Biomedical subjects
Publications and source records attributed to D E Shaw.
The synthesis and biological evaluation of a series of 2-aryl indoles with high affinity for the human neurokinin-1 (hNK1) receptor are reported, concentrating on optimisation of the indole substitution.
We previously reported that the binding of two-chain high molecular weight kininogen (HKa) to endothelial cells may occur through interactions with endothelial urokinase receptors. Since the binding of urokinase to urokinase receptors activates signaling responses and may stimulate mitogenesis, we assessed the effect of HKa binding on endothelial cell proliferation. Unexpectedly, HKa inhibited proliferation in response to several growth factors, with 50% inhibition caused by approximately 10 nM HKa. This activity was Zn(2+) dependent and not shared by either single-chain high molecular weight kininogen (HK) or low molecular weight kininogen. HKa selectively inhibited the proliferation of human umbilical vein and dermal microvascular endothelial cells, but did not affect that of umbilical vein or human aortic smooth muscle cells, trophoblasts, fibroblasts, or carcinoma cells. Inhibition of endothelial proliferation by HKa was associated with endothelial cell apoptosis and unaffected by antibodies that block the binding of HK or HKa to any of their known endothelial receptors. Recombinant HK domain 5 displayed activity similar to that of HKa. In vivo, HKa inhibited neovascularization of subcutaneously implanted Matrigel plugs, as well as rat corneal angiogenesis. These results demonstrate that HKa is a novel inhibitor of angiogenesis, whose activity is dependent on the unique conformation of the two-chain molecule.
PURPOSE: Vigabatrin (VGB) has been shown to be an effective drug in the treatment of infantile spasms (West syndrome) in predominantly retrospective and open but also in prospective studies. This prospective, randomised, and placebo-controlled trial of VGB in infantile spasms was considered to be justified and feasible to confirm or refute these previous findings. METHODS: Forty children with newly diagnosed infantile spasms received either VGB or placebo for 5 days in a double blind, placebo-controlled, parallel-group study, after which all the infants continuing in the study were treated openly with VGB for a minimum of 24 weeks. RESULTS: Compared with baseline, at the end of the double-blind phase, the patients treated with VGB had a 78% (95% confidence interval, 55-89%) reduction in spasms compared with 26% (-56-65%) in the group treated with placebo (p = 0.020). Seven VGB-treated patients and two placebo-treated patients were spasm free on the final day of the double-blind period (p = 0.063). At the end of the study, 15 children (38% of the original 40 patients or 42% of the 36 patients who entered the open phase) were spasm free with VGB monotherapy. No patient withdrew from the study because of an adverse event. CONCLUSIONS: This unique randomized, placebo-controlled study is the first to demonstrate the efficacy of a specific drug in the treatment of West syndrome and supports the results of previously published open and prospective trials. It further confirms that VGB could be considered as the drug of first choice in treating infantile spasms.
Method-comparison studies, in which new 'candidate' techniques are compared with an established 'gold standard', feature commonly in optometric research. Investigators often analyse their findings using least squares regression, Pearson's product-moment correlation coefficient and the paired t-test. We describe more appropriate methods which include: the 'limits of agreement', the intraclass correlation coefficient, and Deming's method for estimating a straight line fit. Comparisons between methods are made with the aid of a computer simulation. Computer program listings are provided to assist in implementing the analyses.
A cohort of infants of birthweight < or = 1700 g studied prospectively for retinopathy of prematurity (ROP) has been reviewed at 6 months corrected age and the findings related to the neonatal data. The overall incidence of strabismus was 6.4% (30/468), rising from 3.1% (7/229) without ROP to 29.2% (7/24) with stage 3. Strabismus and fusional ability were significantly related to presence and severity of ROP, and abnormal neonatal cranial ultrasound findings. Binocular visual acuity was measured in 340 infants between 20 and 40 weeks corrected age. Eight were subnormal, all due to neurological problems. For the remainder, despite falling within the normal range, there was a significant trend (p < 0.001) for lower acuities with increasing ROP severity. Cycloplegic refraction on 387 infants revealed, with increasing ROP severity: 1, a significant trend towards myopia; 2, increased magnitude of astigmatism; 3, alteration of the astigmatic axis; 4, increased incidence of anisometropia. For the first three categories there was an insignificant trend between no ROP and stage 2, reaching significance only between stage 2 and 3. The predominant axis of astigmatism in infants without ROP was between 60 degrees and 120 degrees, but with ROP there was a significant trend away from this direction.
The natural history of retinopathy of prematurity (ROP) has been studied prospectively in 572 infants < or = 1,700 g birthweight using a protocol designed specifically to investigate the subtle features of this condition. Acute ROP developed in 50.9%. All ROP stages 1 and 2 underwent complete resolution and of the 27 (4.7%) infants with stage 3/4 disease, cicatricial sequelae developed in six. Incidence and severity increased with decreasing birthweight and gestational age. Onset was not confined to the temporal retina but exhibited a predilection to start first in the nasal retina of the most immature neonate. The vertical retinal regions were relatively spared. Retinal arteriolar tortuosity developed around three months postnatally and was related to ROP severity but not its presence. The age at onset and rate of progression of retinopathy were largely determined by the stage of development but were also modified by systemic and local factors. The relevance of these findings to ROP screening is discussed.
Nursery illumination has been implicated in the pathogenesis of retinopathy of prematurity (ROP), although the results of recent studies are conflicting. The data base for this article is a prospective ROP study on 607 infants of birth weight less than or equal to 1700 g including 35 larger siblings from multiple births when 1 infant fulfilled the birth weight criteria. Retinopathy commences preferentially in the nasal retina of the most immature neonate and is less likely to develop, or its onset is delayed, in the superior and inferior regions. These findings cannot be fully accounted for by regional vascular and neuroanatomical variations. Radiometric and physiological evidence suggests that the very immature neonate, most at risk of developing severe ROP, receives the greatest retinal irradiance. Furthermore, ROP commences in the areas of the retina receiving the highest light dose, and its onset is either retarded or inhibited in the darker retinal regions. Further studies are required to determine whether early exposure to light is a factor in the development of ROP. If a causal relationship is proven, here at least is one modality that can easily and immediately be controlled.
The effects of phase of eye test and order of eye examined were investigated in 38 normal subjects using a customized 30-point central threshold program of the Humphrey Field Analyzer 640. This program, designed to be completed within 5 minutes, was successively repeated three times for each eye (i.e., three phases for each eye) at two visits separated by an interval of approximately 2 weeks. Both global and pointwise group mean sensitivity decreased in a time-related manner, deterioration being greater for the second eye at each visit, for both 200 ms and 100 ms stimulus durations.
Explore the source record for details and available documents.
The diagnosis of patent ductus arteriosus (PDA) was determined by Doppler examinations of the descending aorta and/or main trunk of the pulmonary artery in a cohort of 120 preterm infants. 55 per cent of the infants had Doppler echocardiographic evidence of ductal patency on the first day of life and this proportion fell to 30 per cent on the second day and 21 per cent on the third day. The incidence remained constant for the rest of the first week. Infants with PDA were significantly more likely to develop periventricular leukomalacia (PVL) than infants without PDA, but the incidence of periventricular haemorrhage was not increased. The cerebral haemodynamic effects of ductal patency were evaluated. Infants with PVL were found to have a significantly higher incidence of retrograde flow in the anterior cerebral artery during diastole, but the study was unable to demonstrate any significant difference in cerebral blood flow velocity between the infants with and without PDA.
The use of topical indomethacin in the prevention of surgically induced miosis has been documented. However, in these previous prospective trials this prostaglandin synthetase inhibitor was administered the day before surgery. With the frequency of 'day case' cataract surgery increasing, an efficient preoperative mydriatic regimen is important. In this study we considered the use of topical indomethacin as an addition to a regimen already implemented. One hundred and fourteen eyes underwent intercapsular cataract surgery, of which 64 were randomised to receive topical aqueous indomethacin one hour beforehand, and 50 eyes, which did not receive indomethacin formed the comparison group. Topical indomethacin reduced the miosis which occurs during cataract surgery whether performed under local or general anaesthesia. The operating time was shorter for eyes with less surgically induced miosis.
We studied primigravid women in spontaneous labor at term and given epidural analgesia. Two hundred such women giving birth in 1983 were compared with similar groups who gave birth in 1985 and 1987 after the introduction of 'delayed pushing' into our labor ward protocol. Four hundred controls were obtained in 1983 and 1985 by selecting from the labor ward register the next normal primigravid woman in spontaneous labor without epidural analgesia. The assisted delivery rate was significantly higher in all three epidural groups than in the controls (p less than 0.001). Among epidural labors, there was no significant difference between 1983 and 1987 in the incidence of rotational or non-rotational forceps, or of cesarean section. In each epidural group, women who waited more than 60 min were less likely to experience a normal spontaneous delivery than were those who did not (p less than 0.001 in 1983; p = 0.006 in 1985 p = 0.035 in 1987). We conclude that to delay pushing beyond 60 min confers no benefit regarding mode of delivery.
The influence of a socially acceptable dose of alcohol (mean blood alcohol level approximately 90 minutes after ingestion 69.5 mg%; SE 6.20 mg%) on the central visual field as determined by automated static perimetry was investigated in 17 female subjects (17 eyes) trained in automated perimetry (mean age 22.5 years, SE 1.29 years). Central visual field examination was undertaken on the right eye with program 30-2 (stimulus size III) of the Humphrey Field Analyser 630, using a simple cross-over placebo design. Alcohol produced a small (1.0 dB) but statistically significant decrease in the mean deviation (P = 0.002) and small increases (0.6 dB) in the pattern and corrected pattern standard deviations (P = 0.003 and P = 0.046, respectively). The number of stimulus presentations increased by 6% (P = 0.006) and the number of false-negative responses also increased (P = 0.019), indicating impaired patient response. Attenuation of sensitivity as a result of alcohol increased with the increase in eccentricity (P = 0.046) independently of the meridian (P = 0.068) from a mean of 0.8 dB at 3 degrees eccentricity to 1.84 dB at 27 degrees.
Explore the source record for details and available documents.
A multivariate analysis of 30 preoperative risk factors was undertaken in 248 patients who underwent surgery alone for common bile duct (CBD) stones and in 190 patients who had endoscopic sphincterotomy (ES), 77 of whom subsequently also had surgery. Independently significant risk factors in those undergoing surgery were the serum bilirubin level, the use of preoperative ES, and the presence of medical risk factors; in patients undergoing ES, only the serum bilirubin and albumin, but not medical risk factors, were of independent significance. The major implications of this study are, first, that high-risk patients should be treated by ES without subsequent surgery, and second, that "fit patients should be treated by surgery alone without routine preoperative ES.
The incidence and severity of retinopathy of prematurity (ROP) were studied prospectively in a geographically defined area of the East Midlands. Over 23 months, 505 infants weighing 1700 g or less at birth to mothers resident in this area were studied. Acute ROP developed in 248 (49.1%) and there was a significant association between short gestation and low birthweight and greater severity. Most acute ROP underwent complete resolution; only stage 3/4 disease did not and cicatricial sequelae subsequently developed in 5 infants, 23.8% of this group. No infant was blind because of ROP. Black infants had shorter gestations yet were less likely to have any stage of ROP. Although Asians were not smaller than their caucasian counterparts, severe (stage 3/4) ROP was more likely (14.1% vs 2.7% for caucasians); this difference was largely due to their better survival. Since 505 of the available 547 infants in this geographically defined area were examined, it was possible to calculate the incidence of acute and cicatricial ROP on a community population basis. There are dangers in attempting to deduce the incidence of acute ROP from infrequent eye examinations, and in comparing community and hospital-based reports.
In the 47 months from September, 1981, 1531 new cases of amblyopia were identified in the ophthalmic clinics of Leicestershire. Amblyopia was due to strabismus in 689 (45%), combined strabismus and anisometropia in 540 (35%), anisometropia alone in 252 (17%), and form deprivation in 50 (3%). The median age at presentation for strabismic amblyopia (3.64 years) was significantly lower than for combined strabismus and anisometropia (4.68 years) and anisometropia (6.27 years). Boys presented later than girls, as did Asians compared with Caucasians. Only 38 (15%) of children with a visual defect without strabismus (anisometropia) were identified before the age of 5 years. The major reason for this late identification is the lack of a reliable single test for preschool vision assessment.
Review of 26 resected ampullary carcinomas revealed intestinal type adenocarcinoma in all but one and overtly papillary carcinoma in only one case. Co-existing adenoma of the ampulla was present in 11 cases, over half of which were low-grade carcinomas. Flat duct epithelial dysplasia was present in a further eight cases, the adenocarcinoma in only two of these being well differentiated. The estimated 5 year survival rate, overall, was 52% and, with well differentiated adenocarcinoma, 75%. We recommend a new staging system, based on extent of local and lymph node spread: I = invasion confined to wall of common bile duct; II = infiltration of duodenal or retroperitoneal tissues, excluding pancreas; III = infiltration of pancreas; IV = metastasis to nearby lymph nodes. Long-term survival correlates inversely with stage, both by univariate analysis and independently of grade, so that a simple scoring system, based on a combination of both grade and stage, is an excellent predictor of the long-term outcome, defining two groups, with 5 year survival rates of 79% and 0% (P less than 0.001).