to the sprays is discussed in relation to habitat and foraging preferences. Several sampling biases which may contribute to underestimation of the impact of fenitrothion spraying on birds are identified.     

Expression of AML1-ETO in human myelomonocytic cells selectively inhibits granulocytic differentiation and promotes their self-renewal.

The t(8;21) translocation is one of the most frequent translocations in acute myeloid leukaemia (AML), giving rise to the AML1-ETO fusion protein (or RUNX1-CBF2T1). This abnormality is associated with myelocytic leukaemia with dysplastic granulopoiesis. Here, we demonstrate that when expressed in a normal human (CD34(+)) progenitor population, AML1-ETO selectively inhibits granulocyte colony formation but not monocyte colony formation. In bulk liquid culture, we found that though AML1-ETO transiently inhibited the proliferation of CD34(+) cells, it promoted long-term growth of myeloid cells for more than 80 days, suggesting that differentiation was inhibited. In support of this, cultures expressing AML1-ETO demonstrated enhanced retention of colony-forming capacity. Phenotypic examination of AML1-ETO cultures revealed a defect in granulocytic differentiation in terms of retention of CD34(+) cells within the culture and delayed CD11b upregulation. Morphologically, granulocyte terminal differentiation in AML1-ETO-expressing cells was inhibited by 83+/-5%, giving rise to a build-up of early to intermediate granulocytes that exhibited a number of morphological features associated with t(8;21) leukaemias. In contrast, AML1-ETO had little or no effect on monocytic differentiation. Taken together, these results suggest that expression of AML1-ETO selectively inhibits the differentiation of granulocytic cells and promoted extensive self-renewal, supporting a causal role for t(8;21) translocations in leukaemogenesis.     

Isolated hypercalciuria with mutation in CLCN5: relevance to idiopathic hypercalciuria

Isolated hypercalciuria with mutation in CLCN5: Relevance to idiopathic hypercalciuria. BACKGROUND: Idiopathic hypercalciuria (IH) is the most common risk factor for kidney stones and often has a genetic component. Dent's disease (X-linked nephrolithiasis) is associated with mutations in the CLCN5 chloride channel gene, and low molecular weight (LMW) proteinuria was universally observed in affected males. We sought to identify mutations in CLCN5 or abnormalities in LMW protein excretion in a large group of patients with IH and in a rat model of genetic hypercalciuria. METHODS: One hundred and seven patients with IH (82 adults and 25 children) and one asymptomatic hypercalciuric man with a known inactivating mutation in CLCN5 were studied. Secondary causes of hypercalciuria were excluded in all. The excretion of retinol-binding protein and beta2-microglobulin was measured by immunoassay in 101 patients with IH. Mutation analysis of the CLCN5 gene was performed in 32 patients with IH and in the genetic hypercalciuric stone-forming (GHS) rat strain. RESULTS: LMW protein excretion was normal in 92 patients with IH, and only slight abnormalities were found in the other nine, none of whom had a mutation in CLCN5. One 27-year-old man who had a CLCN5 mutation was found to have isolated hypercalciuria without LMW proteinuria, renal failure, or other evidence of renal disease. Mutation analysis was normal in 32 patients with IH. The CLCN5 sequence was normal in the GHS rat. CONCLUSIONS: Inactivation of CLCN5 can be found in the setting of hypercalciuria without other features of X-linked nephrolithiasis. However, mutations in CLCN5 do not represent a common cause of IH.