Combined heart-liver transplantation with extended cardiopulmonary bypass.

We report a case of combined heart and liver transplantation for familial amyloid polyneuropathy. This is the first such combined transplant performed in Asia, and differs from previously described cases, in that cardiopulmonary bypass was continued at partial flow during liver transplantation in our case. This was done in order to provide haemodynamic support to the cardiac graft and to protect it from the impending reperfusion insult that frequently accompanies liver transplantation. The utility of this management course is discussed, along with its actual and potential complications. We also describe the impact of a lung-protective ventilation strategy employed during cardiac transplantation.

Macroautophagy inhibition sensitizes tamoxifen-resistant breast cancer cells and enhances mitochondrial depolarization.

Macroautophagy (autophagy), a process for lysosomal degradation of organelles and long-lived proteins, has been linked to various pathologies including cancer and to the cellular response to anticancer therapies. In the human estrogen receptor positive MCF7 breast adenocarcinoma cell line, treatment with the endocrine therapeutic tamoxifen was shown previously to induce cell cycle arrest, cell death, and autophagy. To investigate specifically the role of autophagy in tamoxifen treated breast cancer cell lines, we used a siRNA approach, targeting three different autophagy genes, Atg5, Beclin-1, and Atg7. We found that knockdown of autophagy, in combination with tamoxifen in MCF7 cells, results in decreased cell viability concomitant with increased mitochondrial-mediated apoptosis. The combination of autophagy knockdown and tamoxifen treatment similarly resulted in reduced cell viability in the breast cancer cell lines, estrogen receptor positive T-47D and tamoxifen-resistant MCF7-HER2. Together, these results indicate that autophagy has a primary pro-survival role following tamoxifen treatment, and suggest that autophagy knockdown may be useful in a combination therapy setting to sensitize breast cancer cells, including tamoxifen-resistant breast cancer cells, to tamoxifen therapy.

Central neurocytoma in third and fourth ventricles with aqueductal involvement.

Central neurocytomas are characterized by their intraventricular locations, usually arising from the lateral ventricles and their benign clinical course. Variations in location, histology and clinical behaviour have been reported in recent years. The authors present two cases of central neurocytomas arising in the third and fourth ventricles with aqueductal involvement. The atypical features in their location and behaviour are discussed. The cases represent the extended spectrum of central neurocytomas.

Medical therapy in heart failure--is polypharmacy necessary?

The concept of heart failure has undergone several paradigm shifts in the past few decades. Therapeutic targets directed at the heart pump have shifted to circulatory haemodynamics to the current neurohormonal model. Consequently, therapeutic modalities have similarly evolved alongside clinical trials. Successive trials have tested newer drugs in addition to established therapies, resulting in evidence-based treatments necessitating polypharmacy. Optimal heart failure therapy has therefore become increasingly complex. It is only after understanding the precise modes of drug action, as well as the relevance of the design of clinical trials, will physicians hopefully be able to tailor the medical therapy optimally towards the individual patient with heart failure.

Variability in normative urine flow rates.

PURPOSE: Parameters derived from uroflowmetry are frequently used in the evaluation and reassessment of children presenting with lower urinary tract dysfunction. Since current nomograms have been constructed from 1 to 2 voids per child, variability of flow parameters is unknown. We evaluate intraindividual variability of flow parameters in children free of lower urinary tract symptoms. MATERIALS AND METHODS: Children between 4 and 16 years old (mean age 9.8) who were hospitalized but not suffering from urinary tract infection, pyelonephritis or neurological disturbance, and who had neither structural abnormality of the urinary tract nor acute pain or disorientation voided spontaneously over a flowmeter on 4 to 6 occasions. Post-void urine was estimated by ultrasound within 5 minutes of micturition to confirm complete emptying. RESULTS: A total of 98 subjects provided a mean of 4.4 traces each. Neither maximum nor average flow rate showed great intraindividual variability (maximum flow rate r >0.8, average flow rate r >0.74). Flow rates significantly correlated with flow duration, volume voided and patient age. Initial flow curves were bell-shaped in 63% of cases, staccato in 30% and intermittent in 6%. These proportions did not change with subsequent voids. There was no significant difference between genders with respect to staccato voiding, although boys demonstrated 70% of intermittent voids and were significantly older than girls. CONCLUSIONS: In normal children there is minimal variability in flow rates and the phenomenon of staccato voiding is seen approximately 30% of the time, despite no significant levels of post-void residual urine.

The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IkappaB kinase.

BACKGROUND: Biologically active natural products continue to be useful in the exploration and control of intracellular signaling processes. For example, the sesquiterpene lactone parthenolide from the anti-inflammatory medicinal herb Feverfew (Tanacetum parthenium) appears to inhibit the pro-inflammatory signaling pathway. Parthenolide's direct molecular target, however, remains unknown. We set out to identify the molecular mechanisms of parthenolide's anti-inflammatory activity. RESULTS: A parthenolide affinity reagent was synthesized and shown to bind directly to and inhibit IkappaB kinase beta (IKKbeta), the kinase subunit known to play a critical role in cytokine-mediated signaling. Mutation of cysteine 179 in the activation loop of IKKbeta abolished sensitivity towards parthenolide. Moreover, we showed that parthenolide's in vitro and in vivo anti-inflammatory activity is mediated through the alpha-methylene gamma-lactone moiety shared by other sesquiterpene lactones. CONCLUSIONS: In recent years, the multi-subunit IKK complex has been shown to be responsible for cytokine-mediated stimulation of genes involved in inflammation and as such represents an attractive target for pharmaceutical intervention. Our finding that parthenolide targets this kinase complex provides a possible molecular basis for the anti-inflammatory properties of parthenolide. In addition, these results may be useful in the development of additional anti-inflammatory agents.

Craniofacial resection for paranasal sinus cancers.

BACKGROUND: Combined anterior craniofacial resection (CFR) has been in use for more than 25 years. The advent of the free revascularized tissue transfer flap in l980 permitted safe resection of tumors that had spread beyond the confines of the paranasal sinuses with immediate reconstruction of the sino-orbital cranial defect. The purpose of this study was to examine the outcomes and morbidity of a management policy of primary CFR and postoperative radiotherapy for paranasal sinus cancers infiltrating the skull base over a 21-year period. METHODS: Seventy-three patients with paranasal sinus cancers were treated at the Prince of Wales Hospital between l975 and l996. All were newly diagnosed with the exception of one patient who had received radiotherapy elsewhere 5 years earlier. Only 22% were early lesions and 31% were advanced (more than six sites involved). There were 59 men and 14 women. The mean age was 57 years. All but two patients had a performance status of either 0 or 1. Orbital exenteration was performed in 31 patients. Since l980, all major defects were reconstructed with free tissue transfer flaps. RESULTS: The 5-year cancer-specific survival (CSS) for the 73 patients was 69%, which was unchanged at 10 years. Twenty two patients died from or with their index cancer. An additional 11 patients died from unrelated causes. The actuarial overall survival (OS) at 5 and 10 years was 61% and 48%, respectively. The 5-year recurrence-free rate was 59%. The CSS for the three dominant pathologic conditions were adenocarcinoma 70%, squamous cancer 51%, and olfactory neuroblastoma 84%. The difference was not significant; however, there was a significant difference in OS, with olfactory neuroblastoma having the best prognosis. Orbital involvement, radiologic evidence of skull base erosion, and involvement of the infratemporal fossa were not poor prognostic indicators. Patients with a performance status of 0 had improved OS. There was no operative mortality. CONCLUSIONS: An aggressive policy of combined CFR and postoperative radiotherapy with free-flap reconstruction for large defects gave survival results that were comparable to less-advanced lesions and superior to many other treatment alternatives. There was a high exenteration rate (42%). Squamous cancers were associated with the greatest morbidity and poorest OS.

Neoplasia after heart transplantation.

Transplant recipients have a higher incidence of cancer compared with the general population. This increased risk is related to the intensity and chronicity of immunosuppression that these patients receive. The common types and presentations of posttransplant tumors are reviewed and discussed. Regular surveillance is of paramount importance in detecting such tumors. Treatment invariably includes attempts to reduce immunosuppression.

Cortical blindness following coronary angiography.

A 53-year-old man developed transient cortical blindness after coronary angiography, which appears to be an adverse reaction to contrast agent. A possible mechanism of this complication is contrast penetration of the blood-brain barrier with direct neurotoxicity to the occipital cortex.

Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity.

The proteasome regulates cellular processes as diverse as cell cycle progression and NF-kappaB activation. In this study, we show that the potent antitumor natural product epoxomicin specifically targets the proteasome. Utilizing biotinylated-epoxomicin as a molecular probe, we demonstrate that epoxomicin covalently binds to the LMP7, X, MECL1, and Z catalytic subunits of the proteasome. Enzymatic analyses with purified bovine erythrocyte proteasome reveal that epoxomicin potently inhibits primarily the chymotrypsin-like activity. The trypsin-like and peptidyl-glutamyl peptide hydrolyzing catalytic activities also are inhibited at 100- and 1,000-fold slower rates, respectively. In contrast to peptide aldehyde proteasome inhibitors, epoxomicin does not inhibit nonproteasomal proteases such trypsin, chymotrypsin, papain, calpain, and cathepsin B at concentrations of up to 50 microM. In addition, epoxomicin is a more potent inhibitor of the chymotrypsin-like activity than lactacystin and the peptide vinyl sulfone NLVS. Epoxomicin also effectively inhibits NF-kappaB activation in vitro and potently blocks in vivo inflammation in the murine ear edema assay. These results thus define epoxomicin as a novel proteasome inhibitor that likely will prove useful in exploring the role of the proteasome in various in vivo and in vitro systems.

Total synthesis of the potent proteasome inhibitor epoxomicin: a useful tool for understanding proteasome biology.

Epoxomicin (1), a peptide alpha',beta'-epoxyketone isolated from the actinomycete strain No.Q996-17, possesses potent in vivo anti-tumor and anti-inflammatory activities. In this paper, we report the first syntheses of epoxomicin, [3H]-epoxomicin, and a biotinylated epoxomicin analog as well as the absolute configuration of the epoxide stereocenter. The natural product and derivatives have permitted the first identification of the proteasome as the specific cellular target of epoxomicin.

Eponemycin exerts its antitumor effect through the inhibition of proteasome function.

Cell cycle progression requires the proteasome-mediated degradation of key regulatory proteins such as cyclins, cyclin-dependent kinase inhibitors, and anaphase-inhibitory proteins. Given the central role of the proteasome in the destruction of these proteins, proteasome inhibition has been proposed as a possible cancer therapy. We report here that dihydroeponemycin, an analogue of the antitumor and antiangiogenic natural product eponemycin, selectively targets the 20S proteasome. Dihydroeponemycin covalently modifies a subset of catalytic proteasomal subunits, binding preferentially to the IFN-gamma-inducible subunits LMP2 and LMP7. Moreover, the three major peptidolytic activities of the proteasome are inhibited by dihydroeponemycin at different rates. In addition, dihydroeponemycin-mediated proteasome inhibition induces a spindle-like cellular morphological change and apoptosis. These results validate the proteasome as a target for antitumor pharmacological intervention and are relevant for the design of novel chemotherapeutic strategies.

Third ventriculostomy for hydrocephalus associated with spinal dysraphism: indications and contraindications.

Twenty-five patients have undergone this procedure at our unit. These constitute 25% of our total experience with endoscopic third ventriculostomy (4). In the patients under 6 months of age, only one out of 11 patients has had a successful long-term result despite initial good fenestration of the floor of the third ventricle. These patients were selected on the basis of their adequate third ventricular size and a relatively slowly progressive hydrocephalus. Fourteen patients had a ventriculostomy performed instead of shunt revision. In 13 patients this has been a success long term. All of these patients had a Heyer-Schulte valve with antisiphon device installed for months, or more often, years, prior to the third ventriculestomy. We believe that the difference in these two groups is due to a very poor cerebrospinal fluid(CSF)-resorptive capability in patients immediately after back closure due to the prior venting of CSF into the amniotic sac. The absorptive capacity seems to improve with the passage of time in our patients who have had a shunt system that maintains a relatively normal intracranial pressure and thus contributes to the development of the patient's CSF-absorptive system.

The current status of endoscopic third ventriculostomy in the management of non-communicating hydrocephalus.

Improvements in the technology have made endoscopic third ventriculostomy safer than earlier technics of open third ventriculostomy as described by Scarf (14). Similarly, it is safer than the stereotactic technics used by Pierre-Kahn (10), Sayers (13), and Hoffman (4). The morbidity and mortality have decreased and the effectiveness has also increased (12, 15). Modern operations are based on Guiot's technique (2). In the management of hydrocephalus third ventriculostomy has to be compared with the treatment with intracranial shunts. Currently in our hands the procedure has a higher morbidity rate than a shunt operation. Our figures include those from our early experience (5)--more recent figures show a lower complication rate. We believe the higher morbidity is acceptable as the chance of being permanently cured is 80% in favourable cases.

Neuroendoscopic third ventriculostomy. A practical alternative to extracranial shunts in non-communicating hydrocephalus.

The outcomes in 103 patients who have undergone third ventriculostomy for non-communicating hydrocephalus at our institution form 1978-1994 have been analysed. The group has been sub-divided by age, cause of hydrocephalus and whether the third ventriculostomy was the initial definitive procedure or whether progression of their hydrocephalus had been arrested for a long time (usually years) by an extracranial shunt prior to third ventriculostomy. At the time of shunt malfunction (usually blockage) a third ventriculostomy was performed if the anatomy was, or could be made suitable for the safe performance of the procedure. Third ventriculostomy under the age of 6 months was successful in only 8 of 25 patients. Seventeen patients in whom the onset of hydrocephalus was under the age of six months and the ventriculostomy was performed between 6 months and 18 years, 8 were successful. Sixteen of these had had previous long term shunts. In 40 patients in whom the onset of hydrocephalus was over the age of 6 months and the ventriculostomy performed after the age of 19 years, 32 were successful. In 28 patients over the age of 20 years, 13 had previously been shunted and in 8 of these the procedure was successful. In 15 patients not previously shunted, 9 ventriculostomies were successful. Three failed, 2 died before evaluation could be done and one was lost to follow-up. There were no deaths caused by the procedure. Two patients suffered from a hemiparesis, (1 transient) 1 patient suffered mid-brain damage. There were 2 subdural effusions. Two patients had infections, 1 superficial and 1 a ventriculitis.

Third ventriculostomy for shunt infections in children.

Four children with extracranial shunts for noncommunicating hydrocephalus suffered from recurrent or intractable shunt infections. All patients were resistant to or relapsed after treatment with intravenous and intrathecal antibiotics with change of the shunt apparatus. They were treated with neuroendoscopic third ventriculostomy and the removal of all implants, except for a reservoir in one patient. That child later had the reservoir removed because of persistent proteus infection. All patients received antibiotics for approximately 2 weeks after the operation. There was no morbidity associated with the procedure, and all patients remain shunt independent with follow-up periods of 21 to 46 months (mean, 33 mo), although one has needed another third ventriculostomy. We have shown that third ventriculostomy is a successful surgical intervention for the management of shunt infections in patients with noncommunicating hydrocephalus.