Persistently High Antibody Titers and Deficient Specific Cellular Immunity to Varicella-Zoster Virus in a Retarded Patient after Varicella Infection

We report on a 19 month old female who has been retarded developmentally after a severe varicella infection contracted from her mother 4 months after delivery. Her titer of varicella-zoster virus (VZV) IgG antibody has been remarkably high for 4 years after the infection. Natural killer activity and the specific cellular immunity to VZV, as tested by delayed type hypersensitivity skin test and lymphocyte-proliferation assay, were impaired. She had an improvement of ataxia and then progressed developmentally after administration of an anti-viral agent. Administration of oral corticosteroids and methylprednisolone transiently decreased titers of VZV antibody and, contrary to previous reports, returned natural killer activity to normal levels. We suggest that this case may be a persistent VZV infection similar to congenital cytomegalovirus infection due to selective defects in cellular immunity including NK cells. Whether this specific deficient cellular immunity is genetically determined or secondary to the viral infection is speculative. This is the first known report of such a case.     

Lack of correlated expression between the glutathione S-transferase P-form and the oncogene products c-Jun and c-Fos in rat tissues and preneoplastic hepatic foci

Since the expression of glutathione S-transferase P-form (GST-P)has been suggested from in vitro studies to be partly regulatedby the oncogene products, c-Jun and c-Fos, their distributionswere compared in normal rat tissues and preneoplastic hepaticlesions induced by the Solt—Farber protocol. Immunohistochemicallydemonstrated GST-P protein was positively correlated with expressionof both c-Jun and c-Fos in the epidermis of the skin and thesmooth muscle of adult lung and with either c-Jun or c-Fos respectivelyin the bile ducts and bronchial epithelium. However, GST-P expressionwas also observed in proximal and distal straight segments ofthe kidney and other tissues negative for c-Jun and c-Fos andboth c-Jun and c-Fos were present in the renal proximal anddistal convoluted tubules, where GST-P was lacking. Thus, thelocalization of GST-P was in some cases clearly separable fromthose of c-Jun or c-Fos. GST-P was found to be focally expressedfrom an early stage of hepatocarcinogenesis, when c-Jun wasnot detectable. At later stages, this oncogene product was stainedin 35.7% of GST-P-positive foci, with a clear relation to thedegree of GST-P staining. Since GST-P is not always accompaniedby appreciable c-Jun or c-Fos, these oncogene products are apparentlynot prerequisites for its expression. However, c-Jun may bepartly responsible for maintaining high levels of GST-P in hepaticfoci at later stages of hepatocarcinogenesis.     

Prognostic Factors in Synovial Sarcoma: A Clinicopathologic Study of 18 Cases

The prognostic factors for synovial sarcoma were analyzed retrospectivelyin 18 patients. Variables evaluated for their use in predictingsurvival included the location of the primary tumor, tumor size,local recurrence, completeness of surgical resection, and histologicsubtype. Chemotherapy was not evaluated because the patientsreceived various regimens and/or inadequate doses. Tumor sizewas the most significant prognostic factor, and a diameter ofmore than 10 cm was associated with a significantly worse prognosis(risk ratio: 5.38) (P=0.012).We conclude that complete surgicalresection of tumors less than 5 cm in maximum diameter may becurative and that adjuvant chemotherapy may not be necessaryfor such patients, because the value of chemotherapy for synovialsarcoma is still controversial.     

Macular nerve fibers temporal to fovea may have a greater potential to recover function in patients with Leber's hereditary optic neuropathy

PURPOSE: It is known that even after visual loss, younger patients with Leber's hereditary optic neuropathy (LHON) can recover vision. The purpose of this study was to determine the mean age at onset for LHON patients with and without visual recovery who carried the 11778 mutation, and to determine the pattern of central vision recovery. METHODS: Thirty-five LHON patients with the 11778 mutation of mitochondrial DNA who had visited the Keio University Hospital between 1980 and 1999 and were followed for 2 to 20 years, were the subjects of this retrospective study. The patients who had recovered vision were tested by Goldmann perimetry, Humphrey perimetry, and landmark-driven fundus microperimetry with a scanning laser ophthalmoscope (SLO). The fixation status was assessed by SLO microperimetry. RESULTS: Nine of the 35 patients (14 of 70 eyes) demonstrated a recovery of visual acuity to better than 0.3 in at least one eye. The mean age of disease onset was 15.9 +/- 4.6 years in patients with visual recovery and 25.5 +/- 8.9 years in patients without visual recovery. This difference in the mean age at onset was significant (P =.0001; Welch t-test). These 9 patients (14 eyes) showed fenestrated central scotomas in testing by Humphrey 10-2 threshold and SLO microperimetry. The nasal side of the central visual fields had a higher sensitivity than the temporal side in 7 of the 9 patients in Humphrey 10-2 threshold testing. Areas insensitive to 0 dB were detected on the nasal side of the central retina in these patients by SLO microperimetry, and fixation stability was related to the degree of clinical visual acuity. CONCLUSION: The LHON patients with the 11778 mutation and a younger age of onset were more likely to show visual recovery. The findings made by perimetry suggest that the nerve fiber bundles in the nasal field (retina temporal to the fovea) may have a greater potential to recover function in LHON patients.     

Stress management in European countries and US]

In recent years, job stress and stress management have emerged as key issues in health promotion in the workplace in all of the post-industrialized countries. In the EU, the European Survey on Working Conditions has reveals that stress and musculo-skeletal disorders are the main health risks at work. In the US, NORA (national occupational research agenda) identifies 21 research priorities, in which "organization of work" is included as a job stress related factor. In this paper, trends and characteristics in occupational stress management in western countries, especially in the EU are overviewed. Presently, most stress management activities are oriented towards secondary or tertiary prevention, and are worker-oriented. But in future, priority strategy for intervention should be primary prevention, and focused on the organization as the generator of risk. In the group of countries paying a lot of attention to work stress, health policies or legal framework at the national level and a variety of activities for stress prevention at the company level are well integrated. By analyzing various stress management cases or projects, key factors for a successful approach to stress prevention are extracted as follows: 1. A stepwise and systematic approach, 2. clear determination of aims, tasks, responsibilities, planning and financial means, 3. An adequate diagnosis of risk analysis, 4. A combination of work-directed and worker-directed measures, 5. A participative approach, 6. Top management support. Costs-benefit assessment should be introduced to evaluate the effectiveness of stress prevention and to promote more integrated approaches in the workplace.     

Synthesis and protein kinase inhibitory activity of balanol analogues with modified benzophenone subunits

A series of analogues of the protein kinase C (PKC) inhibitory natural product balanol which bear modified benzophenone subunits are described. The analogues were designed with the goal of uncovering structure-activity features that could be used in the development of PKC inhibitors with a reduced polar character compared to balanol itself. The results of these studies suggest that most of the benzophenone features found in the natural product are important for obtaining potent PKC inhibitory compounds. However, several modifications were found to lead to selective inhibitors of the related enzyme protein kinase A (PKA), and several specific modifications to the polar structural elements of the benzophenone were found to provide potent PKC inhibitors. In particular, it was found that replacement of the benzophenone carboxylate with bioisosteric equivalents could lead to potent analogues. Further, a tolerance for lipophilic substituents on the terminal benzophenone ring was uncovered. These results are discussed in light of recently available structural information for PKA.     

Effects of serum albumin and liver cytosol on CYP2C9- and CYP3A4-mediated drug metabolism

To investigate whether the free-drug theory is accurate in that only unbound drug is available for drug metabolism or enzyme inhibition. The effect of addition of rat liver cytosol to an in vitro system using human liver microsomes was examined by measuring the catalytic activities of CYP2C9 (tolbutamide and diclofenac) and CYP3A4 (terfenadine). And, the results were compared with those obtained when human serum albumin (HSA) was added to microsomes as far as unbound drug concentrations were concerned. After addition of rat liver cytosol, the unbound Km value (Km,u) for terfenadine metabolism by CYP3A4, and the unbound Ki value of miconazole (Ki,u) for CYP2C9 were smaller than for the controls. Addition of HSA resulted in smaller Km,u values for diclofenac and terfenadine metabolism by CYP2C9 and CYP3A4, respectively, and the Ki,u value for ketoconazole inhibition of CYP3A4 was also reduced. These results suggest protein-facilitated effects on drug metabolism and enzyme inhibition for both CYP2C9 and CYP3A4. However, no protein-facilitated drug metabolism was observed for tolbutamide in the presence of HSA or cytosol, or for diclofenac in the presence of cytosol. Protein-facilitated enzyme inhibition did not occur with miconazole in the presence of HSA or with ketoconazole in the presence of rat liver cytosol. Protein-facilitated metabolism and enzyme inhibition were observed for CYP2C9 and CYP3A4 in five cases but there was no obvious pattern of enzyme, substrate, or binding protein specificity. Further investigations are necessary to clarify the relevance of these results to in vivo observations.     

Sentinel lymph node biopsy without axillary dissection after an intraoperative negative histological investigation in 358 invasive breast cancer cases

BACKGROUND: Sentinel lymph node biopsy (SLNB) is an important treatment option for breast cancer patients, as it can accurately predict axillary status. Our previous study using dye with or without radioisotope showed the accuracy and sensitivity of SLNB to be 97% and 94%, respectively. Based on these results, axillary lymph node dissection (ALND) was eliminated starting in January, 1999 in patients with intraoperatively negative SLNB at our institution. The present study shows the results and outcomes of SLNB as a sole procedure for patients with invasive breast cancer. PATIENTS AND METHODS: Three-hundred-fifty-four patients and 358 cases of invasive breast cancer (4 bilateral breast carcinoma) treated with SLNB alone after an intraoperative negative SLNB were studied prospectively from January 1999 to December 2001. RESULTS: The number of the identified SLNs per case ranged from 1 to 8 (mean, 2.5). Of a total of 358 cases, 297 (83%) were treated with hormone therapy and/or chemotherapy, and 281 (78%) were treated with radiotherapy to the conserved breast (50 Gy+/-10 Gy boost), the axilla (50 Gy), or the both sites. After a median follow-up of 21 (range 6-42) months, no patient developed an axillary relapse. Four cases initially recurred in distant organs and one case in the conserved breast. CONCLUSIONS: Our results indicate that an intraoperative negative SLNB without further ALND may be a safe procedure when strict SLNB is performed. To better assess the safety, however, may require longer follow-up.     

Experience of intravenous digital subtraction angiography (IV-DSA) in evaluation of neoadjuvant chemotherapy for advanced breast cancer

 Intravenous digital subtraction angiography (IV-DSA) was performed before and after neoadjuvant chemotherapy (NACT) in five patients with locally advanced breast cancer, and the efficacy of NACT was evaluated on the basis of the results of IV-DSA and histopathological examination. Following NACT, the maximum density of tumor enhancement (MAX) in the IV-DSA image decreased by 61.6% in case 1, 50% in case 2, 58.1% in case 3, 90.8% in case 4, and 97.2% in case 5. In all five patients, the efficacy of chemotherapy was rated as a partial response in terms of tumor size, while histological efficacy was rated as slightly effective in cases 1–4 and moderately effective in case 5. The pathological efficacy of NACT was highest in case 5, which showed the greatest decrease in MAX. These results indicate that variations in MAX reflect clinical efficacy, and, to some extent, also permit prediction of pathological efficacy. Received: March 4, 2002 / Accepted: June 10, 2002 Correspondence to:O. Watanabe