The risks associated with short-term placebo-controlled antihypertensive clinical trials: a descriptive meta-analysis.

Short-term (4-8 weeks) placebo-controlled trials are used to evaluate new antihypertensive drug treatment. To evaluate the consequences of such practice, a descriptive meta-analysis was conducted, consisting of blinded review of original case report forms for all patients who died or left a study before its completion for all short-term, placebo-controlled hypertension trials submitted to the Food and Drug Administration from 1973 through 2001. There were 93 marketing applications or supplements involving 590 individual trials that involved 86137 randomized patients (64438 randomized to experimental drug and 21 699 randomized to placebo) with 12658 patient years of observation. There were 9636 dropouts (mean time to dropout was 28 days) and relative risk (RR (placebo/drug))= 1.33 (95% confidence limits, 1.28, 1.39; P < 10(-16)). As expected, lack of blood pressure (BP) control was far more common in patients randomized to placebo; therapeutic failure, RR = 2.53 (2.35, 2.73; P < 10(s15)) and hypertensive emergency, RR = 2.75 (2.19, 3.57; P < 10(-15)). When administrative dropouts and dropouts resulting from inadequate BP control were excluded, the remaining 38% of dropouts were disproportionately more from drug (2810 drug, 816 placebo), RR = 0.80 (0.74, 0.86; P < 10(-8)). There were 43 deaths, RR=0.72 (0.33, 1.45; P=0.37); 40 strokes, RR = 1.43 (0.68, 2.81; P=0.33) and 77 myocardial infarctions, RR=1.06 (0.62, 1.75; P= 0.82). Irreversible harm (a combination of death, stroke and myocardial infarction, 160 total events) was equally distributed between the drug and placebo groups, RR=1.03 (0.71, 1.47; P=0.86).

Novel embryonic and adult homeotic phenotypes are produced by pleiohomeotic mutations in Drosophila.

We have investigated the effects of mutations of the pleiohomeotic (pho) locus (formerly called l(4)29) on embryonic and adult development of Drosophila melanogaster. The normal function of pho is vital for pattern formation during embryonic and adult development. The hypomorphic, adult-viable phocv allele produces maternal-effect embryonic lethality, and the lethal embryos show homeotic transformations of head, thoracic, and abdominal segments and abnormal development of the central and peripheral nervous systems. Hypomorphic and amorphic pho alleles are recessive lethals with the lethal individuals showing partial homeotic transformations of antennae, legs, abdominal segments, and internal structures. In addition, pho mutations product pattern abnormalities in the legs and a novel sixth tarsal segment phenotype. The pho adult phenotypic effects are restricted to discrete spatial regions of the imaginal discs. In leg discs these effects are localized in the upper medial quarter of the discs and show a striking correlation with the organization of positional information as proposed by the polar coordinate model.

Blackpatch, a neural degeneration mutation that interacts with the Notch locus in Drosophila.

We have identified a gene in Drosophila melanogaster that is involved in the development of the adult eye and optic lobe of the brain and that interacts with facet alleles at the Notch locus. We have named this locus Blackpatch (Bpt). Mutant alleles of Bpt produce a variety of abnormal phenotypes in the presence of facet alleles. These phenotypes include neural degeneration in the eye and in the optic lobe of the adult brain that begins 60 hr after pupariation and produces a dark, necrotic eye spot in the adult eye. Other phenotypes include recessive embryonic lethality, pharate adult lethality, and premature adult death. We have isolated and characterized 10 Bpt alleles, all of which yield the neural eye/brain degeneration phenotype in individuals who are also homozygous or hemizygous for facet mutations. Only some of the facet alleles interact with Bpt. Bpt mutations also interact with the split mutation but do not interact with other types of Notch mutation. Somatic mosaic analysis and imaginal disc transplantation experiments suggest that the optic lobe of the brain may be the focus of Bpt action. We conclude that the Notch and Bpt genes have important functions during the interaction between the retina and the optic lobe of the brain.

A genetic analysis of deltex and its interaction with the Notch locus in Drosophila melanogaster.

During Drosophila development networks of genes control the developmental pathways that specify cell fates. The Notch gene is a well characterized member of some cell fate pathways, and several other genes belonging to these same pathways have been identified because they share a neurogenic null phenotype with Notch. However, it is unlikely that the neurogenic genes represent all of the genes in these pathways. The goal of this research was to use a genetic approach to identify and characterize one of the other genes that acts with Notch to specify cell fate. Mutant alleles of genes in the same pathway should have phenotypes similar to Notch alleles and should show phenotypic interactions with Notch alleles. With this approach we identified the deltex gene as a potential cell fate gene. An extensive phenotypic characterization of loss-of-function deltex phenotypes showed abnormalities (such as thick wing veins, double bristles and extra cone cells) that suggest that deltex is involved in cell fate decision processes. Phenotypic interactions between deltex and Notch as seen in double mutants showed that Notch and deltex do not code for duplicate functions and that the two genes function together in many different developing tissues. The results of these investigations lead to the conclusion that the deltex gene functions with the Notch gene in one or more developmental pathways to specify cell fate.

The suppressor of forked locus in Drosophila melanogaster: genetic and molecular analyses.

The suppressor of forked, su(f) locus is one of a class of loci in Drosophila whose mutant alleles are trans-acting allele-specific modifiers of transposable element-insertion mutations at other loci. Mutations of su(f) suppress gypsy insert alleles of forked and enhance the copia insert allele white apricot. Our investigations of su(f) include genetic and molecular analyses of 19 alleles to determine the numbers and types of genetic functions present at the locus. Our results suggest the su(f) locus contains multiple genetic functions. There are two distinct modifier functions and two vital functions. One modifier function is specific for enhancement and the other for suppression. One vital function is required for normal ecdysterone production in the third larval instar, the other is not. We present a restriction map of the su(f) genomic region and the results of an RFLP analysis of several su(f) alleles.

Morphological and somatic clonal analyses of pattern triplications.

The growth of pattern triplications induced by a 48-hr 29 degrees C treatment given to larvae homo- or hemizygous for a ts cell-lethal mutation was examined to determine which structures result from new, regulative growth and which are produced by the original imaginal disc cells. Pattern triplications contain one complete leg pattern (orthodrome) and two partial patterns (antidrome and paradrome). The results of two morphological analyses and one somatic clonal analysis suggest that in triplications in which the antidrome and paradrome become more complete distally (diverge) the paradrome is formed by a portion of the original leg pattern, and the antidrome and orthodrome are formed by extra, regulative growth. A different result is suggested for triplications in which the antidrome and paradrome become less complete distally (converge). In these, the orthodrome appears to be formed by the original leg pattern and the antidrome and paradrome by extra growth. These results agree with predictions based on the polar coordinate model of positional information.

Laser microsurgery in cell and developmental biology.

New applications of laser microbeam irradiation to cell and developmental biology include a new instrument with a tunable wavelength (217- to 800-nanometer) laser microbeam and a wide range of energies and exposure durations (down to 25 X 10(-12) second). Laser microbeams can be used for microirradiation of selected nucleolar genetic regions and for laser microdissection of mitotic and cytoplasmic organelles. They are also used to disrupt the developing neurosensory appendages of the cricket and the imaginal discs of Drosophila.

Pattern formation in a ts-cell-lethal mutant ofDrosophila: The range of phenotypes induced by larval heat treatments.

We describe the range of phenotypes caused by cell death when larvae of the heat-sensitive cell-lethal mutant,l(1)ts726 ofDrosophila, are subjected to heat treatment at different stages of development. When the treatment extends into the pupal period, certain bristles fail to develop but the disc derivatives are otherwise normal. Earlier treatments cause the replacement of sets of leg and eye-antennal markers by mirror image duplications of neighbouring sets. The results are compared in detail with those expected under a gradient model proposed earlier to account for the phenotype. It is found that although the results for the second leg are in excellent agreement with the predictions of the model, a more elaborate hypothesis is necessary to account for the eye-antennal disc data. Abnormal head patterns fall into several distinct categories, any one of which could be explained by postulating the existence of a gradient, if other categories did not also occur. The markers affected in each case belong to overlapping sets, and each category of pattern can be induced by heat treatments administered throughout the temperature-sensitive period. The statistical distribution of the data is such that only one category of pattern would be detected in a small scale experiment. The possible implications relative to pattern formation in normal development are discussed.

Development in genetic mosaics of aristapedia, a homoeotic mutant of Drosophila melanogaster.

Development of the homoeotic mutation, aristapedia (ss(a)), was investigated by means of genetic mosaics. The wild-type alleles of aristapedia and the bristle markers yellow, singed, and forked were removed from cells at different times in development by X-ray induced somatic crossing-over. The phenotype of the resulting clones was examined in order to ascertain whether it was leg or antenna. The y sn f; ss(a) clones showed a leg phenotype if induced before the mid-third instar, but showed an antennal phenotype if induced after this time. Late non-expression of ss(a) may be due either to an influence of surrounding ss(+) tissues on the small ss(a) clones, or to a persistence of the effect of ss(+) for one or two cell generations after it is removed from a cell line.