Nanosecond laser therapy reverses pathologic and molecular changes in age-related macular degeneration without retinal damage.

Age-related macular degeneration (AMD) is a leading cause of vision loss, characterized by drusen deposits and thickened Bruch's membrane (BM). This study details the capacity of nanosecond laser treatment to reduce drusen and thin BM while maintaining retinal structure. Fifty patients with AMD had a single nanosecond laser treatment session and after 2 yr, change in drusen area was compared with an untreated cohort of patients. The retinal effect of the laser was determined in human and mouse eyes using immunohistochemistry and compared with untreated eyes. In a mouse with thickened BM (ApoEnull), the effect of laser treatment was quantified using electron microscopy and quantitative PCR. In patients with AMD, nanosecond laser treatment reduced drusen load at 2 yr. Retinal structure was not compromised in human and mouse retina after laser treatment, with only a discrete retinal pigment epithelium (RPE) injury, and limited mononuclear cell response observed. BM was thinned in the ApoEnull mouse 3 mo after treatment (ApoEnull treated 683 ± 38 nm, ApoEnull untreated 890 ± 60 nm, C57Bl6J 606 ± 43 nm), with the expression of matrix metalloproteinase-2 and -3 increased (>260%). Nanosecond laser resolved drusen independent of retinal damage and improved BM structure, suggesting this treatment has the potential to reduce AMD progression.

Asian MODY: are we missing an important diagnosis?

AIMS: Maturity onset diabetes of the young (MODY) is a monogenic form of diabetes where correct diagnosis alters treatment, prognosis and genetic counselling. The first UK survey of childhood MODY identified 20 White, but no Asian children with MODY. We hypothesized that MODY causes diabetes in UK Asians, but is underdiagnosed. METHODS: Children with dominant family histories of diabetes were recruited. Direct sequencing for mutations in the two most common MODY genes; HNF1A (TCF1) and GCK was performed in autoantibody-negative probands. We also compared MODY testing data for Asian and White cases from the Exeter MODY database, to 2001 UK census data. RESULTS: We recruited 30 families and identified three Asian families with MODY gene mutations (two HNF1A, one GCK) and three White UK families (two HNF1A, one GCK). Heterozygous MODY phenotypes were similar in Asians and Whites. Only eight (0.5%) of 1369 UK referrals for MODY testing were known to be Asian, but in 2001 Asians represented 4% of the English/Welsh population and have a higher prevalence of diabetes. CONCLUSIONS: We identified three cases of childhood MODY in UK Asians and demonstrated reduced rates of MODY testing in Asians, which has negative implications for treatment. It is unclear why this is. MODY should be considered in autoantibody-negative Asian diabetes patients lacking evidence of insulin resistance.

Solid-phase synthesis of 2,4-diaminoquinazoline libraries.

A series of libraries containing the 2,4-diaminoquinazoline ring system were prepared, starting from polymer-bound amines. The key steps included reaction of the support-bound amine with 6,7-dimethoxy-2,4-dichloroquinazoline, followed by displacement of the second chlorine with an amine and subsequent TFA-mediated cleavage of the product from the support. When a symmetrical or unsymmetrical diamine was used in the displacement step, the free amine could be acylated with an activated acid to generate another set of compounds. The optimization of conditions for the reductive amination and displacement steps will be discussed as well as the final choice of resin for library production. In addition, quality control methods for library analysis is also described.

Physiologic periosteal changes in infancy.

Surface modulation is part of normal bone growth. However, the radiologic appearance of physiologically growing bone in infancy may resemble changes secondary to trauma. This case report reviews bone remodeling in the postnatal infant and describes its unique radiologic and pathologic characteristics, allowing normal to be differentiated from healing and repair.

Staged repair of acute type I aortic dissection and coarctation in pregnancy.

A 29-year-old gravid female presented at 22 weeks gestation with an acute Type I aortic dissection and coarctation of the aorta. She underwent emergent repair of her aortic dissection using cardiopulmonary bypass and hypothermia. At 25 weeks gestation, she underwent repair of her coarctation of the aorta. The patient had a cesarean delivery of a viable, normal male infant at 39 weeks gestation.

The latent structure of substance use among American Indian adolescents: an example using categorical variables.

Researchers frequently have only categorical data to analyze and cannot, for theoretical or methodological reasons, assume that the observed variables are discrete representations of an underlying continuous variable. We present latent class analysis as an alternative method of measuring latent variables in these circumstances. Latent class analysis does not require the assumptions of factor analyses about the nature of manifest and latent variables, but does allow the use of more precise model selection than techniques such as cluster analysis. We modeled the lifetime substance use of American Indian youth. The latent class model of American Indian teenagers' substance use had four classes: Abstaining, Predominantly Alcohol, Predominantly Alcohol and Marijuana, and Plural Substance. We then demonstrated the usefulness of this latent variable by using it to differentiate levels of several variables in a manner consistent with Social Cognitive Theory.

Benzodiazepine compounds as inhibitors of the src protein tyrosine kinase: screening of a combinatorial library of 1,4-benzodiazepines.

We screened 1680 spatially separated compounds of a diverse combinatorial library of 1,4-benzodiazepines for their ability to inhibit the kinase activity of protein tyrosine kinases Src, Yes, Abl, Lck, Csk, and fibroblast growth factor receptor. This screening yielded novel ligands for the protein tyrosine kinase Src. In the 1, 4-benzodiazepine-2-one scaffold, the preferred substituent at position R(1) was 4-hydroxyphenylmethyl or a 3-indolemethyl derived from a tyrosine or tyrptophan used in building the benzodiazepine, while the substituent at R(2), introduced by alkylating agents, was preferably aromatic in nature. The preferred ring structure introduced on the bicyclic ring of the scaffold by acid chlorides was a p-hydroxy phenyl group. The lead compound, designated as N-L-Yaa, has a L-4-hydroxyphenylmethyl ring at R(1) and a biphenylmethyl substituent at R(2). The compound has an IC(50) of 73 microM against Src, 2- to 6-fold lower than against other protein tyrosine kinases and >10-fold lower than against other nucleotide-utilizing enzymes. The mechanism of binding of N-L-Yaa to Src is mixed against the peptidic substrate with a K(i) of 35 microM and noncompetitive against ATP-Mg with a K(i) of 17 microM. Multiple inhibition analysis of the lead compound in the presence of other competitive inhibitors demonstrated that the binding of the lead compound is nonexclusive to the other competitive inhibitor. The inhibitor was found to be nontoxic to the AFB-13-human fibroblasts cells and inhibited the colony formation of HT-29 colon adenocarcinoma cells that are dependent on Src activity.

Interface of epilepsy and sleep disorders.

Obstructive sleep apnoea was first brought to prominence by Henri Gastaut, a French epileptologist. Since that time the interface between epilepsy and sleep disorders has received less attention than might be justified, recognizing that sleep deprivation is a poignant provocateur for seizures. Sleep deprivation is often used as a diagnostic procedure during electroencephalography (EEG) when waking EEG has failed to demonstrate abnormality. Patients referred to an outpatient neurological clinic for evaluation of possible seizures in whom sleep disorder was suspected, either due to snoring during the EEG or based on history, were evaluated with all-night diagnostic polysomnography (PSG) and appropriate intervention administered as indicated. Patient and seizure demography, sleep disorder and response to therapy were reviewed and the interface explored. Fifty patients aged between 10 and 83 years underwent PSG. Approximately half were diagnosed with epilepsy and almost three-quarters had sleep disorders sufficiently intrusive to require therapy (either continuous positive air pressure (CPAP) or medication). With co-existence of epilepsy and sleep disorders, proper management of sleep disorders provided significant benefit for seizure control. Snoring during EEG recordings could alert to the possibility of a sleep disorder even with epilepsy diagnosed. Where both epilepsy and sleep disorder coexist appropriate management of the sleep disorder improves control of the epilepsy.

Computed tomography-guided wire localization of pulmonary lesions before thoracoscopic resection: results in 101 cases.

The authors determine the success rate, safety, and potential complications of computed tomography-guided preoperative hookwire localization of small peripheral pulmonary nodules. One hundred one consecutive wire localizations with addition of methylene blue injection were performed in 94 patients immediately before thoracoscopic resection of small lung lesions. Sixty-two patients had a known primary malignancy, whereas 32 had an asymptomatic nodule. Eighty-eight patients underwent single lesion localization, five underwent double localization, and one underwent triple wire placement. Five patients had previously undergone percutaneous biopsy that was nondiagnostic. The nodule was within the first wedge biopsy of lung tissue in 95 of 97 specimens (98%). A second wedge and an open lobectomy were required in one patient each. Three additional biopsies were intraoperatively deferred after the histologic diagnosis was established after removal of another nodule. The procedure was terminated before wire placement in one patient who was unable to successfully hold his breath. The wire dislodged with the tip in the pleural space rather than in the lung parenchyma in 22 cases; however, methylene blue tattoo allowed localization in 13 of these (59%). In the other nine cases, extra portals, digital palpation, or expanded wedge resection was required. Complications included pneumothorax in 48 cases, moderate pleuritic pain in five cases, seven small intercostal hematomas, and a 7-mm wire fragment retained in one patient's lung along the suture line. No patient required a preoperative drain for treatment of pneumothorax. Wire dislodgement occurred in 6 of 52 (12%) cases without an initial pneumothorax and in 16 of 48 (33%) cases if a pneumothorax occurred. Wires dislodged less frequently if placed either directly into or through the nodule in 11 of 64 (17%) cases than if placed adjacent to the nodule in 11 of 36 (31%) cases. Average wire tip depth from the visceral pleura was significantly less when the wire dislodged (11 mm) than when the wire remained in place (25 mm). Wire localization of small peripheral pulmonary nodules is a safe and effective procedure to assist thoracoscopic sublobectomy resection.

Use of the "chimney patch" technique for Norwood stage I procedures.

The Norwood stage I procedure is often used for the initial treatment of infants with hypoplastic left heart syndrome. This procedure creates a systemic arterial to pulmonary artery shunt to establish pulmonary blood flow. We describe a method to facilitate placement of this shunt by attaching a polytetrafluoroethylene shunt to a pulmonary artery homograft patch before performing the median sternotomy. This technique facilitates the performance of the proximal shunt anastomosis and expedites the procedure.

Homograft replacement of mitral valve in children.

BACKGROUND: Recent reports have demonstrated successful early outcomes using mitral valve homografts in adults. We report our early results after homograft mitral valve replacement in 4 children with previous atrioventricular septal defects, previous placement of a prosthetic valve, and rheumatic valvular disease. METHODS: Between May 1996 and June 1997, 4 children (ages 5, 11, 13, and 15 years) underwent mitral valve replacement with cryopreserved mitral valve homografts at our institution. Preoperative echocardiography confirmed moderately severe to severe mitral regurgitation, stenosis, or both in all 4 patients. RESULTS: Successful homograft valve replacement was achieved in all 4 patients. Based on symptoms, physical examinations, and echocardiographic follow-up, all four homograft mitral valves are functioning well with normal hemodynamics. None of these patients are receiving warfarin. Follow-up has been limited to 10 months. CONCLUSIONS: In children requiring mitral valve replacement, the use of mitral valve homografts offers advantages over prosthetic valves, such as the avoidance of complications associated with thrombosis and anticoagulation. Homograft mitral valve replacement is technically feasible in children with congenital and rheumatic heart disease and previous prosthetic valves.

Cardiac output responses during exercise in volume-expanded heart transplant recipients.

The mechanisms responsible for immediate adjustments in cardiac output at onset of exercise, in the absence of neural drive, are not well defined in heart transplant (HT) recipients. Seven male HT recipients (mean +/- SD 57 +/- 6 years) and 7 age-matched sedentary normal control subjects (mean age 57 +/- 5 years) performed constant load cycle exercise at 40% of peak power output (Watts). Cardiac output and plasma norepinephrine were determined at rest and every 30 seconds during the first 5 minutes of exercise and at minutes 6, 8, and 10. All subjects were admitted to the General Clinical Research Center for determination of plasma volume. After 3 days of equilibration to a controlled and standardized diet, plasma volume was measured using a modified Evans Blue Dye (T-1824) dilution technique. Heart rate at rest was higher in the HT group (105 +/- 12 vs 74 +/- 6 beats/min), but during submaximum exercise, heart rates in the control group increased more rapidly (p < or = 0.05) and to a greater magnitude (54 +/- 7% vs 17 +/- 4% above rest). Stroke volume at rest was lower in HT recipients (45 +/- 4 vs 68 +/- 9 ml) but was significantly augmented immediately after onset of exercise (30 seconds) and the relative increase was greater than controls at peak exercise (61% vs 38% greater than baseline). Cardiac output at rest was within the normal range in both groups (4.58 +/- 0.27 vs 4.94 +/- 0.40 L/min). Relative increases in cardiac output were similar (p > or = 0.05) for the HT (106 +/- 12%) and control groups (97 +/- 10%). Plasma norepinephrine did not become significantly greater than resting values until approximately 4 minutes after onset of exercise in both groups. Blood volume, normalized for body weight, was 12% greater in the HT group. Thus, HT recipients with expanded blood volume (12%) augment stroke volume immediately after the onset of exercise. Plasma norepinephrine levels contribute negligibly to the rapid adjustment in cardiac output. Rather, we speculate that abrupt on-transit increases in stroke volume are due to augmented venous return, secondary to expanded blood volume.

Covert video recordings of life-threatening child abuse: lessons for child protection.

OBJECTIVE: To describe historic markers and clinical observations of life-threatening child abuse as diagnosed using covert video surveillance (CVS). DESIGN: A descriptive, retrospective, partially controlled case study. SETTING: Two hospitals (in London and North Staffordshire, UK) receiving referrals for the investigation of apparent life-threatening events (ALTE), with the availability of CVS. PATIENTS: A total of 39 children (age range at CVS, 2 to 44 months; median, 9 months) in whom hospital CVS was used to investigate suspicions of induced illness. Thirty-six were referred for investigation of ALTE, one with suspected epilepsy, one with failure to thrive, and one with suspected strangulation. A control group consisted of 46 children with recurrent ALTE proven on physiologic recordings to be attributable to a natural medical cause (9 attributable to epileptic seizures, and 37 attributable to respiratory problems). INTERVENTION: Collection of historic details from medical, social service, and police records; interagency collaboration in planning, investigations, and management; development and use of CVS as a clinical tool in the investigation of patients in whom there was suspicion of induced illness. OUTCOME: Confirmation of attempted suffocation or other child abuse from CVS. RESULTS: CVS revealed abuse in 33 of 39 suspected cases, with documentation of intentional suffocation observed in 30 patients. Poisonings (with disinfectant or anticonvulsant), a deliberate fracture, and other emotional and physical abuse were also identified under surveillance. The first ALTE occurred at a median age corrected for the expected date of delivery of 3.6 months in the CVS patients and of 0.3 months in controls. Three CVS patients and 27 of the control children (including 20 at <32 weeks' gestation) were born prematurely. Bleeding from the nose and/or mouth was reported in 11 of the 38 patients with ALTE undergoing CVS but in none of the 46 controls. Four patients who had been subjected to recurrent suffocation before CVS had permanent neurologic deficits and/or required anticonvulsant therapy for epileptic seizures resulting from hypoxic cerebral injury. The 39 patients undergoing CVS had 41 siblings, 12 of whom had previously died suddenly and unexpectedly. Eleven of the deaths had been classified as sudden infant death syndrome but after CVS, four parents admitted to suffocating eight of these siblings. One additional sibling who had died suddenly with rotavirus gastroenteritis was reinvestigated after CVS of her sister revealed poisoning, and death was found to be caused by deliberate salt poisoning. Other signs of abuse were documented in the medical, social, and police records of an additional 15 of the siblings. In the 52 siblings of the 46 controls, 2 had died: one from hypoplastic left heart at 5 days and the other suddenly and unexpectedly (classified as sudden infant death syndrome) at 7 weeks. Twenty-three of the abusive parents were diagnosed by a psychiatrist as having personality disorders. CONCLUSIONS: Induced illness is a severe form of abuse that may cause death or permanent neurologic impairment. It may be accompanied by other severe forms of abuse, may result in behavioral disorders, and may be accompanied by immeasurable suffering. Detection of this abuse requires careful history-taking; thorough examination of the health, social, and police records; and close and focused collaboration between hospital and community child health professionals, child psychiatrists, social workers, and police officers. CVS may help investigate suspicions and ensure that children are protected from additional abuse. When parents have failed to acknowledge that they have deceived health professionals, partnership with them in seeking to protect their children may be neither safe nor effective.

Chronic hypoxia induces adaptive metabolic changes in neonatal myocardium.

The effect of chronic hypoxia on neonatal myocardial metabolism remains undefined. With a new neonatal piglet model, we determined changes in myocardial metabolism during global ischemia after chronic hypoxia. Five-day-old piglets (N = 30) were randomly assigned to two groups and exposed to an atmosphere of 8% oxygen or to room air for 28 days before they were killed. Left ventricular myocardium was then analyzed at control and at 15-minute intervals during 60 minutes of global normothermic ischemia to determine high-energy phosphate levels, glycogen stores, and lactate accumulation. Time to peak ischemic myocardial contracture was measured with intramyocardial needle-tipped Millar catheters as a marker of the onset of irreversible ischemic injury. Results showed an initially greater level of myocardial adenosine triphosphate in the hypoxic group (27 +/- 1.2 vs 19 +/- 1.8 micromol/gm dry wt, p = 0.001) and a delay in adenosine triphosphate depletion during 60 minutes of global ischemia compared with the control group. Initial energy charge ratios (1/2 adenosine diphosphate + adenosine triphosphate/adenosine monophosphate + adenosine diphosphate + adenosine triphosphate) were also greater in the hypoxic group (0.96 +/- 0.01 vs 0.81 +/- 0.04, p = 0.01) and remained so throughout global ischemia. Initial glycogen stores were greater in the hypoxic group (273 +/- 13.3 vs 215 +/- 14.7 micromol/gm dry weight, p = 0.02) when compared with the control group. Lactate levels in the hypoxic group were initially higher (19.1 +/- 6.4 vs 8.9 +/- 3.1 micromol/gm dry weight, p = 0.001) compared with control levels and remained elevated throughout 60 minutes of ischemia. Time to peak ischemic contracture was prolonged in the hypoxic group (69.5 +/- 1.8 vs 48.9 +/- 1.4 minutes, p = 0.001) compared with the controls group. These data show that chronic hypoxia results in significant myocardial metabolic adaptive changes, which in turn result in an improved tolerance to severe normothermic ischemia. These beneficial effects are associated with elevated baseline glycogen storage levels and an accelerated rate of anaerobic glycolysis during ischemia.

Pharmacological intervention in antibody mediated disease.

The use of single signal anergy to inactive pathological B cells in an antigen-specific manner is discussed. Cross-linking surface immunoglobulin, with a construct which contains oligovalent B cell epitopes on a non-immunogenic molecular framework can be used to inactivate the target B cells if the construct lacks T cells epitopes. An example of such a B cell toleragen is LJP 394, which inactivates anti-dsDNA-specific B cells in vivo in murine immunized and spontaneous disease models. The drug enhances survival and lowers renal pathology in BXSB mice. Appropriate definition of epitopes of pathological (auto) antibodies thus offers an opportunity for pharmacological intervention.

Analysis of prostate and seminal vesicle motion: implications for treatment planning.

PURPOSE: To quantify prostate and seminal vesicle positional changes (target motion) between treatment planning and delivery, and to identify the factors contributing to target motion. METHODS AND MATERIALS: Thirty patients with adenocarcinoma of the prostate were prospectively evaluated by analyzing two sequential planning computerized tomography (CT) scans (S1, obtained prior to treatment, and S2, obtained during the fourth week of treatment) for each patient. All anatomical volumes of interest (soft tissue and bony) were reconstructed from transverse CT images and projected onto anterior and lateral beam's-eye view projections. Positional changes between S1 and S2 were eliminated by applying a rigid body translation and rotation. Target motion was then measured by recording the positional change between S1 and S2 at the edges (right, left, superior, inferior). Potential correlation of target motion with bladder volume, rectal volume, and rectal diameter changes were evaluated by linear regression analysis. RESULTS: Neither the prostate nor seminal vesicles remained fixed with respect to bony anatomy between S1 and S2. The distribution of positional changes were generally small (< 0.5 cm), but maximum displacements of 1.5-2.2 cm did occur, particularly in the lateral view. In this study, bladder volume changes between the scans were small and did not correlate with target motion (P = 0.67). Both rectal volume and rectal diameter changes correlated with target motion for both the prostate (p = 0.004 and 0.005, respectively) and seminal vesicles (p < 0.001 and < 0.001, respectively). However, neither the initial rectal volume nor the initial rectal diameter could be used to predict subsequent target motion when evaluated either singly or as part of a multiple regression model. CONCLUSIONS: Target motion occurs during the course of treatment planning and delivery and should be considered when designing conformal radiation fields. Although the target position at the time of planning CT may differ substantially from the mean treatment position, target motion cannot be predicted by evaluating simply measured parameters from a single scan, or double scan sequence.