Effects of dosing frequency on the clinical efficacy of ampicillin/sulbactam in Japanese elderly patients with pneumonia: A single-center retrospective observational study.

This study sought to investigate whether dosing frequency (the number of doses per day) affects the antimicrobial efficacy and safety of ampicillin/sulbactam (ABPC/SBT) in Japanese elderly pneumonia patients treated with ABPC/SBT at 6 g/day. This was a retrospective observational study that included hospitalized elderly patients (aged ≥75 years, 10 ml/min ≤CLcr <50 ml/min) who received 3 g every 12 h (BID; n = 61) or 1.5 g every 6 h (QID; n = 45) for the treatment of pneumonia. The primary endpoint was clinical response, assessed by measuring body temperature, white blood cell count, and C-reactive protein levels. Pharmacokinetic and pharmacodynamic simulations were conducted in silico to rationalize the clinical findings. The clinical response rates (extremely effective and effective) in the BID and QID groups were 36.1% and 55.6%, respectively (p = .0459). QID tended to be more effective in patients with gram-negative rods detected (p = .0563). According to the simulated minimum plasma ABPC concentrations at steady state for BID and QID were 2.5 and 7.3 µg/ml, respectively (p < .0001). Based on the simulated time above minimum inhibitory concentration (MIC), pharmacological (not clinical) efficacy was predicted to be higher with QID. Both groups had similar safety profiles. The main adverse event in both groups was liver damage. The present retrospective survey demonstrated that ABPC/SBT treatment for elderly patients with pneumonia and renal dysfunction was more effective with QID than with BID. Therefore, the QID regimen is worthy of consideration to improve the clinical outcomes of ABPC/SBT therapy in the present patient population.

In vivo optical interferometric imaging of human skin utilizing monochromatic light source.

We have demonstrated tomographic imaging of in vivo human skin with an optical interferometric imaging technique using a monochromatic light source. The axial resolution of this method is determined by the center wavelength and the NA of the objective and is irrelevant to the bandwidth of the light source in contrast to optical coherence tomography. Our imaging system is constructed with low-priced and small-sized compact disk optical pickup components, a laser diode, a high NA objective, and a voice coil actuator. In spite of its low cost and small size, our imaging system can visualize the structure of human skin as clearly as a commercial reflectance confocal microscope.

Downregulation of cytochrome P450scc as an initial adverse effect of adult exposure to diethylstilbestrol on testicular steroidogenesis.

Reproductive toxicities and endocrine disruptions caused by chemicals in adult males are still poorly understood. It is our objectives to understand further details of the initial adverse effects leading severe testicular toxicities of a pharmaceutical endocrine disruptor, diethylstilbestrol (DES). Downregulations of both testicular regulatory proteins, such as the steroidogenic acute regulatory protein (StAR) and the peripheral benzodiazepine receptor (PBR), which play important roles in the transport of cholesterol into the mitochondria, and cytochrome P450 mediating the cholesterol side chain cleavage reaction (P450scc), were observed in the rat orally administered DES (340 µg/kg/2 days) for 2 weeks. We found that after only 1 week treatment with DES, the blood and testicular testosterone (TS) levels were drastically decreased without abnormalities of the StAR and PBR; however, the protein and mRNA levels of P450scc were diminished. Decrease in the conversion rate of cholesterol to pregnenolone was delayed in the in vitro assay using the testicular mitochondrial fraction from the rat treated with DES for 1 week. When the precursors in TS biosynthesis containing the testis were identified and determined by liquid chromatography-mass spectrometry analysis, decreased levels of all precursors except cholesterol were observed. In conclusion, suppressed cytochrome P450scc expression in adult male rat was identified as an initial target of DES in testicular steroidogenesis disorder leading reproductive toxicities.

Accurate determination of tissue steroid hormones, precursors and conjugates in adult male rat.

The actual levels of steroid hormones in organs are vital for endocrine, reproductive and neuronal health and disorders. We developed an accurate method to determine the levels of steroid hormones and steroid conjugates in various organs by an efficient preparation using a solid-phase-extraction cartridge. Each steroid was identified by the precursor ion spectra using liquid chromatography-electrospray ionization time-of-flight mass spectrometry, and the respective steroids were quantitatively analysed in the selected reaction monitoring mode by liquid chromatograph-mass spectrometry/mass spectrometry (LC-MS/MS). The data showed that significant levels of testosterone, corticosterone and precursors of both hormones were detected in all organs except liver. The glucuronide conjugates of steroid hormones and the precursors were detected in all organs except liver, but sulfate conjugates of these steroids were observed only in the target organs of the hormones and kidney. Interestingly, these steroids and the conjugates were not observed in the liver except pregnenolone. In conclusion, an accurate determination of tissue steroids was developed using LC-MS analysis. Biosynthesis of steroid hormones from the precursors was estimated even in the target organs, and the delivery of these steroid conjugates was also suggested via the circulation without any significant hepatic participation.

A percentage analysis of the telomere length in Parkinson's disease patients.

Telomeres are the repeated sequences at the chromosome ends which undergo shortening with cell division. The telomere shortening of the peripheral leukocytes is also facilitated by enhanced oxidative stress in various kinds of disease including ischemic heart disease, diabetes mellitus, apoplexy, and Alzheimer's disease. Telomere shortening in Parkinson's disease (PD) has not yet been reported. The pathogenesis for PD is also regarded to be associated with oxidative stress. We investigated 28 Japanese male PD patients ages 47-69. Although we could not find a statistical difference in the mean telomere length of peripheral leukocytes between the PD patients and the control participants, we found the mean telomere lengths to be shorter than 5 kb in only the PD patients and a significant PD-associated decrease in the telomeres with a length ranging from 23.1 to 9.4 kb in the patients in their 50s and 60s. These observations suggest that telomere shortening is accelerated in PD patients in comparison to the normal population.

Reappraisal of the serum (1-->3)-beta-D-glucan assay for the diagnosis of invasive fungal infections--a study based on autopsy cases from 6 years.

BACKGROUND: The prevalence of invasive fungal infection is increasing. An effective diagnostic test is required to identify and treat them successfully. METHODS: All autopsy records at our hospital for the period from January 2000 through December 2005 [corrected] were reviewed for cases of invasive fungal infection. The diagnostic efficacy of a serum (1-->3)-beta-D-glucan (beta-glucan) assay was examined using only those cases in which patients had been tested for fungal infection within 2 weeks before death. RESULTS: Of 456 autopsies, 54 (11.8%) involved cases of invasive fungal infection. Leukemias were the most frequent underlying disease (in 52% of cases of invasive fungal infection), and Aspergillus species was the most frequent pathogen detected (in 70%). Of the 54 patients with invasive fungal infection, 41 had beta-glucan testing performed within 2 weeks before death, as did 63 patients without invasive fungal infection; 48 of 54 patients with invasive fungal infection had a blood culture performed. The sensitivity and specificity of the beta-glucan test for the detection of invasive fungal infection were 95.1% and 85.7%, respectively, with a cutoff value of 30 pg/mL; 85.4% and 95.2%, respectively, with a cutoff value of 60 pg/mL; and 78.0% and 98.4%, respectively, with a cutoff value of 80 pg/mL. The sensitivity of blood culture testing was 8.3%. With a prevalence of 11.8%, the positive and negative predictive values for the beta-glucan test were 47.1% and 99.2%, respectively, with a cutoff of 30 pg/mL; 70.4% and 98.0%, respectively, with a cutoff of 60 pg/mL; and 86.7% and 97.1%, respectively, with a cutoff of 80 pg/mL. During the 6-year period studied, of 21 patients with fungus-positive blood cultures that were preceded or followed by a beta-glucan test within 2 weeks, 4 had negative beta-glucan test results (beta-glucan level, <30 pg/mL), and 17 had positive results (beta-glucan level, >60 pg/mL); the concordance between culture results and beta-glucan test results was 81.0%. Contrary to the general belief, 5 of 6 cases of cryptococcemia were associated with high serum beta-glucan levels. CONCLUSION: The beta-glucan test is an effective diagnostic tool for invasive fungal infection.

[A case of sepsis caused by Enterobacter cloacae producing both type SHV-12 and type CTX-M-14 ESBLs in a post bone-marrow transplantation patient].

Third-generation cephalosporin-resistant Enterobacter cloacae was isolated from the blood culture of a 31-year-old woman after bone-marrow transplantation. Since this strain was resistant to third-generation cephalosporins, the production of extended-spectrum beta-lactamases (ESBLs) was suspected. PCR and a sequence analysis confirmed two ESBL genes, bla(SHV-12) and bla(CTX-M-14). No bacteria were detected after meropenem was administered, and symptoms abated. This is, to our knowledge, the first report in Japan of E. cloacae clinical isolates simultaneously producing both SHV-12 and CTX-M-14 ESBL. In cases where chromosomal AmpC over-production of E. cloacae concomitantly produces ESBL, caution should be exercised due to the potential development of resistance against extended-spectrum beta-lactam agents.

An analysis of telomere length in sarcoidosis.

We investigated telomere (terminal restriction fragment [TRF]) length in 111 patients with sarcoidosis regarding both the mean TRF length and the telomere length distribution. A significant decrease was observed in the mean TRF length in sarcoidosis patients in comparison to the age-matched controls, whereas a decreased telomere length was only associated with age in men. The mean TRF shortening seemed to be accelerated in men in their 30s and 50s and in women in their 40s and 50s. We also found a significant decrease with age of telomeres with lengths of 9.4-6.6 kb in men and women in their 20s and an increase of telomeres with lengths of 4.4-2.3 kb in men and women in their 20s and in men in their 50s in sarcoidosis patients versus in the controls who were in their 20s and 50s. These findings suggest the occurrence of age-advanced changes in telomere length in patients with sarcoidosis, regardless of the patient age at the onset of sarcoidosis.

[A case of disseminated candidiasis as an initial presentation of AIDS].

A 44-year-old woman referred for skin eruptions and an altered mental status was confirmed to have HIV infection on Western Blot analysis. Her CD4+ T cell count was 15/microl. On admission, she appeared quite ill with respiratory distress. Chest X-ray showed bilateral patchy infiltration and pleural effusions. She was treated with cefotaxime, pentamidine, and antituberculosis drugs, but her condition worsened and dopamine was initiated. Intensive treatment failed, and she died the following day. An autopsy showed purplish papules on her face and trunk and multiple white nodules in her liver, spleen and lungs. Culture was positive for Candida Albicans, yielding a diagnosis and of disseminated candidiasis. It is rare for HIV patients to be diagnosed with disseminated candidiasis, since the pathogenesis usually requires disruption of the mucosal barrier. The defense mechanism against disseminated candidiasis is mainly neutrophils and macrophages, and its dysfunction is not a primary characteristic of HIV infection. To the best of our knowledge, this is the first report in Japan of a HIV patient to have disseminated candidiasis.

[Voriconazole as an effective therapy against pulmonary aspergillosis in a man with immunodeficiency virus-infection: a case report].

A 45-year-old homosexual man with pneumocystis pneumonia and esophageal candidiasis tested positive in ELISA and Western blot analysis for HIV-1. His CD4+ T cell count was 43/microL and his HIV-RNA load was 250,000 copies/mL. He was treated with Trimetoprim-Sulfamethoxazole, Prednisolone and Fluconazole. Valganciclovir was added to treat CMV retinitis. During the clinical course, 21 days after admission, the patient presented with a temperature of 39 degrees C and blood analysis showed neutropenia. Cefepime and G-CSF were initiated, but new consolidation was observed in the upper left lobe in chest radiography. He underwent bronchoscopy and lavage culture was positive for Aspergillus fumigatus. Serum testing of galactomannan was also positive and pulmonary aspergillosis was diagnosed. The patient was initially treated with Micafungin but switched to Voriconazole when clinical symptoms worsened. An eventual clinical response was observed and pulmonary aspergillosis was controlled. Unfortunately, he died of sepsis due to MRSA 2 months later. Pulmonary aspergillosis is a devastating complication with poor prognosis in patients with HIV infection. Amphotericin-B has been the mainstay of pulmonary aspergillosis treatment, but reports indicate mortality exceeding 80%. Use of Voriconazole, a relatively new antifungal agent, may lower mortality with fewer adverse effects than conventional antifungal therapy.

Frequent exacerbation of pulmonary nocardiosis during maintenance antibiotic therapies in a hematopoietic stem cell transplant recipient.

We describe a rare case of recurrent pulmonary nocardiosis (PN) in a hematopoietic stem cell transplant recipient. The patient developed Nocardia farcinica infection while receiving corticosteroid and cyclosporine for the treatment of bronchiolitis obliterans, probably due to chronic graft-versus-host disease (cGVHD). The patient responded well to the initial treatment with meropenem, but PN recurred 3 times during oral maintenance therapies using different antibiotics, which were chosen on the basis of the results of in vitro susceptibility testing against N farcinica Minocycline, amoxicillin/clavulanate, and levofloxacin were not effective as oral maintenance therapies. Frequent exacerbation of PN was considered to have resulted from the low blood concentration of these antibiotics, and decreased gastrointestinal absorption, probably due to cGVHD, might have been the underlying problem.

[Successful treatment with voriconazole for disseminated cutaneous and visceral infection by Fusarium solani in a patient with acute myeloid leukemia].

We report the successful treatment of a disseminated Fusarium infection with skin manifestations in a severely neutropenic patient. A 51-year-old man with acute myeloblastic leukemia (M4) underwent two courses of remission induction therapy with cytarabine and daunorubicin. Despite prophylactic treatment with tosufloxacin and micafungin, the patient developed a febrile scrotal ulcer. Eight days later, we noted the appearance of painful and diffuse cutaneous nodules and a plain chest X-ray disclosed multiple nodular lesions. Microbiological examination of the scrotal ulcer revealed infection by Fusarium solani, which was also confirmed by both histological and microbiological examination of the skin nodules. Although the patient was treated with amphotericin B (AMPH-B), the clinical symptoms worsened. After AMPH-B was replaced with voriconazole (VRCZ), the patient's symptoms and chest radiographic findings dramatically improved. Thus, VRCZ might be an alternative therapy for patients with neutropenia who have fusariosis that is refractory or unresponsive to AMPH-B.

Somatic DNA recombination in the brain.

Possible somatic DNA recombination in the brain has been investigated by attempting to capture direct or indirect evidence of it. Until recently, the biological significance of the DNA event, the genes is involved in the recombination, or even whether the event actually occurs in the brain has remained unclear. The DNA-rearranged locus-oriented approach and the recombination activity-oriented approach have mutually contributed to the elucidation of the biological features of extra-immune system somatic DNA recombination. There have been only 2 loci proposed for the candidate, one is a repetitive sequence and the other DNA recombination is nonrepetitive locus. This review states conventional concepts and discussions chronologically and finally to the newest aspects of DNA rearrangement in the brain.

Somatic DNA recombination in a mouse genomic region, BC-1, in brain and non-brain tissue.

The genomic region BC-1 (GenBank acc. No. AB075899) on mouse chromosome 16 has been reported as a genomic region undergoing somatic DNA recombination producing circular DNA and genomic deletion in brain during late embryogenesis. The present study shows that the BC-1 circular DNA production had already started on the 13th day of embryonic age, earlier than the previous observation that the circular DNA production started on the 15th through 17th embryonic day. The BC-1 deletion was also observed in the spleen and ocular lens. In situ hybridization analysis indicated that a human-homologous region in the BC-1 sequence was expressed in the lens at a perinatal period. These data suggest that the somatic DNA recombination in the BC-1 region is not restricted to brain tissue, and that the BC-1 DNA recombination relates to lens development.

[A case of chronic mucocutaneous candidasis cured with micafungin].

Chronic mucocutaneous candidasis (CMC) is a chronic intractable infection of skin, nails, and mucous membrane with Candida. Until very recently, the main stay of therapy had been the use of transfer factor or antifungal azole derivatives. Although they show definite benefits, the effects are temporal and recurrences are inevitable. Furthermore, the prolonged use of antifungals will sometimes induce resistant strains, making the treatment more difficult. Recently we experienced a case of CMC caused by resistant Candida spp. and treated it successfully with a new antifungal agent, micafungin (MCFG). The patient is a 37-year-old woman. She was eight month, her tongue was covered with a white coat. Two months later, intractable cutaneous eruptions appeared on the head and back and the diagnosis of CMC was made. Since then she has been treated on multiple occasions with transfer factor, recombinant IL-2, ketoconazole or clotrimazole. She was referred to us because of esophageal candidiasis. On admission, oral and esophageal mucous membranes were thickly coated with white pseudomembranes. The titer of Candida antigen test was less than twice ; plasma beta-D-gulcan was 20.14 pg/mL ; and CD4 was 376/microL. A few Candida albicans and (1+) Candida glabrata were cultured from oral swab. Both species were resistant to itraconazole but sensitive to MCFG and amphotericin B (MIC: < 0.03microg/ml for both). A drip infusion of MCFG (75mg/day) was started and three days later the oral lesions disappeared. At the end of a 2-week course of i. v. MCFG, the interior of the esophagus was clear. No recurrence was noted in one month. Less toxic than amphotericin B, MCFG will be a drug of choice in patients infected with azole-resistant fungi. To avoid the abuse of MCFG and the development of the resistant strains, the susceptibility test is recommended in every case of systemic candidiasis.