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PubMed2004

Charge and substituent effects on affinity and metabolism of benzbromarone-based CYP2C19 inhibitors.

Human cytochrome P450 (CYP) 2C19 is one of the most important CYP2C family members responsible for metabolizing commonly prescribed drugs. This research describes synthetic modifications to benzbromarone (Bzbr) to create the most potent CYP2C19 inhibitor ever reported. The most important features enabling analogues of Bzbr to bind to CYP2C19 with high affinity are low acidity (high pK(a) or nonionizability) and hydrophobic substituents adjacent to the phenol moiety. Though CYP2C19 was known to prefer neutral substrates, the extent was perhaps not realized until the anionic, parent compound Bzbr (K(i) = 3.7 microM) was compared to a less acidic dimethyl analogue (K(i) = 0.033 microM). However, differences in affinity for anionic and neutral Bzbr analogues did not appear to affect the regiospecificity of their metabolism by CYP's 2C19 and 2C9. In addition, some Bzbr analogues were metabolized both on the phenol and benzofuran rings. By using a substrate with a methyl ether in place of the Bzbr phenol, it was shown that some Bzbr analogues must be able to freely reposition after binding and oxidize the more energetically favorable position. Normally, O-demethylation of this methyl ether is favored over benzofuran hydroxylation based on ion current from LC/MS. Deuterium substitution of the methyl ether results in an inverse isotope effect on benzofuran hydroxylation (i.e. increased oxidation of this less favorable site). Likewise, Bzbr-based CoMFA models of CYP2C19 demonstrated no clear preference for any one ligand alignment. This suggests results from this modeling method must be interpreted carefully for each CYP isoform. In summary, Bzbr analogues have demonstrated they can be adapted to other CYP2C enzymes in order to probe isoform-specific properties.

Aryl Hydrocarbon Hydroxylases↗
PubMed2004

Glucocorticoid receptor ligand binding domain is sufficient for the modulation of glucocorticoid induction properties by homologous receptors, coactivator transcription intermediary factor 2, and Ubc9.

Several factors modulate the position of the dose-response curve of steroid receptor-agonist complexes and the partial agonist activity of antagonist complexes, thereby causing differential gene activation by circulating hormones and unequal gene repression during endocrine therapies with antisteroids. We now ask whether the modulatory activity of three factors (homologous receptor, coactivator transcription intermediary factor 2, and Ubc9) requires the same or different domains of glucocorticoid receptors (GRs). In all cases, we find that neither the amino terminal half of the receptor, which contains the activation function-1 activation domain, nor the DNA binding domain is required. This contrasts with the major role of activation function-1 in determining the amount of gene expression and partial agonist activity of antisteroids with most steroid receptors. However, the situation is more complicated with Ubc9, where GR N-terminal sequences prevent the actions of Ubc9, but not added GR or transcription intermediary factor 2, at low GR concentrations. Inhibition is relieved by deletion of these sequences or by replacement with the comparable region of progesterone receptors but not by overexpression of the repressive sequences. These results plus the binding of C-terminal GR sequences to the suppressive N-terminal domain implicate an intramolecular mechanism for the inhibition of Ubc9 actions at low GR concentrations. A shift from noncooperative to cooperative steroid binding at high GR concentrations suggests that conformational changes reposition the inhibitory N-terminal sequence to allow Ubc9 interaction with elements of the ligand binding domain. Collectively, these results indicate a dominant role of GR C-terminal sequences in the modulation of the dose-response curve and partial agonist activity of GR complexes. They also reveal mechanistic differences both among individual modulators and between the ability of the same factors to regulate the total amount of gene expression.

Animals↗
PubMedDate not supplied

Preconditioning the human myocardium with intracoronary adenosine.

This study was designed to study the role of adenosine in ischaemic preconditioning. The clinical, electrocardiographic and metabolic parameters of ischaemia were compared before and after intracoronary adenosine during percutaneous transluminal coronary angioplasty in 15 patients with significant stenosis of the left anterior descending artery. Baseline ischaemia was demonstrated by inflating the balloon of appropriate size at its nominal pressure for 30 seconds. Intracoronary adenosine was then administered in dose of 1000 to 6000 mgm/ml. The balloon was repositioned and inflated at nominal pressure for 180 seconds. As compared to 1st balloon inflation, the 2nd balloon inflation produced less severe chest pain, less ST segment deviation on the intracoronary ECG (7.40 +/- 3.94 vs 4.30 +/- 2.15 mm; p < 0.05) and lower coronary sinus lactate levels as compared to the first (0.28 +/- 0.06 vs 0.22 +/- 0.04 mmol/lit; p < 0.05). In conclusion, this study proves that by injecting intracoronary adenosine it is possible to precondition the human myocardium.

Adenosine↗
PubMed2004

Reproducibility of the semiflexed (metatarsophalangeal) radiographic knee position and automated measurements of medial tibiofemoral joint space width in a multicenter clinical trial of knee osteoarthritis.

OBJECTIVE: To determine the baseline and longitudinal consistency in reproducibility of the semiflexed metatarsophalangeal (MTP) position in repeat examinations of patients with knee osteoarthritis (OA) recruited for a multicenter clinical trial that terminated within one year (mean duration 0.81 yr), based on precise measurements both of minimum medial tibiofemoral compartment joint space width (JSW) and of tibial inter-rim distance. METHODS: Two technologists from 8 and one technologist from 14 clinical radiology units had received previous training in performing nonfluoroscopic semiflexed MTP knee examinations and in quality control criteria for film acceptance. Patients (N = 402; F = 269) were recruited from 58 rheumatology sites and referred to 22 centers, or "x-ray hubs," across North America. At baseline and at study exit, both knees were x-rayed twice on the same day. All films had quality control, and accepted films were digitized at the Central Radiographic Facility and transmitted to the Central Analysis Facility for computerized measurement of minimum medial compartment JSW and tibial inter-rim distance. JSW loss was calculated in the placebo group for the study period. RESULTS: The median SD of the difference in JSW between same-day test/retest film pairs was 0.9 mm for 767 baseline film pairs (knees with JSW > 0 mm), and 0.08 mm for 631 exit film pairs. JSW reproducibility was unaffected by subject's sex, age, and degree of JSW loss. Among all x-ray hubs, JSW reproducibility was excellent in 14 (SD < 0.1 mm), good in 6 (0.1 < SD < 0.2 mm), and moderate in 2 hubs (0.2 < SD < 0.3 mm). No statistical difference was found in technologists' ability either in positioning OA knees or in their test/retest reproducibility in repositioning joints at baseline and at study exit. JSW did not alter significantly during the study period. CONCLUSION: The protocol for the semiflexed MTP knee position provides a highly reproducible method for anatomically repositioning the knee and for measuring JSW, necessary for OA clinical trials. It is a simple method that can be employed readily at clinical radiology units, as shown by the similarity in JSW precision between x-ray hubs. The results from this large dataset show that throughout the study precise measurements of JSW were obtained from same-day repeat radiographs, findings that together with previous single-center studies confirm the reliability of this method for clinical trial use.

Arthrography↗
PubMed2002

Intraperitoneal distribution of ultrasound contrast medium imaged with B-mode ultrasound and colour-stimulated acoustic emission imaging.

Intraperitoneal port catheter systems for local delivery of cytotoxic drugs require imaging prior to chemotherapy to confirm homogenous distribution of an injected fluid in the entire peritoneal cavity. This study was performed to assess whether contrast-enhanced ultrasound (US) is a suitable imaging modality for this task. Twelve patients with peritoneal carcinosis and an implanted intraperitoneal port catheter system were studied before chemotherapy. Ultrasound examinations were performed after bolus injections of the microbubble contrast medium Levovist. Distribution of the contrast medium in the peritoneal cavity was imaged using B-mode US and colour-stimulated acoustic emission imaging (SAE). Contrast-enhanced CT imaging was used as term of reference for evaluating the US results. Distribution of the microbubbles in the peritoneal cavity was easily detected by both US methods. In 10 of 12 patients a free distribution in all abdominal quadrants was seen with both US techniques. In 2 of 12 patients, CT and US showed contrast medium limited to the perihepatic area. Therapy was stopped and surgical repositioning of the catheter was performed. Ultrasound after intraperitoneal injection of a microbubble contrast agent provides reliable information about the distribution of intraperitoneally injected fluid in the peritoneal cavity. This method is therefore well suited for imaging port catheter systems prior to chemotherapy.

Acoustics↗
PubMed2000

Non-classic 21-hydroxylase deficiency in an 18-year-old female athlete. A case report

Background: In non-classic 21-hydroxylase deficiency, age at presentation and genital findings are variable. Late diagnosis with dramatic signs of virilization precludes early treatment and thus prevention of anatomic and psychosocial consequences. The following case illustrates the complexity of late diagnosis.Case: An 18-year-old West Indian female was seen for evaluation of clitoromegaly and hirsutism discovered in the emergency department when she presented after sexual assault. She had allegedly been drugged and raped in her dorm room. She was a college student with an athletic scholarship and had a striking masculinized, broad-shouldered appearance. She denied any use of anabolic steroids or other drugs. Menarche was at age 16 with infrequent menses. She was sexually active with 4 life-time partners, all male. On physical exam, her height was 152 cm, weight 50 kg, blood pressure 110/70 mm Hg. Breasts were hypoplastic with hyperpigmented nipples. She was hirsute with a Ferriman-Gallwey score of 14. Genitalia were abnormal with clitoris measuring 5.5 x 1.5 cm and posterior labial fusion. Initial non-fasting serum 17-hydroxyprogesterone level was 2890 ng/dL, testosterone was 274 ng/dL, and cortisol was 9 &mgr;g/dL. Chromosome analysis was 46, XX and ACTH stimulation test confirmed the diagnosis of 21-hydroxylase deficiency. The patient was initially reluctant to begin glucocorticoid treatment because of concern that it would decrease her muscle mass and negatively impact on her athletic performance and scholarship support. One year after diagnosis and 10 months after beginning treatment, she elected surgical correction of her clitoromegaly because of extreme embarrassment over having erections during sex. She underwent excision of most of the corpus cavernosum with repositioning of the glans. The neurovascular elements were preserved. The patient is pleased with the cosmetic result and reports no change in achieving orgasm. She has not notices any change in muscle mass or athletic performance since beginning glucocorticoid therapy.Conclusion: This case illustrates the somatic and genital abnormalities as well as the psychosocial impact of a delayed diagnosis of 21-hydroxylase deficiency in this young female athlete.

Journal Article↗
PubMed1999

End-tidal carbon dioxide monitoring during sedation with a combination of midazolam and ketamine for children undergoing painful, invasive procedures.

BACKGROUND: Previous studies evaluating the respiratory effects of sedation regimens have focused on events such as a decline in O2 saturation or apnea. The current study used both end-tidal carbon dioxide (ETCO2) monitoring and pulse oximetry to evaluate the respiratory effects of midazolam and ketamine. METHODS: Fifty children who required sedation during invasive procedures formed the cohort for the study. During sedation, ETCO2 was sampled from nasal cannulae of spontaneously breathing patients and measured by a side-stream aspirating infrared device. RESULTS: During the procedure, O2 saturation decreased by 3% or more in three patients. Supplemental oxygen at 2 liters per minute was administered to these patients. The lowest oxygen saturation was 84%. During the total of 767 minutes of monitoring, there were 3068 ETCO2 values recorded. The high ETCO2 values ranged from 37 to 53 mmHg (40.5 +/- 3.3 mmHg). Ninety percent, or 2760, of the values were 40 mmHg or less, 7% or 214 were between 41 and 45 mmHg, 3% or 92 were between 46 and 49 mmHg, and 2 isolated values were greater than 50 mmHg. One episode of airway obstruction was identified by noting cessation of the ETCO2 waveform. This was relieved by repositioning the patient's airway. The three episodes of O2 desaturation, two ETCO2 values greater than 50 mmHg, and the episode of upper airway obstruction all occurred in three patients. Two of these patients had trisomy 21 with macroglossia, and the third had had a recent upper respiratory infection and a history of tonsillar hypertrophy. CONCLUSION: The incidence of adverse cardiorespiratory events associated with the current sedation regimen of midazolam-ketamine is lower than that reported with other commonly used regimens. The addition of ETCO2 monitoring provides an additional monitor to allow for early detection of airway obstruction or subclinical degrees of respiratory depression.

Capnography↗
PubMed1989

Transfer of a beta-turn structure to a new protein context.

Four-residue beta-turns and larger loop structures represent a significant fraction of globular protein surfaces and play an important role in determining the conformation and specificity of enzyme active sites and antibody-combining sites. Turns are an attractive starting point to develop protein design methods, as they involve a small number of consecutive residues, adopt a limited number of defined conformations and are minimally constrained by packing interactions with the remainder of the protein. The ability to substitute one beta-turn geometry for another will extend protein engineering beyond the redecoration of fixed backbone conformations to include local restructuring and the repositioning of surface side chains. To determine the feasibility and to examine the effect of such a structural modification on the fold and thermodynamic stability of a globular protein, we have substituted a five-residue turn sequence from concanavalin A for a type I' beta-turn in staphylococcal nuclease. The resulting hybrid protein is folded and has full nuclease enzymatic activity but reduced thermodynamic stability. The crystal structure of the hybrid protein reveals that the guest turn sequence retains the conformation of the parent concanavalin A structure when substituted in the nuclease host.

Binding Sites↗
PubMed2003

Immediate and short-term reliability of distortion-product otoacoustic emissions.

This study assessed the test-retest reliability of distortion-product otoacoustic emissions (DPOAEs) at four frequencies (550, 1000, 2000 and 4000 Hz) over three time intervals. The time intervals were: (1) immediate test-retest reliability, in which the retest followed the test without any delay or repositioning of the probe tip; (2) very short-term test-retest reliability, in which the retest followed a 10-20-min break and involved removal and re-insertion of the probe tip; and (3) short-term test-retest reliability, in which the retest was conducted 5-10 days after the test. Fifty normal-hearing women were tested with a commercially available system for measuring DPOAEs (Grason-Stadler, GSI-60), which generated primary tones at 65 dB SPL (L1=L2). Standard errors of measurement at 550 Hz (approximately 4.6 dB) were nearly twice as large as those found for 1000 Hz, 2000 Hz, and 4000 Hz (approximately 2.5 dB). The short-term test-retest data suggest that there is a 95% probability that an individual's true DPOAE will fall within 5 dB of the obtained distortion product at 1000-4000 Hz and within 10 dB at 550 Hz. The standard error of measurement of the difference was calculated to assess whether two or more DPOAE measurements are significantly different (e.g. before versus after administration of an ototoxic drug or noise exposure). The data revealed that short-term differences (probe removed and subject retested on the same day or on different days) between two DPOAEs must exceed approximately 14 dB at 550 Hz and 7 dB at 1000-4000 Hz to be statistically significant at the 0.05 level of confidence.

Acoustic Stimulation↗
PubMed2001

Why don't patients do their exercises? Understanding non-compliance with physiotherapy in patients with osteoarthritis of the knee.

STUDY OBJECTIVES: To understand reasons for compliance and non-compliance with a home based exercise regimen by patients with osteoarthritis of the knee. DESIGN: A qualitative study, nested within a randomised controlled trial, examining the effectiveness of physiotherapy in reducing pain and increasing mobility in knee osteoarthritis. In the intervention arm, participants undertook a series of simple exercises and repositioning of the kneecap using tape. In depth interviews were conducted with a subset of participants in the intervention arm using open ended questions, guided by a topic schedule, to encourage patients to describe their experiences and reflect on why they did or did not comply with the physiotherapy. Interviews were audiotaped, fully transcribed and analysed thematically according to the method of constant comparison. A model explaining factors influencing compliance was developed. SETTING: Patients were interviewed at home. The study was nested within a pragmatic randomised controlled trial. PARTICIPANTS: Twenty participants in the intervention arm of the randomised trial were interviewed three months after they had completed the physiotherapy programme. Eight were interviewed again one year later. MAIN RESULTS: Initial compliance was high because of loyalty to the physiotherapist. Reasoning underpinning continued compliance was more complex, involving willingness and ability to accommodate exercises within everyday life, the perceived severity of symptoms, attitudes towards arthritis and comorbidity and previous experiences of osteoarthritis. A necessary precondition for continued compliance was the perception that the physiotherapy was effective in ameliorating unpleasant symptoms. CONCLUSIONS: Non-compliance with physiotherapy, as with drug therapies, is common. From the patient's perspective, decisions about whether or not to comply are rational but often cannot be predicted by therapists or researchers. Ultimately, this study suggests that health professionals need to understand reasons for non-compliance if they are to provide supportive care and trialists should include qualitative research within trials whenever levels of compliance may have an impact on the effectiveness of the intervention.

Aged↗
PubMed1995

Assessing bone quantity by pQCT.

We have tested the ability of the XCT960A to detect bone loss in OVX-rats, as well as bone gain in the proximal tibial metaphysis of healthy rats treated with hPTH(1-34). The results demonstrated that high precision can be achieved, with CV's for most measurement parameters in the range of 1.6 to 5.9% being obtained in vivo with repositioning of animals. Significant changes in bone parameters in the tibia were observed already at 2 weeks following OVX or PTH-therapy, while whole bone mass measured in the tibia by DEXA ex vivo did not change significantly for up to 24 weeks. For the proximal rat tibia at location 5mm distal to the knee joint was identified as an optimal site. At this location, cortices are fairly parallel thus reducing the partial volume effect, the area is relatively rich in cancellous bone increasing the magnitude of bone gain or loss, and the site (2mm below the growth plate) is relevant for comparisons with histomorphometric measurements. The results demonstrate that pQCT can be adapted for use in small animals such as rats, and that it is a sensitive, reproducible, non-invasive method available to monitor changes in bone mass, bone density, and geometric properties. Future studies should help to establish whether the moment of inertia, moment of resistance and the newly added bone strength index provided by the machine are predictive in any way for bone strength as obtained from biomechanical testing procedures. Peripheral QCT in small animals is an important addition for drug evaluation because it is more sensitive than DEXA and allows for shorter duration of experiments. This non-invasive method can reliably measure changes in cancellous and cortical bone mass over time following ovariectomy or administration of the bone anabolic hormone hPTH(1-34). pQCT should be viewed as a complimentary technique to static and dynamic histomorphometry, which does not replace either of these methods. Its value in the field of basic research should be evaluated.

Analysis of Variance↗
PubMedDate not supplied

[Cryptorchidism].

Cryptorchidism is the most frequent anomaly of an endocrine gland; it entails risks of infertility and testicular cancer. Its pathogenesis is thought to be multifactorial including anatomical and mechanical together with endocrine causes. In the last decades most Authors favoured the hypothesis that some degree of androgen insufficiency during fetal life may play a role in determining testicular maldescent. Morphological alterations have been demonstrated in cryptorchidism testes since birth; both tubular and interstitial damage already can be found in the first months of life. A critical phase in germinal development occurs during the third month when gonadotropin and testosterone postnatal surge induces the first maturational step in germ cells development. In cryptorchid infants, gonadotropin insufficiency at this time reduces germ cells differentiation, leading to progressive germinal decline, which becomes manifest after 12 months of life. In the opinion of some Authors, germinal alteration can be partially reversed by early scrotal reposition of the cryptorchid testes. Hormonal therapy with human chorionic gonadotropin (HCG) and luteinizing hormone releasing hormone (LHRH) has been used in the past decades with variable results. A combination of the two hormones has had a greater effect in inducing testicular descent compared to single hormone treatment. Although some surgeons already treat cryptorchid patients during childhood, an increasing number of pediatric surgeons believe that early treatment, performed during infancy is preferable, when considering the early and progressive histological damage seen in cryptorchid gonads. In our opinion, also hormonal treatment performed during the first year of life seems preferable since it can at the same time induce scrotal descent of cryptorchid testes and substitute postnatal gonadotropin insufficiency.

Adolescent↗
PubMed2006

A prospective evaluation of "ketofol" (ketamine/propofol combination) for procedural sedation and analgesia in the emergency department.

STUDY OBJECTIVE: We evaluate the effectiveness and consider the safety of intravenous ketamine/propofol combination ("ketofol") in the same syringe for procedural sedation and analgesia in the emergency department (ED). METHODS: A prospective case series of consecutive ketofol procedural sedation and analgesia events in the ED of a trauma-receiving community teaching hospital from July 2005 to February 2006 was studied. Patients of all ages, with any comorbid conditions, were included. Ketofol (1:1 mixture of ketamine 10 mg/mL and propofol 10 mg/mL) was administered intravenously at the discretion of the treating physician by using titrated aliquots. The presence or absence of adverse events was documented, as were procedural success, recovery time, and physician, nurse, and patient satisfaction. Physiologic data were recorded with established hospital procedural sedation and analgesia guidelines. RESULTS: One hundred fourteen procedural sedation and analgesia events using ketofol were performed for primarily orthopedic procedures. The median dose of medication administered was ketamine at 0.75 mg/kg and propofol at 0.75 mg/kg (range 0.2 to 2.05 mg/kg each of propofol and ketamine; interquartile range [IQR] 0.6 to 1.0 mg/kg). Procedures were successfully performed without adjunctive sedatives in 110 (96.5%) patients. Three patients (2.6%; 95% confidence interval [CI] 0.6% to 7.5%) had transient hypoxia; of these, 1 (0.9%; 95% CI 0.02% to 4.8%) required bag-valve-mask ventilation. Four patients (3.5%; 95% CI 1.0% to 8.7%) required repositioning for airway malalignment, 4 patients (3.5%; 95% CI 1.0% to 8.7%) required adjunctive medication for sedation, and 3 patients (2.6%; 95% CI 0.6% to 7.5%) had mild unpleasant emergence, of whom 1 (0.9%; 95% CI 0.02% to 4.8%) received midazolam. No patient had hypotension or vomiting or received endotracheal intubation. Median recovery time was 15 minutes (range 5 to 45 minutes; IQR 12 to 19 minutes). Median physician, nurse, and patient satisfaction scores were 10 on a 1-to-10 scale. CONCLUSION: Ketofol procedural sedation and analgesia is effective and appears to be safe for painful procedures in the ED. Few adverse events occurred and were either self-limited or responded to minimal interventions. Recoveries were rapid, and staff and patients were highly satisfied.

Adult↗
PubMed1993

Myocardial distribution of cardioplegic solution after retrograde delivery in patients undergoing cardiac surgical procedures.

The myocardial distribution of both antegrade and retrograde cardioplegia for cardiac surgical intervention, after induction of cardioplegia via the aortic root, was directly assessed and compared in 19 patients by means of contrast echocardiography. Two-dimensional transesophageal echocardiographic images of the short axis of the left ventricle at the level of the papillary muscles were obtained after sonicated Renografin-76 microbubbles were injected into an aortic root and/or transatrial coronary sinus catheter during delivery of cardioplegic solution. Segmental distribution of cardioplegic solution was immediately noted in the myocardium at the time of contrast injections. In 11 of 18 patients (61%) cardioplegic solution was dispersed to all left ventricular myocardial segments after antegrade delivery. In 17 of 19 patients (90%) retrogradely delivered cardioplegic solution (after antegrade induction of cardioplegia in 18 of the 19 patients) was dispersed to all the left ventricular myocardial segments, including the septum. In 2 of the patients, initial lack of retrograde distribution of cardioplegic solution was remedied when the coronary sinus catheter was repositioned and contrast cardioplegic solution was reinjected. Imaging of the right ventricle was possible in only 4 of the 19 patients and revealed that after retrograde delivery, cardioplegic solution had been at least partially distributed to the right ventricle as well. We performed off-line videodensitometric analysis in 9 patients after retrograde delivery of cardioplegic solution. Mean peak pixel-intensity ratio of flow from the endocardium to the epicardium in the left ventricular free wall was 1.46 +/- 0.27, and mean peak pixel-intensity ratio of flow from the left to the right intraventricular septal endocardium was 1.39 +/- 0.33 (p < or = 0.05).

Aged↗
PubMed1999

The IOLAB, Inc pediatric intraocular lens study. AAPOS Reasearch Committee. American Association for Pediatric Ophthalmology and Strabismus.

PURPOSE: This report is a summary of the data of the IOLAB, Inc pediatric intraocular lens (IOL) implantation investigation. The goal of this study was to evaluate the safety and efficacy of IOL implantation for the treatment of pediatric aphakia, pending approval by the Food and Drug Administration. METHODS: From May 1981 to July 1994, a total of 1260 pediatric eyes received 171 styles of IOLs implanted by 361 US investigators. Preoperative, operative, and postoperative status reports over the first year were required for each eye entered into the study. Annual visit reports were requested thereafter to determine the long-term effects. The study was terminated in November 1995. All IOLs were obtained from IOLAB, Inc (now Chiron Vision Corp). RESULTS: Reporting compliance was 98.3% for the preoperative and operative reports, 45.1% at 1 year, and 13.8% at 3 years. The subjects' ages ranged from younger than 1 yearto 17 years. Nine subjects (0.7%) were younger than 1 year, with the largest group of 533 subjects (42.3%) aged between 6 and 12 years atthe time of surgery. Cataract types were congenital (45.6%), traumatic (37.1%), secondary (11%), senile (0.95%), and unrecorded (5.4%). The IOL was implanted primarily in 74.8% of cases and secondarily in 21.4% of cases. There was no record in 3.8% of the cases. IOL types included anterior chamber (4.1%), iridocapsular (0.71%), posterior chamber (93.6%), and unrecorded (1.59%). There were 130 adverse reactions that required secondary surgical intervention. The most frequently performed surgical procedures included lens removal without replacement, vitrectomy, lens repositioning, and lens replacement. More than half (52%) of all eyes had a visual acuity of 20/200 or worse before surgery; amblyopia was reported in 21.1% of all participants at baseline. Postoperative visual acuity data were available on 563 eyes at 1 year after surgery. Overall, 52.8% of all eyes attained a visual acuity of 20/40 or better by the 1-year visit, and only 15.5% had visual acuity worse than 20/200. In general, the older patient, traumatic cataract, and secondary cataract categories were overrepresented in the better visual acuity outcome group. CONCLUSION: The IOLAB, Inc pediatric IOL study is the first multiple-practitioner, national study designed to evaluate the safety and efficacy of IOL implantation in children. The study results are compromised by the almost 50% loss of follow-up at the 1-year evaluation. Other variables that most likely influenced outcome results were the methods of cataract extraction, medical management, and IOL design, all of which evolved dramatically over the time course of the study. Despite these issues, pediatric IOL implantation seems to be a reasonable treatment modality for aphakia, on the basis of the available 1-year follow-up data of the remaining 45.1% of eyes in the study.

Adolescent↗
PubMed1983

Treatment of hepatic metastases by transaxillary hepatic artery chemotherapy using an implanted drug pump.

The objective of this study was to evaluate the feasibility of integrating an implantable, refillable drug infusion pump with transaxillary angiographic hepatic arterial catheterization. The implantation is performed under local anesthesia in the radiology suite. A 2-3 cm incision in the left upper arm is made through skin and subcutaneous tissue. Through an axillary artery puncture, a 5.3F polyethylene catheter is fluoroscopically placed into the hepatic artery. To minimize gastroduodenitis, the gastroduodenal artery is occluded with a Gianturco coil and Gelfoam. The Model 400 Infusaid pump is implanted in the upper chest and attached subcutaneously to the angiography catheter using a friction connector. Patients are discharged 2-3 days later. Over a two-year period, 20 such implants have been performed. Floxyuridine (FUdR) has been used by continuous infusion; mitomycin-C (MMC) and 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) by intermittent intra-arterial infusion. The pump/catheter system has been left in place for as long as 18 months. Partial responses in the colorectal cases are as follows: FUdR four of nine patients, MMC two of three, FUdR + MMC one of one, and FUdR + MMC + BCNU three of three. No arm vascular complications, hepatic arterial occlusions, peripheral emboli, pump malfunctions, or catheter occlusions took place over a total experience of 3210 patient days. Three catheter migrations occurred requiring repositioning in two patients, and three cracked catheters required replacement. This innovative approach offers a comfortable, convenient method for long-term ambulatory hepatic arterial chemotherapy obviating both laparotomy and extra-corporeal pumps.

Antineoplastic Agents↗
PubMed2004

Technical modification in the intracarotid chemotherapy and osmotic blood-brain barrier disruption procedure to prevent the relapse of carboplatin-induced orbital pseudotumor.

The blood-brain barrier disruption (BBBD) procedure is an established strategy to enhance drug delivery to brain tumors. Complication rates associated with this procedure are usually low, but when complications do occur, they usually mandate discontinuation of treatment. Orbital pseudotumor is an inflammatory condition of one or more extraocular muscles that produces limitation of ocular motility. Patients usually experience sudden diplopia associated with orbital pain, conjunctival chemosis and injection, and proptosis. Imaging of the orbit shows diffuse enlargement of the extraocular muscles, exophthalmia, and, rarely, sinusal or intracranial infiltration. On pathologic examinations, the soft tissues of the orbit are infiltrated with a mixture of eosinophils, lymphocytes, and plasma cells. Many etiologies can induce this syndrome, including the intracarotid infusion of platinum molecules. As part of a phase II study, a total of 110 patients were treated for malignant brain tumors with intra-arterial carboplatin, enhanced by the BBBD procedure, at the Sherbrooke University Hospital. Here we report on three patients who developed orbital pseudotumor ipsilateral to the carotid infused a few hours to days after the procedure. After the occurrence of this syndrome in the first patient, we developed a technical modification to the procedure that enabled uninterrupted treatment in the other two patients. This modification was as follows: after the mannitol infusion, and before carboplatin, the catheter was changed for a 3.5 tracker and was repositioned just above the emergence of the ophthalmic artery.

Adult↗
PubMed2006

Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease.

OBJECTIVE: Glial cell line-derived neurotrophic factor (GDNF) exerts potent trophic influence on midbrain dopaminergic neurons. This randomized controlled clinical trial was designed to confirm initial clinical benefits observed in a small, open-label trial using intraputamenal (Ipu) infusion of recombinant human GDNF (liatermin). METHODS: Thirty-four PD patients were randomized 1 to 1 to receive bilateral continuous Ipu infusion of liatermin 15 microg/putamen/day or placebo. The primary end point was the change in Unified Parkinson Disease Rating Scale (UPDRS) motor score in the practically defined off condition at 6 months. Secondary end points included other UPDRS scores, motor tests, dyskinesia ratings, patient diaries, and (18)F-dopa uptake. RESULTS: At 6 months, mean percentage changes in "off" UPDRS motor score were -10.0% and -4.5% in the liatermin and placebo groups, respectively. This treatment difference was not significant (95% confidence interval, -23.0 to 12.0, p = 0.53). Secondary end point results were similar between the groups. A 32.5% treatment difference favoring liatermin in mean (18)F-dopa influx constant (p = 0.019) was observed. Serious, device-related adverse events required surgical repositioning of catheters in two patients and removal of devices in another. Neutralizing antiliatermin antibodies were detected in three patients (one on-study and two in the open-label extension). INTERPRETATION: Liatermin did not confer the predetermined level of clinical benefit to patients with PD despite increased (18)F-dopa uptake. It is uncertain whether technical differences between this trial and positive open-label studies contributed in any way this negative outcome.

Adult↗