Liver-specific DICER1 syndrome model mice develop cystic liver tumors with defective primary cilia.

DICER1 syndrome is a tumor predisposition syndrome caused by familial genetic mutations in DICER1. Pathogenic variants of DICER1 have been discovered in many rare cancers, including cystic liver tumors. However, the molecular mechanisms underlying liver lesions induced by these variants remain unclear. In the present study, we sought to gain a better understanding of the pathogenesis of these variants by generating a mouse model of liver-specific DICER1 syndrome. The mouse model developed bile duct hyperplasia with fibrosis, similar to congenital hepatic fibrosis, as well as cystic liver tumors resembling those in Caroli's syndrome, intrahepatic cholangiocarcinoma, and hepatocellular carcinoma. Interestingly, the mouse model of DICER1 syndrome showed abnormal formation of primary cilia in the bile duct epithelium, which is a known cause of bile duct hyperplasia and cyst formation. These results indicated that DICER1 mutations contribute to cystic liver tumors by inducing defective primary cilia. The mouse model generated in this study will be useful for elucidating the potential mechanisms of tumorigenesis induced by DICER1 variants and for obtaining a comprehensive understanding of DICER1 syndrome. © 2024 The Pathological Society of Great Britain and Ireland.

Factors associated with physical function in patients after surgery for soft tissue sarcoma in the thigh.

PURPOSE: This study aimed to examine the validity of the timed up and go test (TUGT), which is a representative, objective, and functional assessment that can evaluate walking speed, strength, and balance, and determine the significant factors associated with physical dysfunction in the early postoperative period in patients with soft tissue sarcomas (STSs). METHODS: This retrospective, single-center, observational study conducted at the National Cancer Center Hospital included 54 patients with STSs in the thigh who underwent surgery. The Musculoskeletal Tumor Society (MSTS) score, which subjectively evaluates the affected limb, was evaluated at discharge, and TUGT was performed preoperatively and at discharge. Higher scores indicated good limb function in the MSTS score and poor performance in the TUGT. Spearman's correlation analysis was performed to identify the relationship between the MSTS score and TUGT. A receiver operating characteristic curve was used to calculate the cut-off value of the change in pre- and postoperative TUGT for an MSTS score of ≥ 80%. To examine the significant factors associated with physical dysfunction, multivariate regression analysis was performed using the change in pre- and postoperative TUGT as the dependent variable. RESULTS: Postoperative TUGT and the change in pre- and postoperative TUGT were significantly associated with the MSTS score. The cut-off value for the change in pre- and postoperative TUGT for acceptable affected lower-limb function was 3.7 s. Furthermore, quadriceps muscle resection was significantly associated with the change in pre- and postoperative TUGT in the early postoperative period. CONCLUSIONS: TUGT could be a useful objective evaluation tool for postoperative patients with STSs. The cut-off value for the change in TUGT can be used to monitor postoperative recovery. If recovery is prolonged, a rehabilitation program can be designed according to the severity of the functional impairment in muscle strength, balance, or gait. In addition, sufficient information should be obtained regarding the presence or absence of quadriceps resection, which has a significant impact on postoperative performance.

The evaluation of the association between preoperative sarcopenia and postoperative pneumonia and factors for preoperative sarcopenia in patients undergoing thoracoscopic-laparoscopic esophagectomy for esophageal cancer.

PURPOSE: This study identified the relationship between postoperative pneumonia and preoperative sarcopenia as well as the factors for preoperative sarcopenia in patients with esophageal cancer. METHODS: In this retrospective, single-center, observational study, we evaluated the data of 274 patients who were scheduled for thoracoscopic-laparoscopic esophagectomy. Sarcopenia was defined using the skeletal muscle index, handgrip strength, and gait speed. The physical activity and nutritional status were evaluated. A multivariate logistic regression analysis was performed to confirm the association between sarcopenia and postoperative pneumonia and identify sarcopenia-related factors. A Spearman's correlation analysis was used to identify the relationship between physical activity and nutritional status. RESULTS: Age, male sex, sarcopenia, and postoperative recurrent laryngeal nerve palsy were significantly associated with postoperative pneumonia. Age, male sex, physical activity, and nutritional status were significantly associated with preoperative sarcopenia. There was a significant correlation between physical activity and nutritional status. CONCLUSIONS: Preoperative sarcopenia was confirmed to be a predictor of postoperative pneumonia. Furthermore, age, sex, physical activity, and nutritional status were significantly associated with preoperative sarcopenia. Physical activity and nutritional status are closely associated with each other in patients with esophageal cancer. A multidisciplinary approach to preoperative sarcopenia, taking exercise and nutrition into account, is recommended.

Development of antigen-prediction algorithm for personalized neoantigen vaccine using human leukocyte antigen transgenic mouse.

Immunotherapy is currently recognized as the fourth modality in cancer therapy. CTL can detect cancer cells via complexes involving human leukocyte antigen (HLA) class I molecules and peptides derived from tumor antigens, resulting in antigen-specific cancer rejection. The peptides may be predicted in silico using machine learning-based algorithms. Neopeptides, derived from neoantigens encoded by somatic mutations in cancer cells, are putative immunotherapy targets, as they have high tumor specificity and immunogenicity. Here, we used our pipeline to select 278 neoepitopes with high predictive "SCORE" from the tumor tissues of 46 patients with hepatocellular carcinoma or metastasis of colorectal carcinoma. We validated peptide immunogenicity and specificity by in vivo vaccination with HLA-A2, A24, B35, and B07 transgenic mice using ELISpot assay, in vitro and in vivo killing assays. We statistically evaluated the power of our prediction algorithm and demonstrated the capacity of our pipeline to predict neopeptides (area under the curve = 0.687, P < 0.0001). We also analyzed the potential of long peptides containing the predicted neoepitopes to induce CTLs. Our study indicated that the short peptides predicted using our algorithm may be intrinsically present in tumor cells as cleavage products of long peptides. Thus, we empirically demonstrated that the accuracy and specificity of our prediction tools may be potentially improved in vivo using the HLA transgenic mouse model. Our data will help to design feedback algorithms to improve in silico prediction, potentially allowing researchers to predict peptides for personalized immunotherapy.

Kidney vascular congestion exacerbates acute kidney injury in mice.

Heart failure is frequently accompanied by kidney failure and co-incidence of these organ failures worsens the mortality in patients with heart failure. Recent clinical observations revealed that increased kidney venous pressure, rather than decreased cardiac output, causes the deterioration of kidney function in patients with heart failure. However, the underlying pathophysiology is unknown. Here, we found that decreased blood flow velocity in peritubular capillaries by kidney congestion and upregulation of endothelial nuclear factor-κB (NF-κB) signaling synergistically exacerbate kidney injury. We generated a novel mouse model with unilateral kidney congestion by constriction of the inferior vena cava between kidney veins. Intravital imaging highlighted the notable dilatation of peritubular capillaries and decreased kidney blood flow velocity in the congestive kidney. Damage after ischemia reperfusion injury was exacerbated in the congestive kidney and accumulation of polymorphonuclear leukocytes within peritubular capillaries was noted at the acute phase after injury. Similar results were obtained in vitro, in which polymorphonuclear leukocytes adhesion on activated endothelial cells was decreased in flow velocity-dependent manner but cancelled by inhibition of NF-κB signaling. Pharmacological inhibition of NF-κB for the mice subjected by both kidney congestion and ischemia reperfusion injury ameliorated the accumulation of polymorphonuclear leukocytes and subsequent exacerbation of kidney injury. Thus, our study demonstrates the importance of decreased blood flow velocity accompanying activated NF-κB signaling in aggravation of kidney injury. Hence, inhibition of NF-κB signaling may be a therapeutic candidate for the vicious cycle between heart and kidney failure with increased kidney venous pressure.

The importance of specific citrullinated clusterin and vimentin found in a multi-coloured bead-based citrulline-peptide array system in rheumatoid arthritis.

OBJECTIVES: The importance of citrullination in rheumatoid arthritis (RA) has been reported, but the degree to which individual citrullinated proteins affect the onset and progression of RA is still unclear. We aimed to identify citrullinated proteins that may play an important role in the onset and progression of RA using an individualised anti-citrullinated protein antibody (ACPA) evaluation system with citrullinated peptides as probes. METHODS: Serum samples from 50 normal donors and 51 RA patients were evaluated using a custom MagPlexTM bead array with 13 types of citrullinated peptide. The presence/absence of ACPAs that react to each citrullinated peptide in each subject was determined using the Z-score, which was calculated based on the fluorescence intensity distribution of a sample from a normal donor. Whether the fluorescence intensity was inhibited when free citrullinated peptides were added to a system was also evaluated. RESULTS: Median fluorescence intensities obtained from beads coupled with the 13 types of citrullinated peptide were all significantly higher in RA patients versus normal donors. With a Z-score ≥2 as the cut-off value for the presence of ACPAs, ACPAs that recognised five types of citrullinated peptides derived from fibrinogen A, fillagrin, clusterin, and vimentin were widely detected in RA patients. In addition, inhibition experiments showed that citrullinated vimentin, clusterin, and enolase 1A peptides inhibited coupling of ACPAs to other citrullinated peptides. CONCLUSIONS: ACPAs to many citrullinated proteins exhibited cross-reactivity to citrullinated clusterin and vimentin, suggesting the importance of citrullinated clusterin and vimentin in the early stages of RA pathogenesis.

Optimal DNA quality preservation process for comprehensive genomic testing of pediatric clinical autopsy formalin-fixed, paraffin-embedded tissues.

Clinical autopsies are performed to reveal the process of the disease that caused patient death and validate the diagnosis and treatment decisions. In pediatric clinical autopsy, the feedback provided to bereaved families has a considerable social impact; however, pediatric diseases are diverse, which makes it difficult to elucidate them. Therefore, it is necessary to employ molecular biology techniques in addition to conventional methods. Formalin-fixed, paraffin-embedded (FFPE) tissues are routinely prepared. However, clinical autopsy FFPE tissue processing is not standardized, and it is unclear whether DNA from such tissues can be used for comprehensive genomic analysis. In this study, we evaluated the DNA quality of FFPE tissues from 15 recent autopsy cases at a single-center children's hospital using quantitative polymerase chain reaction [PCR (Q129/Q41)] and nanoelectrophoresis (DNA integrity number (DIN)). Good quality DNA was obtained from every organ type excluding bone marrow within 6 days of formalin fixation. Prolonged proteinase K digestion (48 h > 24 h > 1 h) and thicker tissue sections (10 µm > 1 µm) improved Q129/Q41; however, 24 h fixed FFPE tissues showed better DNA quality. We propose an optimal and feasible workflow for storing short-term fixed FFPE tissues as DNA-preserved FFPE tissues for future comprehensive genomic searches.

Effects of antioxidant co-supplementation therapy on spermatogenesis dysfunction in relation to the basal oxidation-reduction potential levels in spermatozoa: A pilot study.

Purpose: In this pilot study, the authors compared the effects of antioxidant co-supplementation therapy and methylcobalamin therapy in patients with impaired semen quality. Methods: Eighty-four subjects who visited male infertility clinics and showed abnormal semen test results were randomly subjected to one of the two therapies: antioxidant co-supplementation therapy with vitamin C, vitamin E, coenzyme Q10, and flaxseed oil or methylcobalamin therapy. The oxidation-reduction potential (ORP) and 8-hydroxy-2'-deoxyguanosine levels were used as indicators of oxidative stress levels in semen. Semen analysis was also performed. Results: The authors obtained results from 67 patients who had completed 3 months of treatment. Neither antioxidant co-supplementation therapy nor methylcobalamin therapy changed the semen parameters significantly (except for the sperm concentration, which was increased by the latter therapy). When the pre-treatment ORP value in semen was higher than the cutoff value, both therapies significantly increased the sperm concentration. The 8-hydroxy-2'-deoxyguanosine level did not yield any meaningful predictive value with regard to increased sperm concentrations. Conclusions: Both antioxidant co-supplementation therapy and methylcobalamin therapy increased the sperm concentration in patients with impaired semen quality when the basal ORP levels in their semen were elevated.

Endoscopic resection of local recurrences of diminutive polyps by cold forceps polypectomy.

OBJECTIVES: Cold forceps polypectomy (CFP) is an effective treatment for diminutive colorectal polyps. However, polyps occasionally recur, and there is no consensus on their long-term clinical management. Therefore, we investigated the short- and long-term clinical outcomes of re-CFP for recurrent diminutive colorectal polyps. MATERIALS AND METHODS: This was a follow-up of a multicenter, prospective study investigating the clinical outcomes of diminutive colorectal polyps excised by CFP with narrowband imaging-enhanced endoscopy and jumbo forceps. We evaluated short-term outcomes of re-CFP and patients at 1-year follow-up post re-CFP for recurrent colorectal polyps to determine long-term recurrence rates. Additionally, complete resection rates, clinicopathological features, number of forceps bites, and rate of short-term adverse events managed by re-CFP were evaluated. RESULTS: At 1-year follow-up, local recurrence was identified in 18 patients from the original study. The mean size of local recurrent polyps was 1.5 ± 0.6 mm, and all recurrent lesions were < 3 mm. Re-CFP could successfully excise locally recurrent polyps in all cases. All recurrent lesions were low-grade adenomas; no adverse events were reported. Additionally, 16 of 18 patients were evaluated endoscopically at 2-year follow-up; no recurrence was observed. CONCLUSIONS: Recurrent lesions following initial CFP were small and pathologically benign, and re-CFP was an effective treatment.

Facile and simple purification method for small extracellular vesicles obtained from a culture medium through cationic particle capture.

Although small extracellular vesicles (sEVs) carry DNA, miRNA, and proteins, and they play an important role in long-distance intercellular communication, their generation and circulation mechanisms are unclear. sEVs can be used as biomarkers for the early diagnosis of diseases (e.g., cancer, Alzheimer's disease, melanoma, and cardiovascular diseases) and as drug delivery carriers to the target tissues. Hence, sEVs are attracting considerable attention from scientists and medical professionals. In the present study, we investigated four different commercially available cationic particles (two silica particles modified with diethylaminopropyl or trimethylaminopropyl groups, and two agarose particles modified with diethylaminopropyl or trimethylaminopropyl groups) for the purification of sEVs obtained from a cell culture medium. All the cationic particles captured the sEVs well. The NaCl concentrations required for elution of the captured sEVs differed for the different cationic particles. sEVs were most efficiently captured by silica particles modified with diethylaminopropyl groups, and they were eluted from these particles using 200 mM NaCl as the elution solution. Because the developed method can be used to easily purify sEVs obtained from a culture medium, it is expected to facilitate the functional analysis of sEVs, as well as early diagnosis and treatment of diseases using sEVs.

The current status of inpatient cancer rehabilitation provided by designated cancer hospitals in Japan.

OBJECTIVE: This survey was conducted to clarify the current status of inpatient cancer rehabilitation provided by designated cancer hospitals in Japan. METHODS: A survey questionnaire was sent to 427 designated cancer hospitals in Japan. Information was sought regarding whether inpatient cancer rehabilitation was provided by the center, and if so, whether respondents regarded such provision as satisfactory. RESULTS: Responses were obtained from 235/427 surveyed institutions (55.0%). Cancer rehabilitation was provided in inpatient settings by 97.4%. Two-thirds of respondents (67.7%) regarded inpatient cancer rehabilitation provision as still inadequate. The primary reasons claimed for this inadequacy were a lack of human resources, a lack of rehabilitation professionals with the requisite knowledge/skills and patients who would benefit from cancer rehabilitation present but not prescribed. The total number of rehabilitation staff was identified as associated factor of inadequate inpatient cancer rehabilitation in multivariate analysis (odds ratio = 0.979, 95% confidence interval = 0.96-1.00, P = 0.009). CONCLUSIONS: In order to provide adequate cancer rehabilitation, a sufficient supply of rehabilitation staff, education and recognition of the need for cancer rehabilitation within oncology units are necessary.

Risk Factors for Delayed Bleeding after Therapeutic Gastrointestinal Endoscopy in Patients Receiving Oral Anticoagulants: A Multicenter Retrospective Study.

BACKGROUND/AIMS: Delayed bleeding is among the adverse events associated with therapeutic gastrointestinal endoscopy. The aim of this study was to evaluate risk factors for delayed bleeding after gastrointestinal endoscopic resection in patients receiving oral anticoagulants as well as to compare the rates of occurrence of delayed bleeding between the oral anticoagulants used. METHODS: We retrospectively analyzed a total of 772 patients receiving anticoagulants. Of these, 389 and 383 patients were receiving direct oral anticoagulants (DOACs) and warfarin, respectively. Therapeutic endoscopic procedures performed included endoscopic submucosal dissection (ESD), endoscopic mucosal resection, polypectomy, and cold polypectomy. RESULTS: Delayed bleeding occurred in 90 patients (11.7%) with no significant difference between the DOAC and warfarin groups (9.5 and 13.8%, respectively). Delayed bleeding occurred significantly more frequently with apixaban than with rivaroxaban (13.5 vs. 6.4%; p < 0.05). A multivariate analysis identified continued anticoagulant therapy (OR 2.29), anticoagulant withdrawal with heparin bridging therapy (HBT; OR 2.18), anticoagulant therapy combined with 1 antiplatelet drug (OR 1.72), and ESD (OR 3.87) as risk factors for delayed bleeding. CONCLUSION: This study identified continued anticoagulant therapy, anticoagulant withdrawal with HBT, anticoagulant therapy combined with 1 antiplatelet drug, and ESD as risk factors for delayed bleeding after therapeutic endoscopy in patients receiving oral anticoagulants. Delayed bleeding rates were not significantly different between those receiving DOACs and warfarin. It was also suggested that the occurrence of delayed bleeding may vary between different DOACs and that oral anticoagulant withdrawal should be minimized during therapeutic gastrointestinal endoscopy, given the thromboembolic risk involved.

Local recurrence of diminutive colorectal polyps after cold forceps polypectomy with jumbo forceps followed by magnified narrow-band imaging: a multicenter prospective study.

BACKGROUND: Cold polypectomy has been increasingly used to remove diminutive colorectal polyps. We evaluated the local recurrence rate of diminutive polyps at the 1-year follow-up after cold forceps polypectomy (CFP). METHODS: In a prospective, multicenter, observational cohort study, patients with diminutive colorectal polyps ( ≤ 5 mm) were treated by CFP using jumbo forceps followed by magnified narrow-band imaging (NBI). Patients were assessed for local recurrence at 1-year follow-up. Risk factors associated with local recurrence were analyzed using logistic regression analysis. RESULTS: Overall, 955 lesions were resected in 471 patients who completed the 1-year follow-up. The endoscopic complete resection rate was 99.4 %. Immediate and delayed bleeding occurred in 0.8 % and 0.2 % of cases, respectively, with no perforations observed. Local recurrence occurred in 2.1 % of cases at the 1-year follow-up. Univariable analyses indicated that polyps > 3 mm (P < 0.01) and immediate bleeding (P = 0.04) were significantly associated with local recurrence. A trend was observed for patients ≥ 65 years (P = 0.06) and fractional resection (P = 0.09). Multivariable analyses confirmed that lesions > 3 mm were significantly associated with local recurrence (odds ratio 3.4, P = 0.02). CONCLUSIONS: CFP with jumbo forceps followed by NBI-magnified observation had a low local recurrence rate and is an acceptable therapeutic option for diminutive colorectal polyps. Although we recommend limiting the use of CFP with jumbo forceps to polyps ≤ 3 mm in size, future comparative studies are needed to make recommendations on cold polypectomy using either forceps or snares as the preferred approach for diminutive polyp resection.

Enhanced angiotensinogen expression in neonates during kidney development.

BACKGROUND: We recently demonstrated that preterm neonates have higher urinary angiotensinogen (AGT) levels than full-term neonates. Here, we tested the hypothesis that enhanced neonatal AGT expression is associated with intrarenal renin-angiotensin system (RAS) status during kidney development. METHODS: We prospectively recruited neonates born at our hospital and healthy children with minor glomerular abnormalities between April 2013 and March 2017. We measured neonatal plasma and urinary AGT levels at birth and 1 year later and assessed renal AGT expression in kidney tissues from neonates and healthy children using immunohistochemical (IHC) analysis. RESULTS: Fifty-four neonates and eight children were enrolled. Although there were no changes in plasma AGT levels, urinary AGT levels were significantly decreased 1 year after birth. Urinary AGT levels at birth were inversely correlated with gestational age, and urinary AGT levels at birth and 1 year later were inversely correlated with estimated glomerular filtration rate 1 year after birth. IHC analysis showed that renal AGT expression in neonates was higher than that in healthy children and inversely correlated with gestational age. CONCLUSIONS: Enhanced AGT expression and urinary AGT excretion may reflect intrarenal RAS activation associated with kidney development in utero.

Anaplastic sarcomas of the kidney are characterized by DICER1 mutations.

Anaplastic sarcoma of the kidney is a rare tumor (≤25 reported cases) characterized by the presence of cysts, and solid areas composed of bundles of undifferentiated spindle cells, showing marked cellular anaplasia (usually accompanied by TP53 overexpression). These tumors often feature prominent areas of cartilage or chondroid material. Germline mutations in DICER1, encoding the microRNA (miRNA) processor DICER1, cause an eponymous syndrome. Recent reports suggest that anaplastic sarcoma of the kidney should be included in DICER1 syndrome as germline DICER1 mutations are associated with the occurrence of such tumors. Therefore, we sought to determine the following: (1) what proportion of anaplastic sarcoma of the kidney have DICER1 mutations; (2) whether the identified mutations affect both alleles of DICER1 (ie, are biallelic); (3) whether somatic missense mutations in the DICER1 RNase IIIb domain impact miRNA generation; and (4) whether TP53 alteration always occurs in these tumors. DICER1 mutations were evaluated by Sanger sequencing and next-generation sequencing in nine tumor/normal pairs. Impact of DICER1 mutations on miRNA generation was evaluated via an in vitro DICER1 cleavage assay. TP53 status was assessed by immunohistochemistry and next-generation sequencing. Eight of the nine cases had at least one RNase IIIb DICER1 mutation that impacted the generation of miRNAs. There were six tumors with truncating DICER1 mutations and in four of them, the mutation found in the tumor was also detected in adjacent normal tissue, and therefore was likely to be either mosaic or germline in origin. Analysis of mutation phase revealed that two of three tumors had biallelic DICER1 mutations. Six of nine anaplastic sarcomas of the kidney had aberrant TP53 immunohistochemisty with damaging TP53 mutations identified in three cases. Taken together, these data suggest that the great majority of anaplastic sarcomas of the kidney have DICER1 mutations and confirm that these tumors are part of the DICER1 syndrome.

A pathologist's perspective on induced pluripotent stem cells.

Induced pluripotent stem cell (iPSC) technology was originally developed in 2006. Essentially, it converts somatic cells into pluripotent stem cells by transiently expressing a few transcriptional factors. Once generated, these iPSCs can differentiate into all the cell types of our body, theoretically, which has attracted great attention for clinical research including disease pathobiology studies. Could this technology then become an additional research or diagnostic tool widely available to practicing pathologists? Here we summarize progress in iPSC research toward disease pathobiology studies, its future potential, and remaining problems from a pathologist's perspective. A particular focus will be on introducing the effort to recapitulate disease-related morphological changes through three-dimensional culture of stem cells such as organoid differentiation.

Development of short and highly potent self-assembling elastin-derived pentapeptide repeats containing aromatic amino acid residues.

Tropoelastin is the primary component of elastin, which forms the elastic fibers that make up connective tissues. The hydrophobic domains of tropoelastin are thought to mediate the self-assembly of elastin into fibers, and the temperature-mediated self-assembly (coacervation) of one such repetitive peptide sequence (VPGVG) has been utilized in various bio-applications. To elucidate a mechanism for coacervation activity enhancement and to develop more potent coacervatable elastin-derived peptides, we synthesized two series of peptide analogs containing an aromatic amino acid, Trp or Tyr, in addition to Phe-containing analogs and tested their functional characteristics. Thus, position 1 of the hydrophobic pentapeptide repeat of elastin (X(1)P(2)G(3)V(4)G(5)) was substituted by Trp or Tyr. Eventually, we acquired a novel, short Trp-containing elastin-derived peptide analog (WPGVG)3 with potent coacervation ability. From the results obtained during this process, we determined the importance of aromaticity and hydrophobicity for the coacervation potency of elastin-derived peptide analogs. Generally, however, the production of long-chain synthetic polypeptides in quantities sufficient for commercial use remain cost-prohibitive. Therefore, the identification of (WPGVG)3, which is a 15-mer short peptide consisting simply of five natural amino acids and shows temperature-dependent self-assembly activity, might serve as a foundation for the development of various kinds of biomaterials.

Salvage hormonal therapy after failed microdissection testicular sperm extraction: A multi-institutional prospective study.

OBJECTIVE: To validate the efficacy of salvage hormonal therapy in men with non-obstructive azoospermia at their second microdissection testicular sperm extraction. METHODS: This was a multi-institutional study registered at the Japanese University Hospital Medical Information Network clinical trial center. After 1 month of human chorionic gonadotropin therapy (5000 IU, three times a week), patients were treated with recombinant human follicle-stimulating hormone (150 IU, three times a week) and human chorionic gonadotropin for the next 3 months. Three testicular samples were obtained randomly from both testes, and sent for pathological diagnosis at the first and second microdissection testicular sperm extraction. RESULTS: A total of 21 men, excluding those with chromosomal abnormalities, azoospermia factor a or b deletions, extremely small testes (<2 mL), or prior hormonal therapy, were eligible to participate based on our inclusion criteria. At the first microdissection testicular sperm extraction, 13 and six patients had Sertoli cells only and an early maturation arrest, respectively. With the second microdissection testicular sperm extraction, sperm were successfully obtained from two patients (10%). Patient age, testicular volume and hormone profiles were not associated with the results of the second microdissection testicular sperm extraction. However, the testicular histology of the two successful patients were late maturation arrest and hypospermatogenesis. CONCLUSIONS: Effectiveness of human chorionic gonadotropin-based salvage hormonal therapy preceding a second microdissection testicular sperm extraction seems to be limited. Non-obstructive azoospermia men who have differentiated cells in their testes are likely to respond to hormonal stimulation.

A prescription for sustaining community engagement in malaria elimination on Aneityum Island, Vanuatu: an application of Health Empowerment Theory.

BACKGROUND: Community engagement has contributed to disease control and elimination in many countries. Community engagement in malaria elimination (ME) on Aneityum Island has been sustained since its introduction in the early 1990s. Capacity developed within this population has led to a health empowered community response. Health Empowerment Theory (HET) can account for the innovative community actions and capacity development efforts taken to realize and sustain meaningful changes in well-being. This study used the HET framework to investigate participant perceptions of ME efforts on the island focusing on two HET elements, personal and social-contextual resources. The purpose of this study was to explore the role of empowerment as a critical element of community engagement. METHODS: Six focus group discussions, ten key informant interviews and 17 in-depth interviews were conducted in July 2012 on Aneityum. Both deductive and inductive approaches to qualitative content analysis were used to identify themes, which were condensed, coded and classified based on the HET elements above. RESULTS: Awareness and use of personal and social-contextual resources played an important role in ME efforts. Most participants shared their knowledge to prevent malaria reintroduction. Many participants reported their skills needed for behavioral maintenance, problem-solving or leadership. Participants who perceived a threat took preventive actions even in the dry season. Community leaders focused on second generation capacity development. A local health coalition provided ME services. Members of networks were sources of information and assistance. Face-to-face was the preferred method of communication. Barriers to engagement (e.g., financial difficulties, health literacy issues and underdeveloped infrastructure) were minimized through active collaboration and mutual assistance. CONCLUSIONS: In the community engagement continuum, health empowerment develops incrementally overtime as people gain their knowledge and skills, form coalitions and develop collaborative networks (social capital) to make decisions and take action for change. Community engagement, which facilitates local personal and social-contextual resource development, has potential for ME and multilevel empowerment through community-based capacity development processes. These self-empowered communities have written and will continue to write a 'prescription' for sustaining high levels of engagement.

Clarithromycin Versus Metronidazole as First-line Helicobacter pylori Eradication: A Multicenter, Prospective, Randomized Controlled Study in Japan.

BACKGROUND: Helicobacter pylori eradication rates achieved with a first-line regimen of clarithromycin (CLR) combined with amoxicillin (AMX) and a proton pump inhibitor have recently fallen to ≤80% because of the increasing incidence of CLR resistance in Japan. This randomized multicenter trial aimed to compare the eradication success of 2 first-line triple therapy regimens: rabeprazole, amoxicillin, and clarithromycin (RAC) versus rabeprazole, amoxicillin, and metronidazole (RAM). METHODS: A total of 124 consecutive patients infected with H. pylori were randomized into one of two 7-day therapeutic regimens: RAC (n=60) or RAM (n=64). Eradication was confirmed by the C-urea breath test. Adverse effects were also assessed. RESULTS: Intention-to-treat and per protocol H. pylori eradication rates were 73.3%/77.2% in the RAC group and 90.6%/93.5% in the RAM group. The eradication rate of RAM therapy was significantly higher than that of RAC therapy. CLR, metronidazole, and AMX resistance was found in 36.2%, 2.1%, and 0% of patients, respectively. In addition, no relevant differences in adverse effects were observed. CONCLUSIONS: Metronidazole-based therapy (RAM) was superior to standard CLR-based therapy (RAC) for first-line H. pylori eradication. This reflects the progressive increase in CLR resistance observed in Japan.