Anal Canal Carcinoma in a Child With Disorders of Sex Development

Squamous cell carcinoma of the anal canal in children is rare. To date, the etiology and outcome of this condition have been not fully understood. Here, we report an 11‐year‐old child with anal canal cancer who had concomitant disorders of sex development. Radiotherapy followed by salvage surgery achieved disease‐free survival of 3 years. Since overexpression of cell cycle regulatory protein p16 was immunohistochemically evident in tumor tissue, human papillomavirus infection was considered as a causative factor in the carcinogenesis.     

Revised generative concern scale and generative behavior checklist (GCS-R, GBC-R): scale reconstruction, reliability, and validity

The generative concern scale (GCS) and the generative behavior checklist (GBC) based on the multifaceted model of generativity (McAdams & de St. Aubin, 1992) were reconstructed based on item analysis in preliminary research. The reconstructed scales were administered to 996 adults. Factor analysis of GCS-R and GBC-R data revealed the following three factors which showed high internal consistency: offering, maintaining, and creativity. Significant positive correlations between the GCS-R and the GBC-R implied that generative concern may lead to generative behavior. The GCS-R and GBC-R showed significant positive correlations with the Erikson Psychosocial Stage Inventory (Nakanishi & Sakata, 1993) and the Inventory of Psychosocial Balance (Domino & Affonso, 1990), which supports concurrent validity. Adults with higher scores on the GCS-R were more extroverted, open-minded to experiences, and the less depressive based on scores on the Big Five Scale (Wada, 1996) and the Beck Depression Inventory (Hayashi & Takimoto, 1991). These results indicate convergent and predictive validity.     

Health-related quality of life and prognosis in patients with chronic kidney disease: a 3-year follow-up study

Background

Chronic kidney disease (CKD) is a major global problem and is also associated with a decreased health-related quality of life (HRQOL). The aim of this study was to evaluate measured HRQOL based on the new CKD classification including proteinuria stage, and the effect of measured HRQOL on CKD progression and clinical outcomes over a 3-year period.

Methods

EuroQol (EQ-5D), a generic preference-based questionnaire, was administered to 537 CKD outpatients at the University of Tsukuba Hospital between November and December 2008. We evaluated disease progression in CKD patients including the incidence of end-stage kidney disease (ESKD), cardiovascular disease (CVD) and all-cause mortality over a 3-year follow-up period.

Results

The proportions progressing to the higher stages were 32.6, 20.0, 36.6, 39.5, and 45.8 % from glomerular filtration rate (GFR) stages (G) 1–4, respectively. The proportion progressing to ESKD (G5D) was 0.7 % from G2, 3.9 % from G3b, 20.8 % from G4 and 63.4 % from G5. The incidence of CVD and/or death was 1.2, 4.6, 4.9, 5.3, 8.3 and 21.1 % from G1?G5, respectively. The quality-adjustment weights at G4–5 were significantly lower than at G1–2 and the weights at proteinuria stage (A) 3 were significantly lower than at A1–2. The quality-adjustment weights of patients with events such as 50 % estimated GFR decline, dialysis, CVD, and/or death were significantly lower than those without events.

Conclusion

We showed CKD progression and clinical outcomes over a 3-year period. Quality-adjustment weights in CKD patients were associated with not only disease progression such as initiation of dialysis treatment and incidence of CVD events and all-cause death, but also the level of proteinuria at baseline.     

The effects of antifungal stewardship programs at a tertiary-care teaching hospital in Japan

Patients with invasive fungal diseases (IFDs) generally have a high mortality rate, and resistance to antifungal drugs and the high costs associated with it have led to recent problems, necessitating the appropriate use of antifungals. To this end, we launched Antifungal Stewardship Programs (AFSPs) in our hospital. Patients who were systemically administered antifungals from January 2011 to December 2016 were enrolled this study and divided into pre-intervention and intervention groups. No significant difference was observed in defined daily doses per 1000 patient-days (23.3 ± 8.0 vs 20.4 ± 10.8, p = 0.251) between the groups. The monthly average for the days of therapy per 1000 patient-days was significantly lower in the intervention group (15.1 ± 3.1 vs 12.7 ± 4.3, p = 0.009). The cost of the antifungals reduced over the 3-year period by $260,520 (13.5%). Furthermore, a decreasing trend was observed in both the 30-day mortality (40.9% vs 30.0%, p = 0.414) and in-hospital mortality (63.6% vs 36.7%, p = 0.054) in patients with candidemia. Our results indicate that AFSPs are efficacious and cost-effective approaches.     

Successful treatment of invasive pulmonary aspergillosis caused by Aspergillus felis,a cryptic species within the Aspergillus section Fumigati: A case report

Aspergillus species are a major cause of life-threatening infections in immunocompromised hosts, and the most common pathogen of invasive aspergillosis is Aspergillus fumigatus. Recently, the development of molecular identification has revealed cryptic Aspergillus species, and A. felis is one such species within the Aspergillus section Fumigati reported in 2013.We describe a case of invasive pulmonary aspergillosis caused by A. felis in a 41-year-old Japanese woman diagnosed with myelodysplastic syndrome. She presented with fever 19 days after undergoing autologous peripheral blood stem cell transplantation and was clinically diagnosed with invasive pulmonary aspergillosis. Bronchoscopy and bronchoalveolar lavage were performed for definitive diagnosis. The β-tubulin genes of the mold isolated from the bronchoalveolar lavage fluid, and sequenced directly from the PCR products using a primer pair were found to have 100% homology with A. felis. We successfully treated the patient with echinocandin following careful susceptibility testing.To the best of our knowledge, this is the first published case reporting the clinical course for diagnosis and successful treatment of invasive aspergillosis by A. felis.     

Noise-driven growth rate gain in clonal cellular populations

Cellular populations in both nature and the laboratory are composed of phenotypically heterogeneous individuals that compete with each other resulting in complex population dynamics. Predicting population growth characteristics based on knowledge of heterogeneous single-cell dynamics remains challenging. By observing groups of cells for hundreds of generations at single-cell resolution, we reveal that growth noise causes clonal populations of Escherichia coli to double faster than the mean doubling time of their constituent single cells across a broad set of balanced-growth conditions. We show that the population-level growth rate gain as well as age structures of populations and of cell lineages in competition are predictable. Furthermore, we theoretically reveal that the growth rate gain can be linked with the relative entropy of lineage generation time distributions. Unexpectedly, we find an empirical linear relation between the means and the variances of generation times across conditions, which provides a general constraint on maximal growth rates. Together, these results demonstrate a fundamental benefit of noise for population growth, and identify a growth law that sets a “speed limit” for proliferation.Cell growth is an important physiological process that underlies the fitness of organisms. In exponentially growing cell populations, proliferation is usually quantified using the bulk population growth rate, which is assumed to represent the average growth rate of single cells within a population. In addition, basic growth laws exist that relate ribosome function and metabolic efficiency, macromolecular composition, and cell size of the culture as a whole to the bulk population growth rate (1–3). Population growth rate is therefore a quantity of primary importance that reports cellular physiological states and fitness.However, at the single-cell level, growth-related parameters such as the division time interval and division cell size are heterogeneous even in a clonal population growing at a constant rate (4–9). Such “growth noise” causes concurrently living cells to compete within the population for representation among its future descendants. For example, if two sibling cells born from the same mother cell had different division intervals, the faster dividing sibling is likely to have more descendants in the future population compared with its slower dividing sister, despite the fact that progenies of both siblings may proliferate equally well (Fig. 1). Intrapopulation competition complicates single-cell analysis because any growth-correlated quantities measured over the population deviate from intrinsic single-cell properties (10–12). In the case of the toy model described in Fig. 1, cells are assumed to determine their generation times (division interval) randomly by roll of a dice. The mean of intrinsic cellular generation time is thus (1 + 2 +  ?  + 6)/6 = 3.5 h, but population doubling time, which is the time required for a population to double the number of cells, is in fact 3.2 h. This counterintuitive result is a direct consequence of growth noise in a population. Indeed, as we will see, the population doubling time can only equal the mean generation time when no variability of generation time exists at the single-cell level. Population growth rate is determined not only by an average of single cells but also by the details of heterogeneity within a population. Therefore, understanding how population growth rates and other properties arise from single-cell heterogeneity poses a fundamental challenge to single-cell biology.Open in a separate windowFig. 1.Competition within a population caused by growth noise and its consequence to population growth rate. (A) Toy model of cell proliferation. Here, we consider a model of cell proliferation in which all of the cells in a population determine their generation time (interdivision time) randomly by throwing a dice to learn the consequences of intrapopulation growth noise. In this setting, cells can take either of the six possible choices of generation time, τ=1,2,⋯,6 h, with the equal probability of 1/6. The mean generation time is thus ?τ?_g= 3.5 h. (B) Example of pedigree tree showing competition between sibling cells. In this tree, two sibling cells were born from the common mother cell at t = 0 h, and divided with different generation times (sibling cell 1: τ_s1 = 5 h; and sibling cell 2: τ_s2 = 2 h). The descendant cells from the both sibling cells follow the same rule of cell divisions irrespectively of the ancestral generation time. The difference of generation time between the sibling cells 1 and 2 was caused just by chance, but the expected number of descendant cells becomes larger for the fast dividing sibling cell. The ratio of the expected number of descendant cells from those sibling cells at a certain future time point is ?N₁?/?N₂? = e^{?Λ_p(τ_s1?τ_s2)}, where Λ_p is the population growth rate. (C) Growth of cell population. When all of the cells in the population follow the same division rule in A, the number of cells in the population grows exponentially. The rate of this exponential growth is the “population growth rate,” Λ_p. The time required for the population to double the number of cells is the “population doubling time,” T_d, i.e., N(t) = N(0)2^t/T_d. Therefore, T_d = ln2/Λ_p. An interesting consequence of stochasticity in generation time is that population doubling time becomes smaller than the mean generation time, i.e., T_d <?τ?_g. In the case of the dice population, T_d = 3.187 h, which is indeed smaller than ?τ?_g= 3.5 h.A classical study of theoretical and experimental microbiology attempted to reveal the discrepancies between mean cellular generation times and population doubling times in real bacterial populations (13). Experimental methods and techniques available at that time, however, hampered reliable tests. Recently, the techniques of single-cell time-lapse microscopy have advanced to a great extent, revealing the heterogeneous and stochastic nature of single-cell dynamics quantitatively (14). With the aid of microfluidic platforms, tracking single cells over many generations in controlled constant or changing environments has also become feasible, providing insights into the mechanisms of cell size homeostasis and stress responses (3, 6, 7, 9, 15–22).In this study, through microfluidics time-lapse microscopy and single-cell analysis on large-scale, single-cell lineage trees, we reveal that clonal populations of Escherichia coli indeed grow with a doubling time that is smaller than the mean doubling time of their constituent cells under broad, balanced-growth conditions. We show that the observed growth rate gains and population age structures are predictable from cellular generation time distributions based on a simple age-structured population model. Furthermore, we reveal unique features of long single-cell lineages within populations in competition, and provide a history-based formulation that connects growth rate gain with a measure of statistical deviation between isolated and competing lineages. Finally, we demonstrate a linear relation between the means and the variances of generation time across conditions, which constrains the maximum growth rate of this organism.     

A case of lung infection due to Mycobacterium abscessus (M. abscessus) complicated with primary macroamylasemia]

We report a case of lung infection due to Mycobacterium abscessus (M. abscessus), complicated with primary macroamylasemia. A 76-year-old man was admitted to our hospital in August 2002 because of bloody sputum and an abnormal shadow found on chest radiography. The patient had had pulmonary tuberculosis from 1998 to 2000. He was found to be antacid bacillus-positive (Gaffky 5) on examination of the sputum in August 2002, but after hospitalization was negative for tuberculosis bacillus on sputum examination by the PCR method. We had suspected the presence of non-tuberculous mycobacterial disease since the patient's admission, and had started a regime of three drugs: clarithromycin, rifampicin, and ethambutol. The bacteria were identified as M. abscessus in a later sputum culture examination. It was noticed that the blood amylase level was high, and the disease was diagnosed as primary macroamylasemia. Such a case of lung infection due to M. abscessus complicated with macroamylasemia has rarely been reported in Japan.     

Confirmation by FRET in individual living cells of the absence of significant amyloid beta -mediated caspase 8 activation

When cells are exposed to death-inducing molecules such as tumor necrosis factor-alpha or Fas, caspase 8 is activated and cleaves an apoptotic facilitator, Bid, that is a member of the Bcl-2 family. After additional modification, the C-terminal moiety of Bid is translocated to the mitochondria and induces the release of cytochrome c into the cytoplasm. In an attempt to directly observe the cleavage of Bid and the following events in living cells, we constructed a vector that encoded Bid fused with yellow fluorescent protein (YFP) and cyan fluorescent protein (CFP) (YFP-Bid-CFP). On expression of YFP-Bid-CFP in mammalian cells, we were able to observe the efficient transfer of energy from excited CFP to YFP within the YFP-Bid-CFP molecule and, importantly, the fusion protein YFP-Bid-CFP was fully functional in cells. When YFP-Bid-CFP was cleaved by caspase 8, on activation by anti-Fas Abs but not by Abeta or tunicamycin, no such transfer of energy was detected. To our knowledge, this is the first report of (i) visualization of the activation of Bid by proteolytic cleavage, with direct observation of the cleavage of YFP-Bid-CFP in the cytoplasm and subsequent translocation of the cleaved Bid to mitochondria and (ii) the absence of Abeta- or tunicamycin-mediated significant activation of caspase 8 in individual living cells.