Fetal aortic valvuloplasty: investigating institutional bias in surgical decision-making.

OBJECTIVES: Fetal aortic valvuloplasty may prevent the progression of aortic stenosis to hypoplastic left heart syndrome and allow biventricular rather than univentricular postnatal treatment. This study aimed to investigate whether blinded simulation of a multidisciplinary team approach aids interpretation of multicenter data to uncover institutional bias in postnatal decision-making following fetal cardiac intervention for aortic stenosis. METHODS: The study included 109 cases of prenatally diagnosed aortic stenosis from 13 European countries, of which 32 had undergone fetal cardiac intervention. The multidisciplinary team, blinded to fetal cardiac intervention, institutional location and postnatal treatment, retrospectively assigned a surgical pathway (biventricular or univentricular) based on a review of recorded postnatal imaging and clinical characteristics. The team's decisions were the numerical consensus of silent voting, with case review when a decision was split. Funnel plots showing concordance between the multidisciplinary team and the local team's surgical choice (first pathway) and with outcome (final pathway) were created. RESULTS: In 105 cases the multidisciplinary team reached a consensus decision regarding the surgical pathway, with no decision in four cases because the available imaging records were inadequate. Blinded multidisciplinary team consensus for the first pathway matched the decision of the surgical center in 93/105 (89%) cases, with no difference in agreement between those that had undergone successful fetal cardiac intervention (n = 32) and no (n = 74) or unsuccessful (n = 3) valvuloplasty (no fetal cardiac intervention) (κ = 0.73 (95% CI, 0.38-1.00) vs 0.74 (95% CI, 0.51-0.96)). However, funnel plots comparing multidisciplinary team individual decisions with those of the local teams displayed more discordance (meaning biventricular-univentricular conversion) for the final surgical pathway following fetal cardiac intervention than they did for cases without such intervention (36/74 vs 34/130; P = 0.002), and identified one outlying center. CONCLUSIONS: The use of a blinded multidisciplinary team to simulate decision-making and presentation of data in funnel plots may assist in the interpretation of data submitted to multicenter studies and permit the identification of outliers for further investigation. In the case of aortic stenosis, a high level of agreement was observed between the multidisciplinary team and the surgical centers, but one outlying center was identified.

An unusual manifestation of post-transplant lymphoproliferative disorder in the lip after pediatric heart transplantation.

PTLD is a serious and frequently observed complication after solid organ transplantation. We present a six-yr-old girl with a rapidly growing, solid tumor of the lip four yr after orthotopic heart transplantation, which was classified as monomorphic PTLD with the characteristics of a diffuse large B-cell lymphoma. Treatment with reduction in immunosuppression, ganciclovir, and anti B-cell monoclonal antibody (rituximab) resulted in full remission since 12 months. To the best of our knowledge, this report is the first description of PTLD in the lip in a pediatric patient after heart transplantation in the English literature.

Sonographic assessment of fetal cardiac function: introduction and direct measurement of cardiac function.

Noninvasive blood flow measurements based on Doppler ultrasound studies are the main clinical tool for studying the cardiovascular status in fetuses at risk for circulatory compromise. Usually, qualitative analysis of peripheral arteries and, in particular clinical situations such as severe growth restriction or volume overload, also of venous vessels close to the heart or of flow patterns in the heart are being used to gauge the level of compensation in a fetus. Quantitative assessment of the driving force of the fetal circulation, the cardiac output, however, remains an elusive goal in fetal medicine. This article reviews the methods for direct and indirect assessment of cardiac function and explains new clinical applications. Part 1 of this review describes the concept of cardiac function and cardiac output and the techniques that have been used to quantify output. Part 2 summarizes the use of arterial and venous Doppler studies in the fetus and gives a detailed description of indirect measures of cardiac function (like indices derived from the duration of segments of the cardiac cycle) with current examples of their application.

Sonographic assessment of fetal cardiac function: indirect measurements of fetal cardiac function, newer techniques and clinical applications.

Noninvasive blood flow measurements based on Doppler ultrasound studies are the main clinical tool for studying the cardiovascular status of fetuses at risk for circulatory compromise. Usually, qualitative analysis of peripheral arteries and in particular clinical situations such as severe growth restriction or volume overload also of venous vessels close to the heart or of flow patterns in the heart is being used to gauge the level of compensation in a fetus. However, quantitative assessment of the driving force of the fetal circulation, the cardiac output remains an elusive goal in fetal medicine. This article reviews the methods for direct and indirect assessment of cardiac function and explains new clinical applications. Part 1 of this review describes the concept of cardiac function and cardiac output and the techniques that have been used to quantify output. Part 2 summarizes the use of arterial and venous Doppler studies in the fetus and gives a detailed description of indirect measurements of cardiac function (like indices derived from the duration of segments of the cardiac cycle) with current examples of their application.

Pulsed-wave tissue Doppler echocardiography for the analysis of fetal cardiac arrhythmias.

OBJECTIVES: Rhythm analysis of the fetal heart is hampered by the inability to routinely obtain electrocardiographic recordings of the fetus. Doppler studies of fetal cardiac tissue movements, assessing cardiac movements both qualitatively and quantitatively, have recently been described. We used a conventional high-resolution ultrasound system to obtain rhythm data from pulsed-wave tissue Doppler signals of the fetal heart in normal cardiac rhythm and in a variety of fetal cardiac arrhythmias. METHODS: Fifty-five fetuses with normal (sinus) rhythm, 45 fetuses with rhythm disturbances and two neonates (one with arrhythmia and one with normal sinus rhythm) were studied. Using a conventional high-resolution ultrasound system equipped for fetal studies, but without specific tissue Doppler hardware or software, we performed pulsed-wave tissue Doppler echocardiography (PW-TDE) of atrioventricular valve ring excursions to study the atrial and ventricular mechanical actions. In the neonates, electrocardiograms were also recorded. RESULTS: PW-TDE in normal fetuses shows a typical pattern of tissue motion parallel to the long axis of the heart and in the opposite direction to the blood flow, both in systole and diastole. This pattern is easily obtained from the tricuspid valve annulus in normal sinus rhythm and shows characteristic changes in various fetal arrhythmias. CONCLUSION: PW-TDE of atrioventricular valve annulus movement patterns may prove to be a valuable additional tool for assessing fetal cardiac arrhythmias.

Lowering of IOP by echothiophate iodide in pseudophakic eyes with glaucoma.

PURPOSE: We retrospectively investigated the intraocular pressure (IOP)-lowering effects of echothiophate iodide (EI) as adjunctive treatment for pseudophakic glaucoma patients who were receiving maximal medical therapy (MMT), including the newer class of medications, i.e., prostaglandin analogs, alpha-2 agonists, and topical carbonic anhydrase inhibitors. METHODS: The medical records of all pseudophakic glaucoma patients (24 eyes) under MMT who received supplementary EI 0.125% between January 2002 and December 2003 were reviewed. IOP data and number of medications before, during and after EI treatment were collected. RESULTS: Adding EI to MMT further reduced IOP in 23 of 24 eyes. Three eyes (12.5%) showed some lowering of IOP, but not enough to be considered controlled (IOP above the target pressure). The mean baseline IOP of 30.4 +/- 8.2 mmHg (median 29 mmHg) dropped at final follow-up (11.2 +/- 3.9 months) to 16.6 +/- 4.2 mmHg (median 17 mmHg, p < 0.0001) in all eyes that had showed effective pressure reduction upon the addition of EI. Their IOP rose to 27.7 +/- 8.0 mmHg (median 28 mmHg, p < 0.001) when EI was discontinued because of commercial non-availability. IOP reduction was > or =20% in 18 (75%) eyes and > or =30% (a mean decrease of 16.7 +/- 8.3mmHg) in 15 eyes (63%). Four eyes (16.6%) required a trabeculectomy despite EI supplement. Five eyes were re-challenged with EI when a small amount was released for sale: their IOP of 26.6 +/- 7.1 mmHg after the first EI discontinuation had dropped to 16.4 +/- 4.3 mmHg (p < 0.0001) and rose to 29.6 +/- 7.1 mmHg when EI was again discontinued. The recorded EI-associated side effects were increased miosis in all eyes and headache (8/24 patients), neither of which were reasons for discontinuation of the drug in any patient. CONCLUSION: EI substantially decreased the IOPs in pseudophakic glaucoma eyes receiving maximal medical therapy, including the newer class of medications. This drug may be the last resort for post-cataract advanced glaucoma patients and may obviate the need for filtering surgery among the very elderly.

[Comparative investigation of treatments for evaporative dry eye]. / Vergleichende Untersuchung zur Therapie des evaporativen trockenen Auges.

BACKGROUND: Evaporative dry eye is the most common form of tear film dysfunction. The present trial aims to evaluate the efficacy of two established treatment options with different modes of action by comparison. PATIENTS/MATERIAL AND METHODS: 216 patients suffering from evaporative dry eye were included in this prospective, randomised two-centre trial. Divided into two treatment groups, patients either received treatment with hyaluronate artificial tears (Vismed light) or a phospholipid-liposome eye spray (Tears Again), each for three months. Tests (lid-parallel conjunctival folds [LIPCOF], non-invasive break-up time [NIBUT], Schirmer's test, inspection of lids and subjective assessment) were performed before as well as 4 and 12 weeks after initiation of this study. RESULTS: In the patients of the eye spray group there was a significantly greater reduction of the LIPCOF grade (p < 0.02) and the grade of inflammation of the lid margin (p < 0.002). With respect to the tear film break-up time (NIBUT) there was a significant difference between the results of both groups (p < 0.003). The improvement of the break-up time in patients of the eye spray group turned out to be more than twice as high as that in the artificial tears group. CONCLUSIONS: Both therapies improved evaporative dry eye, but patients on phospholipid-liposomal eye spray demonstrated greater clinical benefit from their therapy, particularly regarding the degree of inflammation of the lid margins as well as the grade of LIPCOF. When compared to hyaluronate artificial tears, NIBUT more than doubled in the phospholipid-liposome eye spray group. Clinical severity of dry eye is more pronounced when evaporative dry eye and aqueous tear deficiency coincide. A combination of the phospholipid-liposome eye spray and artificial tears appears to represent a considerable advancement in tear replacement therapy for severe cases of dry eye.

Two further cases supporting nonsurgical management in congenital lobar emphysema.

BACKGROUND: For decades, the well-established standard recommended treatment for patients with congenital lobar emphysema (CLE) and respiratory distress has been lobectomy of the affected lobe or lobes, whereas indications for conservative management have been controversially discussed. PATIENTS/METHODS: Description of the clinical courses including the results of diagnostic procedures and the resulting therapeutic strategies in 2 patients with congenital lobar emphysema. We review the literature on conservatively treated patients with congenital lobar emphysema. RESULTS: Considering that formerly asserted hypotheses postulating benefits of surgical treatment cannot unambiguously be corroborated from cases in literature, we could show that conservative treatment in patients with congenital lobar emphysema is appropriate in mildly to moderately symptomatic children. CONCLUSION: Conservative treatment of children with congenital lobar emphysema is an attractive option, whenever justifiable on medical grounds. Our cases may serve as paradigms in decision-making processes in similar cases and - together with the literature review - may be helpful to avoid unnecessary lobectomies in children. Patients treated conservatively will need a close follow-up, and further data on long-term follow-up courses are desirable.

Present risk of anthracycline or radiation-induced cardiac sequelae following therapy of malignancies in children and adolescents.

Anthracyclines are very potent drugs in the therapy of malignancies in childhood. The major dose limiting adverse effect of these drugs is the risk of dilated cardiomyopathy. We performed a retrospective study on 168 patients who were treated with anthracyclines for a malignant disease with or without chest radiation at the department of Pediatric Hematology and Oncology at the University of Duesseldorf between 2000 and 2004. During and after chemotherapy the patients were screened by echocardiography and ECG examinations prior to each administration of anthracyclines. Only four patients presented with adverse cardiac events, one of whom developed acute cardiac failure. This patient was additionally treated with chest radiation. Three of the four patients showed intermittent arrhythmias, mainly supraventricular tachycardia. One of them presented with atrial ectopic tachycardia and left ventricular dysfunction. We conclude that the frequency of cardiac sequelae after chemotherapy with anthracyclines is low under present guidelines. Detection of early cardiac sequelae may be more difficult than in the past. Only one patient with cardiac sequelae in our study group was diagnosed by regular performed examinations for cardiac sequelae of chemotherapy. We therefore need to modify our screening methods to increase the effectiveness of detection of cardiac dysfunction prior to clinical manifestation.

Levoatrial cardinal vein in mitral atresia and closed foramen ovale: prenatal diagnosis and perinatal management.

A levoatrial cardinal vein is a rare cardiovascular anomaly that may be present in malformed hearts with severe left heart obstruction and restrictive interatrial communication. We report the prenatal diagnosis at 23 weeks of a fetus with mitral atresia, double-outlet right ventricle, premature closure of the foramen ovale and a levoatrial cardinal vein draining into the innominate vein. In a prior examination performed elsewhere the levoatrial cardinal vein had been interpreted as an aortic arch perfused retrogradely, and hypoplastic left heart syndrome with aortic atresia had been diagnosed. Prenatal management, induction at 38 weeks and postnatal examinations and treatment are reported. To the best of our knowledge, this is the first reported prenatal diagnosis of this embryological vessel, presenting a potential pitfall for prenatal echocardiography.

Neurodegenerative diseases of the retina and potential for protection and recovery.

Recent advances in our understanding of the mechanisms in the cascade of events resulting in retinal cell death in ocular pathologies like glaucoma, diabetic retinopathy and age-related macular degeneration led to the common descriptive term of neurodegenerative diseases of the retina. The final common pathophysiologic pathway of these diseases includes a particular form of metabolic stress, resulting in an insufficient supply of nutrients to the respective target structures (optic nerve head, retina). During metabolic stress, glutamate is released initiating the death of neurones containing ionotropic glutamate (N-methyl-D-aspartat, NMDA) receptors present on ganglion cells and a specific type of amacrine cells. Experimental studies demonstrate that several drugs reduce or prevent the death of retinal neurones deficient of nutrients. These agents generally block NMDA receptors to prevent the action of glutamate or halt the subsequent pathophysiologic cycle resulting in cell death. The major causes for cell death following activation of NMDA receptors are the influx of calcium and sodium into cells, the generation of free radicals linked to the formation of advanced glycation endproducts (AGEs) and/or advanced lipoxidation endproducts (ALEs) as well as defects in the mitochondrial respiratory chain. Substances preventing these cytotoxic events are considered to be potentially neuroprotective.

Development and application of a specially designed heating system for temperature-programmed high-performance liquid chromatography using subcritical water as the mobile phase.

A specially designed heating system for temperature-programmed HPLC was developed based on experimental measurements of eluent temperature inside a stainless steel capillary using a very thin thermocouple. The heating system can be operated at temperatures up to 225 degrees C and consists of a preheating, a column heating and a cooling unit. Fast cycle times after a temperature gradient can be realized by an internal silicone oil bath which cools down the preheating and column heating unit. Long-term thermal stability of a polybutadiene-coated zirconium dioxide column has been evaluated using a tubular oven in which the column was placed. The packing material was stable after 50h of operation at 185 degrees C. A mixture containing four steroids was separated at ambient conditions using a mobile phase of 25% acetonitrile:75% deionized water and a mobile phase of pure deionized water at 185 degrees C using the specially designed heating system and the PBD column. Analysis time could be drastically reduced from 17 min at ambient conditions and a flow rate of 1 mL/min to only 1.2 min at 185 degrees C and a flow rate of 5 mL/min. At these extreme conditions, no thermal mismatch was observed and peaks were not distorted, thus underlining the performance of the developed heating system. Temperature programming was performed by separating cytostatic and antibiotic drugs with a temperature gradient using only water as the mobile phase. In contrast to an isocratic elution of this mixture at room temperature, overall analysis time could be reduced two-fold from 20 to 10 min.

Acute hemorrhagic pericarditis in a child with pneumonia due to Chlamydophila pneumoniae.

Chlamydophila pneumoniae is mainly responsible for respiratory tract infections but has also been associated with endocarditis and myocarditis. We report a case of pneumonia in a child with hemorrhagic pericardial effusion with a positive result by a new C. pneumoniae TaqMan PCR, suggesting a pericardial inflammation directly induced by C. pneumoniae. C. pneumoniae should be suspected in patients with community-acquired pneumonia and concurrent pericarditis. Empirical treatment with azithromycin seems feasible.

[Ischemia and hypoxia. An attempt to explain the different rates of retinal ganglion cell death in glaucoma]. / Ischämie und Hypoxie. Ein Erklärungsversuch zur unterschiedlichen Absterberate retinaler Ganglienzellen bei Glaukom.

In hypoxic or ischemic states, the receptors of the ganglion cells are overstimulated by release of neurotransmitters. Glutamate and GABA (gamma-aminobutyric acid) are the decisive neurotransmitters in the retina. It is presumed that the extent of cell death depends on the degree of depolarization, which in turn is determined by the amount of excitatory (glutamate) or inhibitory (GABA) receptors of the corresponding ganglion cell. The assumption is that the receptor profile of the individual ganglion cells determines the sensitivity of these cells to hypoxia or ischemia, i.e., the time up to cell death, and thus represents the underlying cause of the different rates of cell death in primary chronic open-angle glaucoma. Research on this receptor profile could be of pivotal importance for the approach to neuroprotective treatment of primary chronic open-angle glaucoma.

[Mechanisms of neuroprotection against glaucoma]. / Mechanismen der Neuroprotektion bei Glaukomen.

The goal of neuroprotection in glaucoma treatment is to employ agents that prevent or delay apoptosis of retinal ganglion cells (RGC) and facilitate regeneration of already damaged calls. The following contribution discusses the mechanisms of RGC death and current status of neuroprotective in vivo studies and investigations on cell cultures and animal models. Discussions on the etiopathogenesis of PCOAG center on elevated IOP and ocular disorders of vascular function. The mechanisms of axonal damage induced by ischemia are explained and the resultant possible neuroprotective effect mechanisms are discussed (Na(+) or Ca(2+) channel blockers, role of reactive astrocytes). Substitution of axonal survival factors and especially the role of BDNF are described. Glutamate excitotoxicity also plays a role in glaucomatous antegrade RGC death. Relevant questions and possible therapeutic approaches are discussed. The three phases of apoptosis cascade and the key role of mitochondria in the insult-induced apoptosis are considered as well as the still relatively unexplored possibilities of RGC regeneration. Finally, perspectives of neuroprotective treatment of PCOAG are presented.

[Neuroprotection against glaucoma remains a concept]. / Neuroprotektion bei Glaukom bleibt ein Konzept.

According to estimates made by WHO, approximately 105 million people are affected worldwide by glaucoma. This can be defined as progressive optic neuropathy with structural damage of the optic nerve head and death of retinal ganglion cells. Although elevated IOP is considered responsible for glaucoma, lowering the pressure often does not result in improvement. For this reason, other etiological factors are presumed, which are presented in the following contribution. The role of neuroprotective agents in the treatment of glaucoma is discussed. The pattern of ganglion cell death specific to glaucoma seems to suggest that certain ganglion cells could be more sensitive than others. The theory of "cumulative damage" in this case includes the hypothesis that the delayed onset of many neurodegenerative diseases such as glaucoma, Alzheimer's disease, or Parkinson's disease can be attributed to the age-related accumulation of toxic substances in the ganglion cells. On the contrary, the theory of "singular damage" is based on the assumption that certain ganglion cells are in a state of reduced homeostasis caused by the expression of so-called mutant response genes. Therapeutic approaches worthy of consideration based on their side effect profile and efficacy in animal trials, are presented.

[Characteristic features of optic nerve ganglion cells and approaches for neuroprotection. From intracellular to capillary processes and therapeutic considerations]. / Besonderheiten der Optikusganglienzellen und Ansätze zur Neuroprotektion. Von intrazellulären Vorgängen zur Kapillare bis zu therapeutischen Uberlegungen.

In many diseases associated with deterioration of the visual field and eyesight, optic nerve ganglion cells are at the highest risk. The clinical course of primary chronic open-angle glaucoma (PCOAG) is also determined by the degree of damage to these cells. Due to their anatomy, they are subject to extreme stress exerted by metabolic and microcirculatory forces. The interaction between hypoxia and metabolic stress leads to damage of the retinal ganglion cells. This is compounded by oxidative stress and age-dependent increase of advanced glycation end products. The following contribution gives consideration to approaches for delaying ganglion cell death in PCOAG, e.g., with neuroprotective agents. Furthermore, agents that reduce calcium influx into the cells could prevent cell destruction. Likewise, NMDA receptor antagonists could be effective; however, considerable side effects are to be feared. Antioxidants are also attributed with theoretical impact in combating PCOAG by preventing apoptosis. Finally, the ideal glaucoma medication should be well tolerated when taken orally, prevent destruction of retinal ganglion cells, and possess a low side effect profile.

Methamphetamine exacerbates the toxic effect of kainic acid in the adult rat retina.

The recreational use of the psychoactive drug, methamphetamine has increased markedly over the last three decades. It has long been known that this drug has detrimental effects upon the mammalian brain monoaminergic system, but the long- or short-term effects on the retina, a neurological extension of the central nervous system, have received little attention. The aim of this study was, therefore, to determine whether intraocular injection of methamphetamine (MA) is toxic to the healthy adult rat retina and to analyse its effects on the compromised retina after an injection of the ionotropic glutamate receptor agonist, kainate, which is known to cause retinal neuropathology. The equivalent of 1 mM (in the vitreous humour) MA and/or kainate (40 microM) were injected intravitreally. Flash electroretinograms (ERGs) were recorded before and 2 and 4 days after treatment. Five days after treatment, animals were killed and the retinas analysed either for the immunohistochemical localisation of various antigens or for electrophoresis/Western blotting. Some animals were kept for 19 days after treatment and the retinas analysed for tyrosine hydroxylase immunoreactivity. No differences could be found between vehicle- and MA-treated retinas with respect to the nature or localisation of either tyrosine hydroxylase immunoreactivity after 5 or 19 days or other antigens after 5 days. Moreover, the normal ERG and GFAP and calretinin protein antigens were unaffected by MA. Kainate treatment, however, caused a change in the ERGs after 2 and 4 days, an alteration in every antigen localised by immunohistochemistry and an increase in the retinal levels of calretinin and GFAP proteins. Significantly, the changes seen in the b-wave amplitude and implicit time of the ERG after 4 days and the increased level of GFAP protein after 5 days following kainate treatment were enhanced when MA was co-injected. Intravitreal injection of methamphetamine had no detectable detrimental effect on the normal adult rat retina but exacerbated the damaging effects of kainic acid. Such data suggest that a neurotoxic effect of MA may be more obviously illustrated when the tissue is already compromised as occurs in, for example, ischemia.

Effectiveness of levobetaxolol and timolol at blunting retinal ischaemia is related to their calcium and sodium blocking activities: relevance to glaucoma.

Glaucoma is a chronic optic neuropathy in which retinal ganglion cells die over a number of years. The initiation of the disease and its progression may involve an ischaemic-like insult to the ganglion cell axons caused by an alteration in the quality of blood flow. Thus, to effectively treat glaucoma it may be necessary to counteract the ischaemic-like insult to the region of the optic nerve head. Studies on the isolated optic nerve suggest that substances that reduce the influx of sodium would be particularly effective neuroprotectants. Significantly, of the presently used antiglaucoma substances, only beta-blockers can reduce sodium influx into cells. Moreover, they also reduce the influx of calcium and this would be expected to benefit the survival of insulted neurones. Betaxolol is the most effective antiglaucoma drug at reducing sodium/calcium influx. Our electroretinographic data indicated that topical application of levobetaxolol to rats attenuated the effects of ischaemia/reperfusion injury. Timolol was also effective but to a lesser extent. Based on these data we conclude that beta-blockers may be able to blunt ganglion cell death in glaucoma, and that levobetaxolol may be a more effective neuroprotectant than timolol because of its greater capacity to block sodium and calcium influx.