Tuberculous mastoiditis - a case series.

SUMMARY: Tuberculous mastoiditis (TBM) is a rare form of extrapulmonary tuberculosis (TB), which may result in catastrophic complications, including mastoid and ossicle destruction, hearing loss and intracranial spread if untreated. Diagnosis is challenging due to the paucibacillary nature of extrapulmonary TB, compounded by limited theatre access for specimen retrieval, resulting in delayed diagnosis and treatment initiation. In this case series, we discuss three cases of TBM (one paediatric and two adults) who presented to the public and private healthcare sectors in the Eastern Cape in 2022, underscoring that TB does not respect socioeconomic status.

Chia Seeds Oil Suppresses the Resistance of Hepatocellular Carcinoma Cells to Liposomal-doxorubicin and Upregulates the Tumor Suppressor miRNAs.

BACKGROUND: Chia seed is an oil seed with multiple biological activities. Doxorubicin is effective chemotherapy for liver cancer. Resistance and adverse effects are doxorubicin limitations. OBJECTIVE: This study aimed to investigate the effect of chia seeds oil (CSO) on the resistance of HepG2 cells to liposomal-doxorubicin (DOX). METHODS: The objective were investigated through measuring cytotoxicity, doxorubicin-metabolizing enzyme Cytochrome P450 3A4 (CYP-3A4), multidrug resistance-associated protein (MRP1), and the expression of multiple tumor suppressor microRNAs. RESULTS: The findings indicated that low concentration of CSO increased HepG2 cells' sensitivity to DOX, as concluded from its higher cytotoxicity. DOX-induced mRNAs of CYP-3A4 and MRP1 and their protein levels. CSO inhibited both in DOX-treated cells. CSO-induced tumor suppressor miRNAs. Doxorubicin inhibited miR-122 and let-7/b/e expression, while it led to overexpression of let- 7a. CSO/DOX upregulated let-7/b/e, miR-34a, and miR-122 (which inhibits MRP1) and downregulated let-7a, which may lead to increased apoptosis. CONCLUSION: CSO effectively re-sensitized HepG2 cells to liposomal-doxorubicin via inhibiting MRP1 and CYP-3A4, which may increase in vivo doxorubicin bioavailability and decrease its therapeutic dose to diminish its adverse effects.

[Palliative sedation in a man with oral cancer; the Royal Dutch Medical Association guidelines not always sufficient]. / Palliatieve sedatie bij een man met mondkanker: KNMG-richtlijn is niet altijd toereikend.

BACKGROUND: Palliative sedation is an effective treatment option in patients with refractory symptoms in the last phase of life. In 2009 the Royal Dutch Medical Association (KNMG) published revised guidelines. The dosage of propofol recommended in these guidelines is, however, based on one single study. CASE DESCRIPTION: A 60-year-old patient with a history of psychiatric disease and alcohol abuse was admitted to the palliative care unit suffering from unbearable pain from a squamous carcinoma of the floor of the oral cavity. Adequate treatment of his symptoms was initially possible, but when his symptoms became refractory we initiated continual sedation. Adequate symptom control was only achieved when propofol was administered in a high dosage of 150 mg/h and levomepromazine administration was reinitiated. CONCLUSION: In our opinion the advised starting dose of propofol is too low, especially in comparison with sedation in regional anaesthesia described in the literature. Furthermore, we advocate that administration of drugs from step 2, midazolam and levomepromazine, is not discontinued when propofol sedation is commenced in step 3.

Polyamine metabolism in brain tumours: diagnostic relevance of quantitative biochemistry.

OBJECTIVE: Activation of polyamine metabolism is closely associated with cellular proliferation. The purpose was to investigate whether the content of the polyamines putrescine, spermidine, and spermine, and the activity of the first metabolic key enzyme of polyamine metabolism, ornithine decarboxylase (ODC), represent biochemical markers of malignancy in brain tumours. METHODS: The concentration of putrescine, spermidine, and spermine, and the activity of ODC were biochemically quantified in tissue samples obtained during open microsurgery of 670 patients with brain tumours. Biochemical analysis and histopathological classification were carried out in serial tumour samples. RESULTS: The activity of ODC was very low in peritumoral non-neoplastic brain tissue (0.9 (SD 0.6) nmol/g/h). It was significantly higher in gliomas and it significantly increased with a higher grade of malignancy (grade I 2.7 (2.8) nmol/g/h, grade II 3.1 (4.0) nmol/g/h, grade III 5.7 (5.6) nmol/g/h, grade IV 10.6 (11.7) nmol/g/h). High enzyme activity was also found in medulloblastomas (25.5 (15.1) nmol/g/h), malignant lymphomas (52.1 (42.1) nmol/g/h), and metastases from carcinoma (14.9 (22.1) nmol/g/h). Lowest values were measured in epidermoid cysts (0.5 (0.2) nmol/g/h), craniopharyngiomas (1.2 (0.9) nmol/g/h), angioblastomas (1.6 (1.7) nmol/g/h), and neurinomas (2.0 (1.8) nmol/g/h). By contrast with ODC activity, polyamine concentrations did not correlate with the grade of malignancy. Correlation of regional biochemical and histomorphological data in rapidly growing neoplasms showed high enzyme activity in solid tumour parts and low activity in necrotic areas. CONCLUSIONS: Novel data relating ODC activation and polyamine concentrations to neuropathology is presented indicating that high ODC activity represents a biochemical marker of malignancy in brain tumours. This information is important for clinical and therapeutic investigations.

Regional distribution of ornithine decarboxylase activity and polyamine levels in experimental cat brain tumors.

Biosynthesis of the polyamines putrescine, spermidine, and spermine, and activation of the first key enzyme ornithine decarboxylase (ODC) are closely associated with cellular proliferation. In the present study, the distribution of ODC activity and polyamine levels was investigated for the first time regionally in experimental brain tumors of the cat. Brain tumors were produced by stereotactic xenotransplantation of rat glioma cells. Twenty days after implantation, the brains were frozen in situ, cut into slices, and cryostat sections and tissue samples were taken to determine ODC activity and polyamine levels biochemically. The quantified data were color-coded to present the regional distribution of ODC activity and polyamine levels in the respective section. ODC activity significantly increased in some areas within the tumor, whereas peritumoral tissue showed no difference to the non-tumoral, contralateral hemisphere. This increase turned out in parallel to a high number of mitoses in the same tumor parts (r=0.861). Putrescine levels increased both, in the whole tumor and in the peritumoral edema. Regional differences in putrescine content did not correlate with solid and proliferative parts of the tumor. Spermidine and spermine levels were only slightly increased in some parts of the tumor. Thus, these experiments show the close correlation of a high mitotic rate and activation of ODC within experimental gliomas and underline the relevance of ODC as a biochemical marker of proliferation in brain tumors.

Tuberculous meningoencephalitis in HIV-seronegative patients: variety of clinical presentation and impact on diagnostics and treatment.

UNLABELLED: Tuberculous meningoencephalitis (TBM), an infrequent disease in Western European countries, shows a wide heterogeneity of clinical symptoms. MATERIAL AND METHODS: We present 4 patients (age range 42-72 years) with the definite diagnosis of isolated TBM. All patients were HIV-seronegative, only 1 patient was known to be immunoincompetent on admission due to acute myelocytic leukemia; other reasons for immune suppression were detected in 2 other patients (leukemia and idiopathic CD4+ T-lymphocytopenia, respectively). RESULTS: The diagnosis of TBM was confirmed in 3 cases by culture from CSF, in 1 case Mycobacterium tuberculosis was proven only in tracheal aspirate. In 1 patient M. bovis was found, which is an extremely rare cause of TBM in Germany. We report the contributions of different diagnostic tools (CSF analysis, neuroimaging) in reaching the presumptive diagnosis and in monitoring the further course. All patients developed neurological complications despite prompt tuberculostatic treatment. Three of the patients presented a chronic severe loss of consciousness of unclear origin. CONCLUSION: The possible causative relationships of these complications and their impact on the prognosis are discussed.

Quinolinate immunoreactivity in experimental rat brain tumors is present in macrophages but not in astrocytes.

Experimental tumors of the central nervous system were investigated with antibodies to quinolinate to assess the cellular distribution of this endogenous neurotoxin. In advanced F98 and RG-2 glioblastomas and E367 neuroblastomas in the striatum of rats, variable numbers of quinolinate immunoreactive cells were observed in and around the tumors, with the majority being present within tumors, rather than brain parenchyma. The stained cells were morphologically variable, including round, complex, rod-shaped, and sparsely dendritic cells. Neuroblastoma and glioma cells were unstained, as were neurons, astrocytes, oligodendrocytes, ependymal cells, endothelial cells, and cells of the choroid plexus and leptomeninges. Glial fibrillary acidic protein immunoreactivity was strongly elevated in astrocytes surrounding the tumors. Dual labeling immunohistochemistry with antibodies to quinolinate and glial fibrillary acidic protein demonstrated that astrocytes and the cells containing quinolinate immunoreactivity were morphologically disparate and preferentially distributed external and internal to the tumors, respectively, and no dual labeled cells were observed. Lectin histochemistry with Griffonia simplicifolia B4 isolectin and Lycopersicon esculentum lectin demonstrated numerous phagocytic macrophages and reactive microglia in and around the tumors whose distribution was similar to that of quinolinate immunoreactive cells, albeit much more numerous. Dual labeling studies with antibodies to quinolinate and the lectins demonstrated partial codistribution of these markers, with most double-labeled cells having the morphology of phagocytes. The present findings suggest the possibility that quinolinate may serve a functional role in a select population of inflammatory cell infiltrates during the immune response to brain neoplasms.

Polyamine metabolism in gliomas.

Biosynthesis of the polyamines putrescine, spermidine, and spermine has been found to be activated in tissues with cellular proliferation. In the present study we have investigated polyamine levels and the activity of the first rate-limiting enzyme ornithine decarboxylase (ODC) in tumour samples obtained during operation of 202 patients with gliomas. Biochemical data were closely related to the grading of malignancy and to the morphological characteristics of each sample. Mean ODC activity was significantly higher in all gliomas as compared to peritumoural non-neoplastic brain. Furthermore, it was significantly higher (p < or = 0.001) in anaplastic gliomas who grade III and IV (9.0 +/- 9.6 nmol/g/h) than in gliomas WHO grade I and II (3.3 +/- 4.2 nmol/g/h). Highest enzyme activity (58.5 nmol/g/h) was found in solid and vital parts of malignant tumours, whereas predominantly necrotic areas exhibited low ODC activity (< 1 nmol/g/h). Thus, intra- and interindividual variability of ODC activity corresponded well to histomorphological heterogeneity in high-grade gliomas. Putrescine levels also increased with rising grade of malignancy, whereas spermidine and spermine levels did not correlate with the histological grading. In conclusion, high ODC activity represents a biochemical marker of malignancy in gliomas, but low values do not prove benignity. The present study reinforces the need of further and more extensive tumour sampling closely related to follow-up investigations in the heterogeneous group of gliomas.

High resolution quantitative relaxation and diffusion MRI of three different experimental brain tumors in rat.

The potential of quantitative parameter images of the relaxation times T1 and T2, the proton density rho and the apparent diffusion coefficient (ADC) to characterize three different experimental rat brain tumors (F98 glioma, RN6 Schwannoma, and E376 neuroblastoma) was studied. All parameter values, as determined in histologically confirmed regions of interest (ROI), were higher in edema than in tumor, which in turn were elevated with respect to normal brain. ROI values of ADC and T2 delivered statistically significant (P < 0.01) differentiation between tumor and edema. Multidimensional parameter combinations improved differentiation between different tissues. However, the three tumor types could not be differentiated. All parameter maps allowed the identification of the whole tumor-edema area. On T2 images, edema could be identified best, whereas the tumor itself was hardly visualized. In many cases, tumor presentation using T1 maps corresponded best with histology, nevertheless suffering from a poor tumor-edema differentiation.

Diffusion-weighted MR imaging of experimental brain tumors in rats.

Diffusion-weighted magnetic resonance imaging was used for the description of experimental brain tumors in rat. To validate this approach, diffusion-weighted images (DWI) were compared with native T1- and T2-weighted images, and with T1-weighted images following contrast enhancement with the tumor-specific contrast agent manganese (III) tetraphenylporphine sulfonate (MnTPPS). Three tumor types were studied: F98 glioma, RN6 Schwannoma, and E376 neuroblastoma. On heavily diffusion-weighted images, all three tumor types as well as the peritumoral edema were clearly hypointense with respect to the intact brain tissue. T2-weighted images presented mainly peritumoral edema as hyperintense region. A clear demarcation of the tumor was possible only on T1-weighted images after contrast enhancement with MnTPPS. The difference in signal intensity between tumor and homotopic regions in the contralateral hemisphere was comparable in DWIs and in contrast-enhanced T1-weighted images. Spatial comparison of depicted lesion areas in all three imaging modalities indicated that hypointense region on DWI represents both tumor and edema but does not permit their spatial differentiation.

Selective enhancement of experimental rat brain tumors with Gd-TPPS.

The synthetic metalloporphyrin gadolinium (III)-tetraphenylporphine sulfonate (TPPS) was successfully used as a contrast agent for in vivo magnetic resonance (MR) imaging of rat brain glioma. After injection of Gd-TPPS, the signal intensity of experimental rat brain glioma distinctly increased on T1-weighted MR images, an effect similar to that produced by the clinically applied MR imaging contrast agent gadolinium diethylenetriaminepentaacetic acid (DTPA). In contrast to other contrast agents studied (Gd-DTPA, manganese [III]-TPPS), Gd-TPPS produced hypointensity in glioma on T2-weighted images. The tumor-selective accumulation of paramagnetic Gd-TPPS in glioma shortened T1 by 53%, from 1,315 msec +/- 199 to 628 msec +/- 106, and T2 by 34%, from 86 msec +/- 4 to 57 msec +/- 5 (2 days after injection of 0.25 mmol/kg Gd-TPPS). The relaxation times of normal cortex, striatum, corpus callosum, and temporal muscle were not significantly affected. As a result, gliomas appeared hyperintense on T1-weighted images and hypointense on T2-weighted images. Owing to the strong effect of Gd-TPPS on the T2 of glioma, normal brain tissue, tumor, and peritumorous edema could be distinguished on T2-weighted images alone.

Quantitative diffusion MR imaging of cerebral tumor and edema.

The detection of brain tumors using standard techniques of qualitative, relaxation-weighted magnetic resonance imaging (MRI) requires the application of contrast agents. We investigated whether or not it is possible to use diffusion-weighted MRI to localize tumors without contrast enhancement. Three different experimental rat brain tumors were studied: F98 glioma, RN6 Schwannoma and E376 neuroblastoma. We found a marked hypointensity in the region of the tumor and edema in heavily diffusion-weighted images, which corresponded well with the histological presentation. Quantitative maps of the apparent diffusion coefficient (ADC) allowed a better localization of the tumor than that obtained by regional presentation of T2 times, particularly under conditions in which peritumoral edema was absent. The ADC differences of the three tumor types were statistically not significant. Based upon regions-of-interest evaluations, tumor could be distinguished from peritumoral edema and normal brain tissue. However, a sharp demarcation between tumor and peritumoral edema was not possible, and this is attributed to a similar enlargement of interstitial space. It was concluded that diffusion-weighted MRI possesses a high potential for the detection of brain tumors but does not allow precise demarcation of the tumor border.

Localization of experimental brain tumors in MRI by gadolinium porphyrin.

The contrast between edema and F98 glioma in rat brain was distinctly enhanced in T2-weighted MRI (TE 130 ms, TR 3 s) by intraperitoneal injection of the synthetic gadolinium-porphyrin complex, GdTPPS. The T1 relaxation time of the gliomas was selectively shortened by about 50% from 1339 +/- 109 ms to 628 +/- 106 ms, and the T2 relaxation time was shortened by about 35% from 86 +/- 6 ms to 57 +/- 5 ms. The relaxation times of normal tissues under investigation (cortex, corpus callosum, temporal muscle, ventricles) were unaltered. Therefore, GdTPPS-application causes F98 gliomas to appear hyperintense in T1-weighted MRI and hypointense in T2-weighted MRI.

Proton MR spectroscopy of experimental brain tumors in vivo.

F98 gliomas, E367 neuroblastomas, and RN6 Schwannomas in rat brain were studied non-invasively in vivo by localized proton MR spectroscopy (MRS). The spectra obtained from homotopic brain contralateral to the tumors were qualitatively indistinguishable from those of normal rat brain in vivo and showed resonance lines assigned to N-acetylaspartate, glutamate, total creatine (creatine and phosphocreatine), choline, glucose, and myo-inositol. The tumor spectra displayed marked differences compared to those obtained from contralateral brain. There were increases in choline, myo-inositol and lipids, which are presumably associated with increased membrane turnover. The presence of lactate indicated anaerobic glycolysis. Other differences included the absence of signals from NAA resulting from the destruction or displacement of neuronal tissue by the tumor. There was also a loss of total creatine. Although the spectra of all three tumor types were distinct from contralateral brain, there were no obvious differences between the different tumor types.

In vivo relaxometry of three brain tumors in the rat: effect of Mn-TPPS, a tumor-selective contrast agent.

T1 and T2 were determined simultaneously in vivo at 4.7 T in implanted rat brain tumors. Three different tumor cell lines were implanted in the right caudate nucleus: the F98 glioma, the E367 neuroblastoma, and the RN6 schwannoma. Their T1 and T2 values (mean +/- standard deviation [msec]), respectively, were 1,312 +/- 107 and 89 +/- 3 (glioma), 1,284 +/- 86 and 87 +/- 7 (neuroblastoma), and 1,338 +/- 85 and 86 +/- 9 (schwannoma). The T1 values (msec) of normal brain and muscle were 1,090 +/- 59 and 1,139 +/- 77, respectively, and the T2 values (msec) were 76 +/- 3 and 36 +/- 2, respectively. After injection of the contrast agent manganese (III) tetraphenylporphine sulfonate (TPPS) the T1 of all three tumors decreased by 30% and the T2 by 10%, whereas no such change in relaxivity was noted in normal brain. As a result, strong contrast enhancement of the three tumor types was seen on T1-weighted images. The tumor was clearly delineated and correlated with findings at histologic examination. This tumor enhancement was followed up for 4 days with quantitative relaxation time measurements, and the strong, selective reduction in T1 for all three tumor types after Mn-TPPS injection was preserved over the entire observation period.

Comparison of flow disturbances in small carotid atheroma using a multi-gate pulsed Doppler system and Doppler color flow imaging.

The capacity of a multi-gate pulsed Doppler (MPD) system and Doppler color flow imaging (DCFI) for the evaluation of flow patterns was studied in 14 patients with 17 nonstenotic carotid plaques (luminal narrowing less than 40%). Plaque morphology was assessed by means of a high-resolution B-mode system with subsequent three-dimensional reconstruction of the lesion surface. MPD velocity profiles obtained proximally, centrally and distally to the plaque (51 analyses) were normal in 31 sites corresponding to 28 undisturbed and 3 turbulent flow patterns assessed by Doppler color flow imaging (90% specificity). Of the 10 irregular MPD flow profiles, DCFI detected turbulence in 7 (70% sensitivity). 10 asymmetric MPD waveforms without irregularities were normal in 7 and turbulent in 3 DCFI studies. These results suggest, that MPD is superior to DCFI for the detection of nonturbulent flow asymmetry nearby small carotid plaques. However, DCFI displays turbulence with a high specificity and reasonable sensitivity and visualizes the morphologic-hemodynamic interaction in carotid atherosclerosis simultaneously.