Case report: A fatal case of cryptococcosis in an immunocompetent patient due to Cryptococcus deuterogattii (AFLP6/VGII).

INTRODUCTION: Cryptococcosis in immunocompetent adults is a rare disease in Europe, mostly induced by members of the Cryptococcus gattii species complex. The diagnosis can be challenging due to its rarity, unspecific symptoms and long symptomless latency. CASE PRESENTATION: A 49-year-old woman with a three weeks history of headache was admitted to the hospital due to discrete ataxia and impaired vision. Cranial magnetic resonance imaging (MRI) showed a contrast-enhancing mass in the cerebellum. Further investigations detected a slight leukocytosis and a single subpleural nodule in the right inferior lung lobe. The cerebral lesion was surgically removed, and a direct frozen section only showed an unspecific inflammation. In the course of her admission she developed non-treatable cerebral edema and died ten days after surgical intervention. Histopathological examination of the surgical specimen and postmortem evaluation of the lung and the cerebrum demonstrated fungal elements. Molecular identification of the fungal elements in formalin-fixed paraffin-embedded tissue lead to the diagnosis of cryptococcosis induced by C. gattii sensu lato. Molecular genetic analysis identified the involved cryptococcal species as genotype AFLP6/VGII, recently described as Cryptococcus deuterogattii, which is known to be endemic to the west-coast of Canada and the USA. Additional heteroanamnestic information revealed that she had spent her holidays on Vancouver Island, Canada, two years before disease onset, indicating that infection during this stay seems to be plausible. CONCLUSION: Cryptococcosis due to C. deuterogattii is a rarely encountered fungal disease in Europe, not particularly associated with immunodeficiency, and infection is likely to be contracted in endemic areas. Due to its rarity, long symptomless latency, unspecific symptoms and misleading radiological features the diagnosis can be challenging. Physicians need to be aware of this differential diagnosis in immunocompetent patients, as early adequate therapy can be lifesaving.

Assessment of human left ventricle flow using statistical shape modelling and computational fluid dynamics.

Blood flow patterns in the human left ventricle (LV) have shown relation to cardiac health. However, most studies in the literature are limited to a few patients and results are hard to generalize. This study aims to provide a new framework to generate more generalized insights into LV blood flow as a function of changes in anatomy and wall motion. In this framework, we studied the four-dimensional blood flow in LV via computational fluid dynamics (CFD) in conjunction with a statistical shape model (SSM), built from segmented LV shapes of 150 subjects. We validated results in an in-vitro dynamic phantom via time-resolved optical particle image velocimetry (PIV) measurements. This combination of CFD and the SSM may be useful for systematically assessing blood flow patterns in the LV as a function of varying anatomy and has the potential to provide valuable data for diagnosis of LV functionality.

Urokinase plasminogen activator receptor induced non-small cell lung cancer invasion and metastasis requires NHE1 transporter expression and transport activity.

BACKGROUND: Non-small cell lung cancers (NSLC) are aggressive cancers that are insensitive to chemotherapies and accounts for nearly 33% of all cancer deaths in the United States. Two hallmarks of cancer that allow cells to invade and metastasize are sustained proliferation and enhanced motility. In this study we investigate the relationship between urokinase plasminogen activator (uPA)/uPA receptor (uPAR) signaling and Na(+)/H(+) exchanger isoform 1 (NHE1) expression and activity. METHODS AND RESULTS: The addition of 10nM uPA increased the carcinogenic potential of three NSCLC cell lines, NCI-H358, NCI-H460, and NCI-H1299. This included an increase in the rate of cell proliferation 1.6 to 1.9 fold; an increase in the percentage of cells displaying stress fibers 3.05 to 3.17 fold; and an increase in anchorage-independent growth from 1.64 to 2.0 fold. In each of these cases the increase was blocked when the experiments were performed with NHE1 inhibited by 10 µM EIPA (ethylisopropyl amiloride). To further evaluate the role of uPA/uPAR and NHE1 in tumor progression we assessed signaling events using full-length uPA compared to the uPA amino terminal fragment (ATF). Comparing uPA and ATF signaling in H460 cells, we found that both uPA and ATF increased stress fiber formation approximately 2 fold, while uPA increased matrix metalloproteinase 9 (MMP9) activity 5.44 fold compared to 2.81 fold for ATF. To expand this signaling study, two new cell lines were generated, one with reduced NHE1 expression (H460 NHE1 K/D) and one with reduced uPAR expression (H460 uPAR K/D). Using the K/D cell lines we found that neither uPA nor ATF could stimulate stress fiber formation or MMP9 activity in cells with dramatically decreased NHE1 or uPAR expression. Finally, using in vivo tumor formation studies in athymic mice we found that when mice were injected with H460 cells 80% of mice formed tumors with an average volume of 390 mm(3). This was compared to 20% of H460 uPAR K/D injected mice forming tumors with an average volume of 15 mm(3) and 10% of H460 NHE1 K/D injected mice forming tumors with an average volume of 5 mm(3). CONCLUSION: Taken together, these data demonstrate that uPA/uPAR-mediated tumor progression and metastasis requires NHE1 in NSCLC cells and suggests a potential therapeutic approach to blocking cancer progression.

Encapsulated contrast microbubble radial oscillation associated with postexcitation pressure peaks.

This work combines modeling and experiment to assess encapsulated microbubble oscillations associated with broadband pressure peaks detected after microbubble excitation (postexcitation signals). Data were acquired from albumin-shelled and phospholipid-shelled microbubbles using a passive cavitation detector consisting of a confocally aligned 2.8-MHz transmitter and 13-MHz receiver. Microbubbles in weak solutions were insonified with a 5-cycle pulse at a peak rarefactional pressure of 2.0+/-0.2 MPa. For each microbubble type, at least 100 received signals were identified as individual-microbubble responses. The average broadband noise from signals with postexcitation response was 4.2-7.2 dB higher than from signals without postexcitation. Pressure-time responses for each microbubble type were simulated using the model by Marmottant et al. [J. Acoust. Soc. Am. 118, 3499-3505 (2005)], with insonification conditions matching the experiment. Increased broadband noise predicted for microbubbles with postexcitation response was consistent with that observed experimentally (4.0-8.9 dB). The model predicted that postexcitation signals occur only when the radial oscillation exceeds both the shell break-up threshold and twice the initial radius (free bubble inertial cavitation threshold).

Multisequence magnetic resonance imaging study of neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: To investigate the relationship between magnetization transfer imaging (MTI), diffusion-weighted imaging (DWI), proton magnetic resonance spectroscopy (H-MRS), and T2 relaxometry findings in patients with primary neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: The study group consisted of 24 female patients (mean age 36 years [range 23-65]) who had had a variety of neuropsychiatric symptoms that were judged to be due to NPSLE according to the criteria of the American College of Rheumatology. Patients with current active disease were excluded from participation. Quantitative MTI, DWI, H-MRS, and T2 relaxometry data were acquired in all patients, and the correlation coefficients were calculated. RESULTS: MTI results reflecting a decrease in homogeneity of cerebral parenchyma correlated significantly with H-MRS results representing axonal damage. MTI results also correlated significantly with DWI results reflecting increased diffusivity in the cerebral parenchyma. Finally, MTI results reflecting decreased cerebral homogeneity correlated significantly with increased T2 relaxation time, associated with either edema or gliosis. Increased T2 relaxation time correlated significantly with DWI results reflecting increased diffusivity. With the exception of the correlation between H-MRS and MTI findings, there was no significant correlation between H-MRS results and any other parameter. CONCLUSION: The selected study parameters represent different biologic features in the human brain and can be informative with regard to different pathologic processes in NPSLE. The demonstrated associations between MTI, DWI, H-MRS, and T2 data in patients with a history of NPSLE suggest that there is one pathogenesis and/or common neuropathologic outcome in NPSLE despite differences in clinical presentation.

Symptomatology of Graves' disease and Plummer's disease in relation to age and thyroid hormone level.

In order to relate the clinical expression of Graves' disease and Plummer's disease to age and thyroid hormone level, we prospectively studied 39 patients with Graves' disease and 26 patients with Plummer's disease using a standardized clinical score. Multiple regression analyses were performed with the clinical score as dependent variable and FT4I, age and diagnosis as independent variables. Our results show that patients with Graves' disease tend to have more signs and symptoms than patients with Plummer's disease. In addition, we found a positive correlation between the clinical score and FT4I. We did not find an age dependence of the clinical score, after controlling for diagnosis and FT4I. The age dependence reported by other authors is mainly due to the higher prevalence of Graves' disease among younger age groups in contrast to Plummer's disease.

The natural history of euthyroid multinodular goitre.

In this communication data on the natural history of euthyroid multinodular goitres are presented. From a total group of 140 patients (mean age 54.6 years, 14 men and 126 women; 88 with autonomous, 52 with non-autonomous function), follow-up data were available for 90 patients (mean age 54.0 years, 11 men and 79 women; 64 with autonomous, 26 with non-autonomous function). During follow-up (means: 5.0 years, maximum 12.2 years) transitions in function were seen 15 times; 8 autonomous patients became hyperthyroid after less than 1-7 years. There were 6 transitions from non-autonomy to autonomy and 1 from autonomy to non-autonomy. One patient who demonstrated the whole cycle from non-autonomy through autonomy up to hyperthyrodism is described in more detail. In one patient operated upon because of hyperparathyroidism a follicular carcinoma was found by chance. Mechanical problems were the reason for surgery in 6 patients only, 16 patients were operated upon because of cosmetic reasons (mostly in the early years of the study). Finally, results from 19 TRH tests in 16 autonomous patients suggest that TRH tests in patients with autonomously functioning euthyroid multinodular goitres are not yet redundant.

Disseminated histoplasmosis. Typical presentation with involvement of the adrenal glands.

A 67-yr-old Indonesian patient with disseminated histoplasmosis is described. He had general malaise and fever for 6 months; an oral ulcer, bilateral adrenal gland enlargement and partial adrenal insufficiency were found. An adrenal aspirate contained Histoplasma capsulatum. The literature on adrenal involvement in disseminated histoplasmosis is reviewed and it is concluded that bilateral enlargement, demonstrated by sonography or computed tomography, in a patient with general malaise is an important clue to the diagnosis.

Diagnosis and treatment of Graves' disease. Results of a survey of Dutch internists.

The results of a survey of Dutch internists on the diagnostics and treatment of Graves' disease is presented. Eighty-five per cent of all participants chose medical treatment for the uncomplicated patient. Radioiodine was reserved for the case of recurrence after medical treatment and after surgery. Surgical treatment was chosen almost exclusively for a larger goitre by 30% of the participants. Large differences in diagnostics and the treatment were not found between the three categories of hospitals: university, teaching, and general non-teaching hospitals.

Treatment of hypothyroidism in The Netherlands. Results of a survey of Dutch internists.

The results of a survey on the treatment of hypothyroidism by Dutch internists, working in different types of hospitals, are described. Except in cases of cardiac complications or long-standing disease at old age most patients were treated in the out-patient clinic. About 50% of the internists chose 25 micrograms of levothyroxine as the initial dose for uncomplicated hypothyroidism. A lower dose (12.5 micrograms) was chosen by one-third of the internists working in teaching hospitals and general hospitals, while 36% of the internists working in university hospitals start with 50 micrograms of levothyroxine. For all variants of the basic case of uncomplicated hypothyroidism the dose was even lower. Adjustment of the dose was usually made at fixed intervals combined with measurement of plasma thyroid hormone levels and clinical parameters. The final substitution dose was generally based on the TSH levels. Anticoagulant drugs were seldom used except in cases of cardiac complications.

The significance of the initial FT4-index for the management of single daily dose methimazole treatment of hyperthyroidism.

Since the effectiveness of 30 mg methimazole in a single daily dose in gaining initial control of hyperthyroidism may depend largely on patient characteristics, 52 patients (34 with diffuse and 18 with nodular goitre) were investigated in an attempt to determine the relative importance of a number of pretreatment variables. Return to normal thyroid hormone levels after 2 to 6 weeks of treatment appeared to be the rule, although eight of these patients formed notable exceptions (6-20 weeks). The individual duration of treatment until achievement of biochemical euthyroidism correlated with the initial free thyroxine index (r = 0.75, P less than 0.001) and the free triiodothyronine index (r = 0.70, P less than 0.001). For patients with a diffuse goitre it was also related to the thyroid volume estimated by ultrasound (r = 0.73, P less than 0.001). According to multiple linear regression analysis however these variables were found to have no independent prognostic value. The decrease in thyroid volume during initial therapy, the nature of the goitre, a medication compliance score and various other patient variables did not correlate with the effect of treatment. In 12 cases perchlorate discharge tests were performed. The results suggest continued hormone synthesis in patients with highly active iodine trapping as an important mechanism of the postponed attainment of euthyroidism.

Cytomegalovirus infection with perfusion defects on the lung scan.

A patient with dyspnea, skin rash, hypoxemia and mononucleosis was shown to have acute cytomegalovirus infection. The chest X-ray was normal, but the lung scan showed perfusion defects. Although pulmonary embolism cannot be ruled out, it seems likely that the CMV infection was responsible for the abnormalities observed.

Propranolol improves the impaired TSH response to TRH in patients with autonomously functioning euthyroid multinodular goitre.

Ten patients with autonomously functioning euthyroid multinodular goitre received propranolol (Inderal Retard 160 mg daily) for 4 weeks in order to investigate whether normalization of the TRH test or an increased TSH response to TRH could be obtained by decreasing serum T3 levels. Serum T3 decreased significantly after 2 and 4 weeks of propranolol administration. Serum T4 increased during this period, although the change was only significant after 4 weeks of propranolol. T3 resin uptake did not change. The TSH response to TRH increased significantly during the administration of propranolol. Mean delta TSH basally was 1.0, range 0-3.9 mU/l, and mean delta TSH after 4 weeks of propranolol was 2.4, range 0-9.3 mU/l. A strong correlation was found between the increase in delta TSH and the decrease in serum T3 after 4 weeks of propranolol. After withdrawal, delta TSH and T3 returned to premedication levels. Our data suggest that T3 is an important factor in the impairment of the TSH response to TRH in our patients. Normalization of the TRH test was, however, not obtained. These findings support the concept of subclinical hyperthyroidism in 'euthyroid' multinodular goitre with autonomous function.

Pharmacokinetics of 14C-activity after the administration of 14C-azimexone in rats.

The pharmacokinetics of 14C-activity were studied in male Sprague-Dawley rats over 24 and 288 h periods after oral i.v. administration respectively. After oral administration rapid and complete absorption of azimexone occurred. The elimination of radioactivity from plasma after i.v. administration could be best described by an open four-compartment-system yielding a terminal half-life of 74.45 h indicating the existence of deep compartment for azimexone or its metabolites. The renal clearance of 14C-activity decreased considerably after i.v. administration with progressing time. This points to an extensive metabolism of azimexone. Fifty-seven and sixty-seven per cent of the given 14C-activity could be recovered in urine within 24 h after i.v. and p.o. administration respectively and in both cases less than 1% of the doses in feces. Studies on the distribution of the labelled substance 24 h after i.v. administration showed highest concentration in gastric contents, spleen thyroid gland and bone marrow. Twelve days after i.v. administration the ratio of the 14C-content in organ/plasma was greatly increased for spleen, thymus, lung, bone marrow and thyroid gland as compared with the conditions 24 h after administration. Thus it can be assumed that the target organs for the immunomodulating activity of the drug belong to the deep compartment of azimexone or its metabolites.