Cryptococcus neoformans osteomyelitis of the tibia: a case report and review of the literature.

INTRODUCTION: Osteomyelitis is a bone inflammation that can be related to various infectious agents. As with any other type of inflammation, the prevailing symptoms and signs may include redness, swelling, pain, and heat. Fungal osteomyelitis is rare and usually found in immune-compromised patients. CASE PRESENTATION: A non-human immunodeficiency virus immunocompromised Greek female patient, 82 years old, visited the emergency department due to a 3 day pain located mainly over the left tibia's anterior surface, accompanied by swelling and redness. There was also a subcutaneous lesion of her left breast. Medical history revealed that the patient had an unmasked close contact with pigeons, a main host of the disease. Initial x-ray imaging showed an osteolytic area in the upper third of the tibial diaphysis. The patient was admitted and underwent a computed tomography-guided biopsy. The specimen revealed a Cryptococcus neoformans infection of the bone and the breast. She was treated with 400 mg fluconazole twice a day for 3 weeks while in hospital and 200 mg twice a day upon discharge for 9 months. After that, she underwent surgical debridement because of lasting local irritation. She was closely monitored in our outpatient office, and in her last visit, 1 year after the initial admission, inflammatory signs had regressed vastly. CONCLUSIONS: To our knowledge, this is the ninth cryptococcal osteomyelitis of the tibia to be recorded since 1974, and the most unusual finding was the bifocal nature of the infection, affecting both the tibia and the breast.

Platelet-rich Plasma and Mesenchymal Stem Cells Local Infiltration Promote Functional Recovery and Histological Repair of Experimentally Transected Sciatic Nerves in Rats.

Introduction Platelet-rich plasma (PRP) products and mesenchymal stem cells (MSCs) seem to have a significant potential as neurogenic therapeutic modulator systems. This study aimed to investigate such biological blood derivatives that could enhance nerve regeneration when applied locally in the primary repair of peripheral nerve transection of an experimental rat model. Methods A total of 42 two-month-old male Wistar rats were divided into three "treatment" groups (control, PRP, and MSCs). All the subjects were operated under anesthesia, and the surgical site was infiltrated with either normal saline, PRP derived from the animal's peripheral blood, or MSCs derived from the animal's femoral bone marrow. All three groups were also sub-divided into two sub-groups based on the post-operative administration of Non-steroidal anti-inflammatory drugs (NSAIDs) or not in order to evaluate the effect of NSAIDs on the final outcome. Three months post-surgery, electromyography evaluation of both hind limbs (right operated and left non-operated) was performed. The animals were euthanized, and nerve repair specimens were prepared for histology. Results PRP group had a significant effect (p<0.05) on the sciatic nerve repair when compared with the control group, whereas the MSC group had a positive effect but was not statistically significant (p=0.2). The number of counted neural axons at the area distal to the nerve repair site were significantly repetitive (p<0.05) in both the PRP and MSC groups when compared with the control group. Conclusions Both PRP and MSCs appear to play an essential role in the enhancement of nerve repair in terms of functionality and histology. MSCs group demonstrated a positive effect, whereas the PRP group showed statistically significant better results.

The combination of microfracture with induction of Wnt / ß- Catenin pathway, leads to enhanced cartilage regeneration.

INTRODUCTION: Microfracture does not lead to complete healing of full-thickness cartilage defects. The aim of this study was to evaluate the effect of modifying Wnt/ß-catenin signaling following microfracture, on the restoration of a full-thickness cartilage defect in a rabbit model. The modification of the canonical Wnt pathway was achieved through per os administration of lithium carbonate, which is an intracellular inhibitor of glycogen synthase kinase 3-ß (Gsk3-ß) and therefore induces Wnt/ß-catenin signaling. MATERIALS AND METHODS: Full-thickness cartilage defects of 4 mm in diameter were created in the patellar groove of the right femurs of 18 male New Zealand white rabbits. The rabbits were divided into three groups of six (n = 6) based on post-surgery treatment differences, as follows: microfracture only (group 1), microfracture plus lithium carbonate 7 mM in the drinking water for 1 week (group 2), microfracture plus lithium carbonate 7 mM in the drinking water for 4 weeks (group 3). All animals were sacrificed 9 weeks after surgery. The outcome was assessed histologically, by using the International Cartilage Repair Society (ICRS) visual histological scale. Immunohistochemistry for type II collagen was also conducted. RESULTS: Statistical analysis of the histological ICRS scores showed that group 3 was significantly superior to group 1 in four out of six ICRS categories, while group 2 was superior to 1 in only two out of six. CONCLUSION: The combination of microfracture and systematic administration of lithium carbonate 7 mM for 4 weeks shows statistically significant superiority in four out of six ICRS categories compared with microfracture only for the treatment of full-thickness cartilage defects in a rabbit experimental model.

Cavernoma of the cauda equina.

BACKGROUND: Cavernomas are benign malformations of the vasculature. In the central nervous system, they are mostly located supratentorially. However, in adults, cavernomas also comprise about 3% of all subdural spinal cord tumors. Notably, cavernomas of the cauda equina are extremely rare, with only 23 cases reported in the literature. Here, we report the 24th case involving a 77-year-old male. CASE DESCRIPTION: A 77-year-old male presented with low back pain for 3 years duration. His history included prostate cancer, skin melanoma, and a sick sinus syndrome requiring a pacemaker. An enhanced computed tomography of the lumbar spine showed an inhomogeneously enhanced, intramedullary mass, located at the L3 level. The patient underwent an L3 hemilaminectomy with gross total excision of the lesion. Macroscopically, the tumor was mulberry-shaped and well demarcated. However, it was strongly adherent to a nerve root of the cauda equina which required resection. The histologic examination was consistent with a cavernoma. The patient subsequently fully recovered without a focal neurological deficit. CONCLUSIONS: Cavernomas of the cauda equina are extramedullary, arise on the inner aspect of the dura, and may be tightly adhered to the nerve roots. To attain gross total excision, the involved nerve may have to be sacrificed; in some cases, this may result in a permanent neurological deficit. Of interest, half of the cauda equina lesions were previously found in patients who had prior radiotherapy; this was not the case in this patient.

The effect of synbiotics on acute radiation-induced diarrhea and its association with mucosal inflammatory and adaptive responses in rats.

BACKGROUND: Previous clinical studies advocated that probiotics beneficially affect acute radiation-induced diarrhea. These encouraging results were attributed to the restoration of the intestinal flora; however, there is lack of evidence if and how probiotics influence the underlying pathophysiological mechanisms. AIMS: The present study was conducted to investigate the potential supporting role of a synbiotic preparation (combination of pro- and pre-biotics) on experimentally-induced acute radiation diarrhea from the perspective of mucosal inflammation and histological injury. METHODS: Ninety adult Wistar rats were randomly assigned into six groups. Group A (non-irradiated), group B (non-irradiated/synbiotic supplemented), group C (irradiated), and group D (irradiated/synbiotic supplemented) were followed up to a week after the beginning of the experiment. Group E (irradiated) and group F (irradiated/synbiotic supplemented) were followed up for four days. On the last day of the experiments tissues were harvested for structural and molecular assessments. RESULTS: Synbiotic administration could not avert the occurrence of diarrhea, but significantly attenuated its severity. This effect was associated with the significant downregulation of neutrophil accumulation and lipid peroxidation during the acute phase. During the subacute phase, synbiotic treatment significantly improved both the histological profile and radiation mucositis. These mechanisms significantly contributed to the rehabilitation of the intestinal absorptive function as further indicated from the significantly reduced weight loss. CONCLUSIONS: Given the optimization of the intestinal flora exerted by synbiotics, the resolution of diarrhea relies on the suppression of the "reactive" and the augmentation of "regenerative" components of acute radiation-induced intestinal response.

Prognostic significance of replication protein A (RPA) expression levels in bladder urothelial carcinoma.

OBJECTIVE: To elucidate the role of replication protein A (RPA) in both superficial (Ta-T1) and muscle-invasive (T2-T4) urothelial carcinomas (UCs), investigating its potential prognostic usefulness. PATIENTS AND METHODS: Paraffin-embedded tissue from 156 patients with bladder UC was immunostained for RPA1 and RPA2. RESULTS: RPA1 and RPA2 labelling indexes (LIs) decreased with increasing histological grade (both P < 0.001) and T-category in the entire cohort (P = 0.008 and P < 0.001, respectively) and in muscle-invasive carcinomas (P = 0.014 and P = 0.012, respectively). RPA1 expression was positively correlated with RPA2 (Spearman's correlation coefficient ρ = 0.309, P < 0.001). Both RPA1 and RPA2 LIs were positively correlated with cyclin D1 expression (ρ = 0.354, P < 0.001 and ρ = 0.934, P < 0.001). In survival analysis of the entire cohort decreased RPA2 and RPA1 correlated with a lesser probability of survival (P < 0.001 and P = 0.018). In non-muscle-invasive tumours (Ta-T1) only lower RPA2 (P < 0.001) was correlated with shortened survival, whereas in muscle-invasive tumours (T2-T4) decreased RPA2 and RPA1 expression levels were associated with adverse prognosis (P = 0.035 and P = 0.042, respectively). In multivariate survival analysis of the entire cohort and in non-muscle-invasive cases RPA2 expression remained significant, even when adjustment for cyclin D1 expression was applied. CONCLUSIONS: RPA1 and RPA2 overexpression seems to be more important during early T-categories of bladder carcinogenesis. Showing similar kinetics with cyclin D1. RPA2 expression emerges as a valuable marker of favourable prognosis in the entire cohort and in non-muscle-invasive tumours, supplementing the information obtained by standard clinicopathological prognosticators.

D-type cyclins in superficial and muscle-invasive bladder urothelial carcinoma: correlation with clinicopathological data and prognostic significance.

PURPOSE: To elucidate the role of D-type cyclins in both superficial (Ta-T1) and muscle-invasive (T2-T4) urothelial carcinomas (UCs), investigating their potential prognostic usefulness. METHODS: Paraffin-embedded tissues from 157 patients with bladder UC were immunostained for cyclins D1, D2 and D3. RESULTS: Cyclin D1 expression positively correlated with D2 and negatively with D3. Cyclin D1 expression decreased with increasing grade (P = 0.0001) and tumour T-category in the entire cohort and in muscle-invasive carcinomas (P = 0.0001 and P = 0.0033). Cyclin D2 correlated with grade (P = 0.0005) and T-category (P = 0.0078), a relationship which remained significant in muscle-invasive (P = 0.0135). Cyclin D3 immunoreactivity increased with histologic grade and T-category in the entire cohort (P = 0.0001 in both relationships), in superficial (P = 0.0034) and in muscle-invasive carcinomas (P = 0.0036, respectively). Survival analysis in superficial tumours showed that higher cyclin D1 (P = 0.0001) and higher cyclin D3 levels (P = 0.0032) were correlated with a lesser probability of survival. In muscle-invasive tumours, lower cyclin D1 (P = 0.0234), and D2 (P = 0.0424) and higher cyclin D3 (P = 0.0322) correlated with shortened survival. In multivariate analysis in superficial tumours only cyclin D3 expression remained significant. Cyclin D3 expression also retained its adverse significance in muscle-invasive tumours. CONCLUSIONS: Cyclin D1 overexpression seems to be more important during early T-categories of bladder carcinogenesis, whereas cyclin D3 is implicated in the acquisition of a more aggressive phenotype. Cyclin D3 overexpression emerges as an independent adverse prognostic marker in both superficial and muscle-invasive tumours. Cyclin D1 is an independent indicator of shortened survival only in muscle-invasive tumours.

Clinical significance of nuclear factor (NF)-kappaB levels in urothelial carcinoma of the urinary bladder.

Nuclear factor (NF)-kappaB has been reported to be constitutively activated in various human neoplasms. However, its clinical significance in bladder urothelial carcinoma (UC) remains an unresolved issue. We conducted this study trying to elucidate the role of NFkappaB in bladder UC and its potential prognostic significance, by quantifying immunohistochemically the levels of p65/RelA expression in paraffin-embedded tissue from 116 patients. Some of the cases had previously been stained for cellular FLICE-like inhibitory protein (c-FLIP) and bcl-2. Seventy-four cases displayed concurrent cytoplasmic and nuclear immunoreactivity, whereas 18 only nuclear immunoexpression and 21 only cytoplasmic immunoexpression, and the remaining three cases were negative for p65/RelA. Nuclear p65/RelA expression was positively associated with tumour grade and T-category (p=0.0001 in both cases). In addition, cytoplasmic p65/RelA expression was lower in advanced T-category (p=0.0030). Moreover, p65/RelA nuclear expression was positively correlated with c-FLIP (p=0.0109) and bcl-2 (p=0.0452). p65/RelA nuclear expression adversely affected survival in both univariate and multivariate analysis in superficial (Ta-T1; p=0.0010 and p=0.0008) as well as in muscle-invasive carcinomas (T2-T4; p=0.0004 and p=0.0003). Our results demonstrate that NF-kappaB nuclear expression is correlated with histologic grade and T category in bladder UC. Moreover, NF-kappaB nuclear expression emerges as an independent prognosticator of adverse significance, conveying information beyond that obtained by standard clinicopathological prognosticators.

Gastrointestinal stromal tumor of the gastric serosa protruding to the greater omentum. Report of a giant tumor with a rare histological pattern.

We report an unusual case of a 76 year old woman admitted to our hospital for investigation of anemia and palpable epigastric mass. Intraoperatively a huge (19 cm), well defined tumor was found adhering to the stomach wall, protruding into the greater omentum and compressing the transverse colon. A tumorectomy was performed and the greater omentum was removed due to its close relation. Pathology revealed a high risk Gastrointestinal Stromal tumor of the gastric serosa. Histologically the tumor was of mixed type (spindle and epithelioid cells) with hem-angio-peri-cytomatoid pattern peripherally, variably myxoid stroma, central necrosis and cytologic pleomorphism. On immunohistochemical examination there was a consistent positivity for c-kit (CD-117) and CD-34, but without myogenic or neural differentiation. We consider this case unusual because of its huge size, its gastric serosal location and its extremely rare histological pattern.

Acute lung injury in a rat model of intestinal ischemia-reperfusion: the potential time depended role of phospholipases A(2).

BACKGROUND: A pivotal role of phospholipase A(2) (PLA(2)) and platelet-activating factor-acetylhydrolase (PAF-AcH) as enzymes involved in lung inflammation has recently been suggested. The objective of this study was to elucidate the role and the time dependence of PLA(2) and PAF-AcH fluctuations in the lung relative to the evolution of intestinal ischemia-reperfusion (IIR). MATERIALS AND METHODS: Rats were randomly allocated to five groups of IIR induced by occlusion of the superior mesenteric artery for 45 min followed by 1 min, 2, 4, and 8 h of reperfusion (expGroups) and five corresponding sham groups (sGroups). Bronchoalveolar lavage fluid was obtained from the right lung and its biochemical (protein, PLA(2), PAF-AcH) and cytological characteristics were determined. Plasma malonyldialdehyde was measured as a marker of lipid peroxidation. The 4 and 8 h reperfusion expGroups had significantly (P < 0.05) elevated alveolar-arterial O(2) gradient values compared with the corresponding controls. Total protein, PLA(2) and PAF-AcH levels significantly (P < 0.05) increased in expGroups compared with the corresponding shams after 4 h of reperfusion. Total bronchoalveolar lavage fluid cells and plasma malonyldialdehyde were significantly (P < 0.05) elevated in expGroups compared with the sGroups after 2 h of reperfusion. CONCLUSIONS: PLA(2) could act synergistically or parallel with the reactive oxygen species produced during IIR, resulting in the induction or even in the exacerbation of the inflammatory reaction in acute respiratory distress syndrome. PAF-AcH could play an anti-inflammatory role by reducing the concentration of PAF.

Expression of hypoxia-related tissue factors in astrocytic gliomas. A multivariate survival study with emphasis upon carbonic anhydrase IX.

Carbonic anhydrase IX (CAIX) is a transmembrane enzyme involved in the reversible metabolism of carbon dioxide to carbonic acid and, hence, in physiological pH regulation. It also participates in cellular differentiation and proliferation, its expression being absent in most normal tissues. It has been recently postulated that the hypoxia-inducible factor (HIF-1) pathway up-regulated by hypoxia accounts for CAIX overexpression in most human tumors. In the present study, we examined the expression of this enzyme in diffuse gliomas of astrocytic origin in relation to vascular endothelial growth factor (VEGF) and HIF-1alpha expression, proliferation rate (as assessed with Ki-67 antigen), microvessel morphology, and survival. Of 84 cases analyzed, 61 cases (72.6%) displayed strong membrane and/or cytoplasmic expression of CAIX and were grouped as positive. Immunoreactivity tended to have a perinecrotic distribution and increased in parallel with the extent of necrosis (P < .001) and histologic grade (P < .001). A positive correlation was also noted with HIF-1alpha and VEGF expression (P < .001), proliferation rate (P = .010), microvessel density (P = .004), and microvessel caliber parameters (P = .014-.038). In univariate survival analysis, increased CAIX expression was associated with shortened survival in the entire cohort (P < .0001), along with VEGF (P = .0205) and HIF-1alpha levels (P = .0190). Multivariate analysis selected the interaction model of CAIX, with grade and age as the only parameters independently affecting survival. CAIX expression was also the only significant parameter for the survival of patients with grades II/III. We conclude that CAIX may be used as a prognostic indicator in diffuse astrocytomas to refine the information provided by grade. Given the role of CAIX in the acidification of tumor environment and its up-regulation by hypoxia, it is thought that CAIX expression may be linked to resistance of tumor cells to radiotherapy by allowing them to acclimatize to a hypoxic and acidic microenvironment.

Cyclooxygenase-2 expression in astrocytomas. Relationship with microvascular parameters, angiogenic factors expression and survival.

OBJECTIVE: Cyclooxygenase-2 (COX-2) is the enzyme isoform involved in the synthesis of prostaglandins (PGs) and thromboxane from arachidonic acid. The role of the up-regulation of COX-2 in the formation and progression of gliomas has been dealt with in earlier reports, which describe increased levels of PGs within gliomas. In the present study, we examined the expression of COX-2 in diffuse gliomas of astrocytic origin in relation to microvascular parameters, angiogenic factors and survival. MATERIALS AND METHODS: A total of 83 cases of diffuse astrocytomas (grade II-IV) were analyzed by immunohistochemistry for the presence of COX-2. RESULTS: COX-2 expression was detected in 79 cases (95%) with an increased expression in grade IV as compared to grades II/III (p=0.024). A positive correlation occurred between COX-2 and angiogenic factors such as vascular endothelial growth factor (VEGF) (p<0.0001) and hypoxia inducible factor (HIF)-1alpha (p=0.005), as well as the tumours' proliferative activity (expressed as the percentage of Ki-67 positive cells) (p=0.032), and total vascular area (TVA) (p=0.040). In univariate analysis, COX-2 was associated with shortened survival (p = 0.050). Multivariate survival analysis showed that the interaction model of COX-2 with grade along with age were the only significant prognostic indicators. CONCLUSION: These results implicate COX-2 in the angiogenesis and biological aggressiveness of diffuse astrocytomas, and suggest that it would be worthwhile to examine how the inhibition of COX-2 expression may influence astrocytoma patients' survival.