Acute myeloid leukemia following solid organ transplantation: case report and comprehensive review.

Organ transplant recipients are at an increased risk for subsequent malignancies including hematologic malignancies. The development of acute myeloid leukemia (AML) after solid organ transplantation is a rare but well-documented event. It is thought to be a consequence of immune dysregulation secondary to the use of immunosuppressive agents. Herein, we present the management of a liver transplantation recipient who presented with AML and comprehensively review the relevant literature. A 59-year-old male patient presented with fever and cough eight years after an orthotopic liver transplantation for cirrhosis and hepatocellular carcinoma. He received methylprednisolone and mycofenolate mofetil (MMF) followed by tacrolimus and rapamycin as immunosuppression. Upon admission to our hospital, his peripheral blood demonstrated 34% blasts and pancytopenia. A bone marrow biopsy confirmed the diagnosis of myelodysplastic syndrome (MDS) in transformation to AML. He was treated with induction chemotherapy and his sirolimus was continued but he expired four weeks after from refractory disease. No specific guidelines exist for the treatment of AML in solid organ transplant recipients. Treatment should be individualized and concurrent use of chemotherapeutic and immunosuppressive agents should be carefully balanced.

Precursor of prostate-specific antigen expression in prostatic intraepithelial neoplasia and adenocarcinoma: a study of 90 cases.

OBJECTIVE: To assess the expression of the precursor of prostate-specific antigen (pro-PSA), a distinct molecular form of serum-free PSA that includes native and truncated forms, in benign epithelium, high-grade prostatic intraepithelial neoplasia (PIN) and prostatic adenocarcinoma. MATERIALS AND METHODS: We immunohistochemically evaluated 90 formalin-fixed, paraffin-embedded prostate needle biopsies using monoclonal antibodies against [-2] pro-PSA, native [-5/-7] pro-PSA, prostate-specific membrane antigen (PSMA), PSA and racemase. Staining intensity was recorded using a scale of 0-3 (0, no staining; 3, highest staining). The percentage of immunoreactive cells in benign epithelium, high-grade PIN and adenocarcinoma was estimated in increments of 10%. RESULTS: All cases had [-5/-7] pro-PSA immunoreactivity. There was weak focal perinuclear cytoplasmic immunoreactivity for [-5/-7] pro-PSA in 62% (range 0-90%) of benign epithelial cells, whereas there was strong diffuse cytoplasmic staining in 83% (range 10-90%) of high-grade PIN and 87% (range 40-90%) of cancer cells. Almost all (99%) cases were immunoreactive for [-2] pro-PSA. The median (range) proportion of cells expressing [-2] pro-PSA was lower in benign epithelium, at 17 (0-80)%, than in high-grade PIN, at 55 (0-90)% (P < 0.001) and adenocarcinoma, at 55 (0-100)% (P < 0.001). The intensity of immunoreactivity for both isoforms increased from benign to neoplastic (high-grade PIN and adenocarcinoma) epithelium. A total of 31% of high-grade PIN and 11% of cancer cases with negative racemase staining showed strong staining for [-5/-7] pro-PSA. CONCLUSION: The expression of [-5/-7] pro-PSA in benign and neoplastic cells might be used in combination with high molecular weight keratin, p63, and racemase to distinguish benign epithelium from high-grade PIN and adenocarcinoma, particularly when racemase staining is negative. Both isoforms are sensitive markers for prostatic epithelium, making them possible candidates for investigating carcinoma with an unknown primary, particularly in cases in which PSA staining is negative and the level of suspicion is high.

Donor postextubation hypotension and age correlate with outcome after donation after cardiac death transplantation.

BACKGROUND: Compared with standard donors, kidneys recovered from donors after cardiac death (DCD) exhibit higher rates of delayed graft function (DGF), and DCD livers demonstrate higher rates of biliary ischemia, graft loss, and worse patient survival. Current practice limits the use of these organs based on time from donor extubation to asystole, but data to support this is incomplete. We hypothesized that donor postextubation parameters, including duration and severity of hemodynamic instability or hypoxia might be a better predictor of subsequent graft function. METHODS: We performed a retrospective examination of the New England Organ Bank DCD database, concentrating on donor factors including vital signs after withdrawal of support. RESULTS: Prolonged, severe hypotension in the postextubation period was a better predictor of subsequent organ function that time from extubation to asystole. For DCD kidneys, this manifested as a trend toward increased DGF. For DCD livers, this manifested as increased rates of poor outcomes. Maximizing the predictive value of this test in the liver cohort suggested that greater than 15 min between the time when the donor systolic blood pressure drops below 50 mm Hg and flush correlates with increased rates of diffuse biliary ischemia, graft loss, or death. Donor age also correlated with worse outcome. CONCLUSIONS: Time between profound instability and cold perfusion is a better predictor of outcome than time from extubation to asystole. If validated, this information could be used to predict DGF after DCD renal transplant and improve outcomes after DCD liver transplant.

Androgen deprivation therapy for precancerous lesions of the prostate.

Androgen deprivation therapy has become well-established in the treatment of prostate cancer. Luteinizing-hormone-releasing hormone (LHRH) agonists, anti-androgens, orchiectomy, and combination hormonal therapy are treatment options offered to select patients. The prospect of intervention prior to the development of adenocarcinoma is appealing, and high-grade prostate intra-epithelial neoplasia (PIN), the only known precursor, is the best possible target. There is a decrease in the incidence of high-grade PIN in patients treated with combination androgen deprivation therapy (LHRH agonist and anti-androgen). Changes include increased apoptosis, decreased mitotic activity, less conspicuous nucleoli, and basal-layer prominence. Treatment with the 5alpha-reductase inhibitor finasteride results in a significant decrease in the incidence of high-grade PIN. The effect of 5alpha-reductase inhibitors and selective estrogen receptor modulators on histopathologic evaluation remains unclear, as the number of cases evaluated is small, but new data will be forthcoming with completion of multiple clinical trials.

Assessment of antitussive efficacy of dextromethorphan in smoking related cough: objective vs. subjective measures.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Dextromethorphan is widely used as a cough suppressant in over the counter medications. Its efficacy in altering cough reflex sensitivity has been shown in healthy volunteers. In contrast evidence for an effect on clinically important cough is poor. WHAT THIS STUDY ADDS: A significant decrease in evoked cough was seen with dextromethorphan compared with placebo. However, both placebo and active treatment improved subjective data to a similar degree. We doubt the validity of currently used objective tests in the investigation of antitussives. AIMS: Using an established model of smokers cough we measured the antitussive effects of dextromethorphan compared with placebo. METHODS: The study was a randomized, double-blind placebo controlled, crossover comparison of 22 mg 0.8 ml(-1) dextromethorphan delivered pregastrically with matched placebo. Objective and subjective measurements of cough were recorded. Subjective measures included a daily diary record of cough symptoms and the Leicester quality of life questionnaire. Cough frequency was recorded using a manual cough counter. The objective measure of cough reflex sensitivity was the citric acid, dose-response cough challenge. RESULTS: Dextromethorphan was significantly associated with an increase in the concentration of citric acid eliciting an average of two coughs/inhalation (C2) when compared with placebo, 1 h post dose by 0.49 mM (95% CI 0.05, 0.45, geometric mean 3.09) compared with placebo 0.24 mM (geometric mean 1.74) P < 0.05 and at 2 h 0.57 mM (95% CI 0.01, 0.43, geometric mean 3.75) compared with placebo 0.34 mM (geometric mean 2.19) P < 0.05). There was a highly significant improvement in the subjective data when compared with baseline. However, there was no significant difference between placebo and active treatment. No correlation was seen between cough sensitivity to citric acid and recorded cough counts or symptoms. When both subjective and objective data were compared with screening data there was evidence of a marked 'placebo' effect. CONCLUSIONS: The objective measure of cough sensitivity demonstrates dextromethorphan effectively diminishes the cough reflex sensitivity. However, subjective measures do not support this. Other studies support these findings, which may represent a profound sensitivity of the cough reflex to higher influences.

Transplantation of a unilateral fused kidney with inferior ectopia: revascularization utilizing donor aorta and vena cava.

We present a case of kidney transplantation utilizing a fused kidney with inferior ectopia. The kidney had three arteries, five veins and two ureters and was procured en bloc with the donor vena cava and aorta. The caudal end of the donor vena cava was anastomosed to the recipient's external iliac vein. The right common iliac artery of the donor, in continuity with the donor aorta, was anastomosed to the recipient's external iliac artery. The two ureters were implanted separately. The patientwas discharged home with a serum creatinine of 0.9 mg/dl. Through innovative techniques, kidneys that may not have been transplantable in the past can now be used with excellent results. This is the first known report of transplantation using a unilateral fused kidney with inferior ectopia.

Low pH gel intranasal sprays inactivate influenza viruses in vitro and protect ferrets against influenza infection.

BACKGROUND: Developing strategies for controlling the severity of pandemic influenza is a global public health priority. In the event of a pandemic there may be a place for inexpensive, readily available, effective adjunctive therapies to support containment strategies such as prescription antivirals, vaccines, quarantine and restrictions on travel. Inactivation of virus in the intranasal environment is one possible approach. The work described here investigated the sensitivity of influenza viruses to low pH, and the activity of low pH nasal sprays on the course of an influenza infection in the ferret model. METHODS: Inactivation of influenza A and avian reassortment influenza was determined using in vitro solutions tests. Low pH nasal sprays were tested using the ferret model with an influenza A Sydney/5/97 challenge. Clinical measures were shed virus, weight loss and body temperature. RESULTS: The virus inactivation studies showed that influenza viruses are rapidly inactivated by contact with acid buffered solutions at pH 3.5. The titre of influenza A Sydney/5/97 [H3N2] was reduced by at least 3 log cycles with one minute contact with buffers based on simple acid mixtures such as L-pyroglutamic acid, succinic acid, citric acid and ascorbic acid. A pH 3.5 nasal gel composition containing pyroglutamic acid, succinic acid and zinc acetate reduced titres of influenza A Hong Kong/8/68 [H3N2] by 6 log cycles, and avian reassortment influenza A/Washington/897/80 X A Mallard/New York/6750/78 [H3N2] by 5 log cycles, with 1 min contact.Two ferret challenge studies, with influenza A Sydney/5/97, demonstrated a reduction in the severity of the disease with early application of low pH nasal sprays versus a saline control. In the first study there was decreased weight loss in the treatment groups. In the second study there were reductions in virus shedding and weight loss, most notably when a gelling agent was added to the low pH formulation. CONCLUSION: These findings indicate the potential of a low pH nasal spray as an adjunct to current influenza therapies, and warrant further investigation in humans.

Investigations in subjects with cough following upper respiratory tract infection.

The study aimed to investigate subjects with cough following acute upper respiratory tract infection (URTI), and to compare those subjects unable to suppress cough ("non-suppressors") with those who were able to suppress cough ("suppressors"). Forty-three URTI subjects participated, 31 with cough associated with acute URTI and 12 healthy controls; 21 of the coughing subjects were "suppressors", 10 were "non-suppressors". We obtained responses to chemical and mechanical stimulation of the nasal cavity or the pharynx using both psychophysical measures and event-related potentials. The study provided the following results: (1) "non-suppressors" did not exhibit significantly different intensity ratings or event-related potentials in comparison to "suppressors" in terms of responses to intranasal irritant, mechanical, or olfactory stimuli; (2) when pharyngeal mechanical stimuli were investigated "suppressors" rated the stimuli as more intense than "non-suppressors" and controls; (3) latencies of event-related potentials to pharyngeal stimuli were longest in "non-suppressors". Keeping in mind the relatively small sample size, it appears possible to differentiate certain types of cough during uncomplicated URTI. This may help to explain interindividual differences in responsiveness to cough medication.

Investigation of chemosensitivity during and after an acute cold.

BACKGROUND: Viral rhinitis (the "common" cold) is a frequent worldwide disease. Olfactory dysfunction is one complication that arises during infection, which in most cases heals up spontaneously upon recovery, whereas in some cases it may persist as a partial or total loss of olfaction. The aim of this prospective study was to investigate the change of other chemosensory systems during a cold. METHODS: Fifty-eight patients (age 18 to 69 years) with an acute cold were compared to a healthy control group (n = 59; age 19 to 63 years). All patients were examined on 2 occasions separated by approximately 4 weeks. Orthonasal, retronasal, gustatory, and trigeminal nasal function were investigated. Furthermore, ratings of real foods, in terms of intensity and pleasantness, were obtained. RESULTS: Compared to the control group, patients showed a decreased orthonasal (threshold and discrimination) and retronasal function. Furthermore, patients exhibited a decreased sensitivity to salt and a reduced ability to localize menthol, indicating a decreased taste and trigeminal function, respectively. Upon recovery from the infection, orthonasal olfactory and trigeminal sensitivity increased, whereas retronasal sensitivity showed no improvement and salt sensitivity decreased. CONCLUSION: This comprehensive study provides empirical evidence that chemosensory impairment is prevalent during a cold, and additionally shows for the first time that chemosensory features associated with food consumption persist postinfection.

Toward Quantitative Whole Organ Thermoacoustics With a Clinical Array Plus One Very Low-Frequency Channel Applied to Prostate Cancer Imaging.

Thermoacoustics has the potential to provide quantitative images of intrinsic tissue properties, most notably electrical conductivity in Siemens/meter, much as shear wave elastography provides tissue stiffness in kilopascal. Although thermoacoustic imaging with optical excitation has been commercialized for small animals, it has not yet made the transition to clinic for whole organ imaging in humans. The purpose of this work was to develop and validate specifications for a clinical ultrasound array for quantitative whole organ thermoacoustic imaging. Imaging a large organ requires exciting thermoacoustic pulses throughout the volume and broadband detection of those pulses because tomographic image reconstruction preserves frequency content. Applying the half-wavelength limit to a [Formula: see text] inclusion inside a 7.5-cm diameter organ requires measurement sensitivity to frequencies ranging from 4 MHz to 10 kHz, respectively. A dual-transducer system utilizing a P4-1 array connected to a Verasonics V1 system as well as a focused single-element transducer sensitive to lower frequencies was developed. Very high-frequency (VHF) irradiation generated thermoacoustic pulses throughout a [Formula: see text] volume. In the VHF regime, electrical conductivity drives thermoacoustic signal production. Simultaneous acquisition of thermoacoustic pulses by both transducers enabled comparison of transducer performance. Data from the clinical array generated a stack of 96 images with a separation of 0.3 mm, whereas the single-element transducer imaged only in a single plane. In-plane resolution and quantitative accuracy were quantified at isocenter. The array provided volumetric imaging capability with superior resolution whereas the single-element transducer provided superior quantitative accuracy in axial images. Combining axial images from both transducers preserved resolution of the P4-1 array and improved image contrast. Neither transducer was sensitive to frequencies below 50 kHz, resulting in a dc offset and low-frequency shading over fields of view exceeding 15 mm. Fresh human prostates were imaged ex vivo and volumetric reconstructions reveal structures rarely seen in diagnostic images. In conclusion, quantitative whole-organ thermoacoustic tomography will be feasible by sparsely interspersing transducer elements sensitive to the low end of the ultrasonic range.

Primary carcinoid tumor of the common hepatic duct: A rare case with immunohistochemical and molecular findings.

We report immunohistochemical (IHC) and molecular findings in a rare case of a carcinoid tumor of the extrahepatic bile ducts in a 33-year-old woman, who presented with a 3.9x2.8x2.6 cm mass within the right and common hepatic ducts. She underwent surgery and a carcinoid tumor was identified. This lesion is of interest because in addition to the morphological and cytological features of a typical carcinoid, it demonstrated a distinct pleomorphic area immunoreactive for gastrin. By molecular analysis, loss of heterozygosity (LOH) with opposite allelic patterns between the gastrin-positive and gastrin-negative areas of the tumor was identified. The molecular studies for LOH along with the morphology and IHC profiling suggest that this second population of gastrin-positive carcinoid cells may represent a new clone within the carcinoid tumor with differentiation toward gastrin production or may represent the next step in the carcinogenic process with a gradual emergence of a more aggressive clone.

Deconstructing Darwin: Evolutionary theory in context.

The topic of this paper is external versus internal explanations, first, of the genesis of evolutionary theory and, second, its reception. Victorian England was highly competitive and individualistic. So was the view of society promulgated by Malthus and the theory of evolution set out by Charles Darwin and A.R. Wallace. The fact that Darwin and Wallace independently produced a theory of evolution that was just as competitive and individualistic as the society in which they lived is taken as evidence for the impact that society has on science. The same conclusion is reached with respect to the reception of evolutionary theory. Because Darwin's contemporaries lived in such a competitive and individualistic society, they were prone to accept a theory that exhibited these same characteristics. The trouble is that Darwin and Wallace did not live in anything like the same society and did not formulate the same theory. Although the character of Victorian society may have influenced the acceptance of evolutionary theory, it was not the competitive, individualistic theory that Darwin and Wallace set out but a warmer, more comforting theory.

Carbon nanostructure examined by lattice fringe analysis of high-resolution transmission electron microscopy images.

The dimensions of graphitic layer planes directly affect the reactivity of soot towards oxidation and growth. Quantification of graphitic structure could be used to develop and test correlations between the soot nanostructure and its reactivity. Based upon transmission electron microscopy images, this paper provides a demonstration of the robustness of a fringe image analysis code for determining the level of graphitic structure within nanoscale carbon, i.e., soot. Results, in the form of histograms of graphitic layer plane lengths, are compared to their determination through Raman analysis.

Does polyomavirus infection interfere with bladder cancer fluorescence in situ hybridization?

Urine cytology is a proven and widely used screening tool for the detection of urothelial carcinoma. However, morphologic features of polyomavirus infected cells, characterized by nuclear inclusions (decoy cells) are a known source of diagnostic confusion with malignancy. Fluorescence in situ hybridization (FISH) is now routinely used to support the cytological diagnosis of urothelial carcinoma and monitor for recurrence. We sought to determine whether polyomavirus infection could result in positive FISH results (aneuploidy). This study deals with retrospective study of 100 polyomavirus-infected urine samples from patients with no history of urothelial carcinoma or organ transplantation. All cases were stained with Papanicolaou and acid hematoxylin stain. One slide from each sample was de-stained and FISH was performed using chromosome enumeration probes 3, 7, 17, and locus-specific probe 9p21. Adequate cells for FISH analysis (25 cells) were present in 81 cases; 19 cases were insufficient due to loss of cells during de-staining and FISH preparation process. All polyomavirus-infected cells (decoy cells) exhibited a normal chromosome pattern. Four cases were FISH positive, but there were no positive decoy cells. Decoy cells did not exhibit aneuploidy by FISH. The presence of decoy cells does not exclude the possibility of concurrent urothelial carcinoma. Acid hematoxylin stain appeared to supplement the Papanicolou stain in identifying and confirming the presence of polyomavirus infection.

Doxylamine pharmacokinetics following single dose oral administration in children ages 2-17 years.

To characterize doxylamine pharmacokinetics in children. This study was conducted in 41 subjects, ages 2-17 years. Doxylamine succinate doses based on age/weight ranged from 3.125 to 12.5 mg. A single oral dose was administered with 2 to 4 oz. of water or decaffeinated beverages ∼2 hours after a light breakfast. Plasma samples were obtained before and for 72 hours after dosing and analyzed for doxylamine using HPLC MS/MS. Pharmacokinetic parameters were estimated using non-compartmental methods and relationships with age were assessed using linear regression. Over the fourfold dose range, Cmax was similar while AUC increased only 60%, although not statistically significant (P-value = 0.0517). As expected due to increasing body size, CLo and Vz /F increased with age. Due to a similar increase with age for Clo and Vz /F, no age-related differences in t1/2,z were observed (∼16 hours). Allometric scaling indicated no maturation related changes in CLo ; although Vz /F remained age-dependent, the predicted range decreased ∼70%. Overall, the single doses were well tolerated. Somnolence was the most common reported AE with no apparent differences in incidence noted with age. An age/weight dosing nomogram utilizing a fourfold range of doses achieves similar Cmax , whereas AUC increases only 60%.

Defining Darwinism.

Evolutionary theory seems to lend itself to all sorts of misunderstanding. In this paper I strive to decrease such confusions, for example, between Darwinism and Darwinians, propositions and people, organisms and individuals, species as individuals versus species as classes, homologies and homoplasies, and finally essences versus histories.

Periodontitis and inflammatory markers in transplant recipients.

BACKGROUND: Inflammation is associated with the deterioration of solid-organ transplants. Chronic periodontitis is linked to systemic inflammation, although it is unknown whether it plays a causative or comorbid role. We hypothesized that transplant subjects have a greater prevalence of severe periodontitis, accompanied by higher levels of serum interleukin-6 (IL-6) and C-reactive protein (CRP), compared to systemically healthy subjects. METHODS: We recruited 90 renal and cardiac transplant recipients and 72 age-matched controls and compared their periodontal and systemic inflammatory status. RESULTS: The prevalence of severe periodontitis was not statistically significantly different between transplant and control subjects. Serum IL-6 and CRP were higher in transplant subjects compared to control subjects and in subjects with severe periodontitis compared to subjects without periodontitis, but multivariate analysis showed that severe periodontitis was a significant positive predictor of serum IL-6 in the control group only. In the test group, significant predictors of systemic inflammation were age, diabetes, higher body mass index, and a cadaveric transplant donor. CONCLUSION: Despite the presence of higher levels of systemic markers of inflammation in transplant subjects with severe periodontitis compared to transplant subjects without periodontitis, periodontal parameters were not statistical predictors of systemic inflammation in this population in a multivariate model.

Adult urinary bladder rhabdomyosarcoma.

Rhabdomyosarcomas, malignant neoplasms exhibiting skeletal muscle differentiation, are the most common childhood sarcomas and most commonly arise in the head-and-neck region. Embryonal rhabdomyosarcomas of the genitourinary tract also occur in children, but are distinctly uncommon in adults. We report a case of embryonal rhabdomyosarcoma arising in the bladder of a 39-year-old woman who presented with urgency, frequency, and gross hematuria.

A severely affected female infant with x-linked dominant chondrodysplasia punctata: a case report and a brief review of the literature.

We recently performed an autopsy on a premature female newborn with rhizomesoacromelic limb shortening of the upper and lower extremities, craniofacial dysmorphism, and chondrodysplasia punctata. A diagnosis of Conradi-Hunermann-Happle syndrome or X-linked dominant chondrodysplasia punctata was made based on elevated cholest-8(9)-ene-3beta-ol in serum and tissues. Molecular analysis of EBP, mutations of which are responsible for this malformation syndrome, revealed a monoallelic missense mutation, c.328 G>A (R110Q). We present this case as an illustration of an unusually severe manifestation of this disorder in a female, with additional unusual features including lack of skin manifestations and apparent bilateral symmetry of the skeletal findings.