Intracranial invasive aspergillosis originating in the sphenoid sinus: a successful treatment with high-dose itraconazole in three cases

We report three cases of intracranial aspergillosis originating in the sphenoid sinus in immunocompetent patients. The patients presented with an orbital apex syndrome in that a unilateral loss of vision and cranial nerve III palsy were seen in all cases and a contralateral involvement was also seen in one case. Despite the initial treatment with a conventional dose of itraconazole (ITCZ, 200 mg/day), the neurological deficits failed to improve and the granulomatous inflammation was not suppressed. Therefore, we treated with a combination of a high dose of ITCZ at 500-1000 mg/day (16-24 mg/kg/day) and amphotericin B (AMPH-B) at 0.5 mg/kg/day, in conjunction with a pulse dose of methylprednisolone at 1000 mg/day. Two cases responded favorably in that the ocular movements completely recovered, and their maximum serum concentrations of the hydroxy ITCZ were 7816 ng/ml and 5370 ng/ml. However, the other case worsened, despite ITCZ treatment at 16 mg/kg/day, and the serum concentration of the hydroxy ITCZ was 3863 ng/ml. The surgical decompression of the cavernous sinus via an extradural approach was performed, and the dose of ITCZ was increased to 24 mg/kg/day. The resulting serum concentration of the hydroxy ITCZ was 4753 ng/ml, and the outcome of this case has been favorable. These results suggest that a high blood level of the hydroxy ITCZ (more than 4500 ng/ml) is a prerequisite for the successful treatment of intracranial aspergillosis and that the combination treatment of ITCZ with AMPH-B would be preferred. The concomitant use of steroid and/or surgical decompression should be considered, if the invasiveness is not well-controlled in spite of intensive medical therapy.     

Sarcolemmal fragility secondary to the degradation of dystrophin in dilated cardiomyopathy, as estimated by electron microscopy

A common gene deletion or mutation of delta-sarcoglycan (δ-SG) in dystrophin-related proteins (DRPs) is identified in both TO-2 strain hamsters and human families with dilated cardiomyopathy. We have succeeded in the long-lasting in vivo supplementation of a normal δ-SG gene by recombinant adeno-associated virus vector, restoration of the morphological and functional degeneration, and improvement in the prognosis of the TO-2 hamster. To evaluate the integrity of the sarcolemma (SL) and the subsequent change of organelles in cardiomyocytes of the TO-2 strain hamster, we examined electron microscopy (EM) images focusing on the sarcolemmal stability at the end stage of heart failure. Two types of sarcolemmal degradation were detected: the widened and locally thickened SL, and blurred and discontinuous SL. Bizarrely formed mitochondria of varying sizes were also observed. Immuno-EM revealed clear expression of dystrophin in the SL and intense expression at the costamere as well as at the T-tubules in the control F1B strain hearts, but a patchy deposition of dystrophin was observed along the SL without the transgene of δ-SG. In contrast to the previous reports that dystrophin’s integrity was intact, the present results suggest that the gene deletion of δ-SG and the loss of δ-SG protein in the SL cardioselectively cause the morphological and functional deterioration of dystrophin and the resultant instability of the SL. The sarcolemmal fragility may be similar to Duchenne-type progressive muscular dystrophy in skeletal muscle. In addition to the mechanical role, another aspect of DRPs for the intracellular signal transmission is also discussed.     

Covalent binding of nitroso-sulfonamides to glutathione S-transferase in guinea pigs with delayed type hypersensitivity

Drug induced allergies are believed to be induced by conjugates consisting of biological macromolecules and active metabolites. The present study investigated whether guinea pig glutathione S-transferase (gpGST), a protein that binds with sulfanilamide (SA) and sulfamethoxazole (SMX), could be detected in the liver cytosol fraction of guinea pigs that intraperitoneally received SA or SMX, and whether gpGST is a carrier protein. We synthesized three nitroso compounds, i.e., 4-nitroso-sulfanilamide (SA-NO), 4-nitrososulfamethoxazole (SMX-NO) and fluorescent-labeled nitroso compound (DNSBA-NO), and examined binding quantities of nitroso compounds to gpGST purified from untreated female guinea pigs. Furthermore, the concentrations of IgG in serum antibody for nitroso compounds were estimated using ELISA. When guinea pigs were sensitized using the three nitroso compounds, the dose dependent skin reactions were confirmed with each compound. In addition, sensitized guinea pigs using each nitroso compound showed positive skin reactions at an elicitation test performed using gpGST alone. The results confirmed synthesis of antibody against gpGST due to hapten sensitization. Therefore, when a nitroso compound binds with gpGST in the body of guinea pigs, nitroso-gpGST acts as a neoantigen, which induces synthesis of autoantibody. Thus, gpGST appears to be one of the carrier proteins that induce sulfa drug-induced allergies. Immunization of guinea pigs with active metabolite of drugs may give information for predicting the occurrence of delayed type hypersensitivity in human.     

Factor VIII contributes to platelet-fibrin thrombus formation via thrombin generation under low shear conditions

Introduction

Thrombus growth under low blood flow velocity plays an important role in the development of deep venous thrombosis (DVT). Increased plasma levels and activities of coagulation factor VIII (FVIII) comprise risk factors for DVT and pulmonary thromboembolism.

Objective

To localize FVIII in human venous thrombi of DVT and to determine whether FVIII contributes to thrombus formation under low shear conditions.

Methods

The localization of FVIII in venous thrombi obtained from patients with DVT was examined by immunohistochemistry. The role of FVIII in thrombus formation was investigated using a flow chamber system. Venous blood from healthy volunteers were incubated with an anti-FVIII monoclonal antibody (VIII-3776) or non-immunized mouse IgG₁. Blood samples were perfused on immobilized type III collagen at wall shear rates of 70/s and 400/s and then the surface area covered by platelets and fibrin was morphometrically evaluated. Prothrombin fragment 1+2 (PF1+2) generation was measured before and after perfusion.

Results

Venous thrombi of DVT comprised a mixture of platelets, fibrin and erythrocytes. Factor VIII appeared to be colocalized with glycoprotein IIb/IIIa, fibrin and von Willebrand factor in the thrombi. VIII-3776 specifically recognized the light chain of FVIII and prolonged the activated partial thromboplastin time (aPTT), but not prothrombin time (PT). The antibody significantly reduced platelets and fibrin covering, as well as PF1+2 generation at wall shear rates of 70/s and 400/s.

Conclusions

These results suggest that FVIII contributes to platelet aggregation and fibrin formation via thrombin generation under low shear conditions.     

Apparent diffusion coefficients of breast tumors: clinical application.

PURPOSE: To evaluate the usefulness of apparent diffusion coefficient (ADC) for the differential diagnosis of breast tumors and to determine the relation between ADC and tumor cellularity. MATERIALS AND METHODS: One hundred and thirty-six female patients (age range, 17-83 years; average age, 51.7 years) with 140 histologically proven breast tumors underwent diffusion-weighted magnetic resonance (MR) imaging (DWI) using the spin-echo echo-planar technique, and the ADCs of the tumors were calculated using 3 different b values, 0, 500, and 1000 s/mm(2). The diagnoses consisted of fibroadenoma (FA, n=16), invasive ductal carcinoma, not otherwise specified (IDC, n=117), medullary carcinoma (ME, n=3) and mucinous carcinoma (MU, n=4). Tumor cellularity was calculated from surgical specimens. The ADCs of breast tumors and cellularity were compared between different histological types by analysis of variance and Scheffe's post hoc test. The correlation between tumor cellularity and ADC was analyzed by Pearson correlation test. RESULTS: Significant differences were observed in ADCs between FA and all types of cancers (P<0.05) and between MU and other types of cancers (P<0.01) and in cellularity between FA and cancers except MU (P<0.01) and between MU and other types of cancers (P<0.01). There was an inverse correlation between ADC and tumor cellularity (P<0.01, r(2)=0.451). CONCLUSIONS: The ADC may potentially help in differentiating benign and malignant breast tumors. Tumor ADC correlates inversely with tumor cellularity.     

Replantation of the digits amputated by motorcycle chain injury

Summary Over the past 5 years, 134 digits were replanted in 85 patients. In 9 patients — 10 digits (11%) — the causation of injury was a motorcycle chain. The significant incidence of this type of injury has prompted us to report the replantation results. Hopefully, this might be used to caution the public against cleaning the chain while it is in motion. The sites of amputation were 5 in Tamai's Zone I and 5 in Tamai's Zone II. All amputated parts were distal to the DIP joint. The digits were replanted with anastomosis of both the artery and the vein. Eight out of the 10 replanted digits survived to give a success rate of 80%. There was no statistical difference between this rate and that for all other replanted digits resulting from various causes in Zones I and II, i.e. 86%. The high success rate suggests that replantation of the chain-amputated digits should be recommended, and the apparently poor conditions of the crush injury are no contraindications for surgery.     

Trabecular and cortical bone changes in vertebral and peripheral skeletons induced by surgical menopause

Using dual x-ray absorptiometry (DXA), quantitative computed tomography (QCT), and microdensitometry (MD) methods, we performed a 3-year longitudinal study of bone changes induced by surgical menopause, i.e., hysterectomy with unilateral or bilateral oophorectomy (OVX), in 52 nonmenopausal women. In the trabecular spine, bone mineral content (D_c) and bone mineral density (D_d) were determined by DXA, and bone mineral density (L₂ and L₃) was determined by QCT. In the cortical metacarpals, cortical thickness (MCI) and bone mineral density (GSmin/max and ∑ GS/D) were determined by MD. Bone reduction in axial and peripheral body sites was evaluated by all determinations 2.92 years after OVX. In the bilateral OVX group, accelerated bone changes began to appear immediately after OVX, and this rapid phase of bone loss persisted in the follow-up period. In the unilateral OVX group, however, no accelerated changes were detected and the slow phase of bone loss continued throughout the follow-up period; bone reduction in the bilateral group was thus greater than that in the unilateral group. Although there was a significant correlation between trabecular and cortical bone changes, the discrepancies between DXA, QCT, and MD determinations at the two body sites meant that it was not possible to precisely predict one bone measurement from another. The reliability of DXA and QCT determinations was not significantly different, and these two determinations afforded better discrimination than MD for detecting accelerated trabecular bone changes in the rapid phase early after OVX. The sensitivity of indices in MD for detecting cortical bone mass change was found to be, in descending order, MCI, GSmin/max, and ∑ GS/D, whereas on the MD determination, the sensitivity for the follow-up of bone changes was in the reverse order. MD was more suitable for discriminating the small cortical bone changes in the prolonged slow phase after OVX. To evaluate the influence of surgical menopause by determining differential trabecular and cortical bone changes, simultaneous assessment at both vertebral and peripheral sites was indispensable. Changes in the peripheral metacarpals did not prove to be a reliable indicator of changes in the axial spine.     

Mucosal neuroendocrine cell abnormalities in the colon of patients with Hirschsprung's disease.

We studied the distribution of mucosal neuroendocrine (NE) cells in the colon from 13 patients with Hirschsprung's disease (HD) and from 8 controls. Immunohistochemical studies were carried out using monoclonal and polyclonal antibodies against chromogranin A and synaptophysin (general markers of NE cells), 5-hydroxytryptamine (5-HT) (a marker of amine), peptide YY (PYY), and somatostatin (markers of neuropeptides). Chromogranin A immunoreactive cells were significantly increased in the aganglionic bowel compared with ganglionic bowel and controls (P less than .05). There was an increase in the number of synaptophysin immunoreactive cells in the aganglionic bowel compared with ganglionic bowel and controls but the results were not statistically significant. 5-HT immunoreactive cells were also significantly increased in the aganglionic bowel compared with ganglionic bowel and controls (P less than .05). The immunostaining for PYY demonstrated abundance of this NE cell type in the aganglionic bowel and this was highly significant compared with ganglionic bowel and controls (P less than .001). There was a significant increase in somatostatin immunoreactive cells in the aganglionic bowel compared with ganglionic bowel (P less than .01). The increase in neuroendocrine cells was found over the entire length of the aganglionic segment in rectosigmoid HD as well as in long-segment HD. These results demonstrating the increased levels of NE cells in the mucosa of aganglionic colon suggest that the NE cells may have a role in regulating the sustained contraction of the aganglionic intestine in HD.