Roles of the mechanosensitive ion channel Piezo1 in the renal podocyte injury of experimental hypertensive nephropathy.

Glomerular podocyte injury plays an essential role in proteinuria pathogenesis, a hallmark of chronic kidney disease, including hypertensive nephropathy. Although podocytes are susceptible to mechanical stimuli, their mechanotransduction pathways remain elusive. Piezo proteins, including Piezo1 and 2, are mechanosensing ion channels that mediate various biological phenomena. Although renal Piezo2 expression and its alteration in rodent dehydration and hypertension models have been reported, the role of Piezo1 in hypertensive nephropathy and podocyte injury is unclear. In this study, we examined Piezo1 expression and localization in the kidneys of control mice and in those of mice with hypertensive nephrosclerosis. Uninephrectomized, aldosterone-infused, salt-loaded mice developed hypertension, albuminuria, podocyte injury, and glomerulosclerosis. RNAscope in situ hybridization revealed that Piezo1 expression was enhanced in the podocytes, mesangial cells, and distal tubular cells of these mice compared to those of the uninephrectomized, vehicle-infused control group. Piezo1 upregulation in the glomeruli was accompanied by the induction of podocyte injury-related markers, plasminogen activator inhibitor-1 and serum/glucocorticoid regulated kinase 1. These changes were reversed by antihypertensive drug. Exposure of Piezo1-expressing cultured podocytes to mechanical stretch activated Rac1 and upregulated the above-mentioned markers, which was antagonized by the Piezo1 blocker grammostola mechanotoxin #4 (GsMTx4). Administration of Piezo1-specific agonist Yoda1 mimicked the effects of mechanical stretch, which was minimized by the Yoda1-specific inhibitor Dooku1 and Rac inhibitor. Rac1 was also activated in the above-mentioned hypertensive mice, and Rac inhibitor downregulated gene expression of podocyte injury-related markers in vivo. Our results suggest that Piezo1 plays a role in mechanical stress-induced podocyte injury.

NFYA promotes the anti-tumor effects of gluconeogenesis in hepatocellular carcinoma through the regulation of PCK1 expression.

Reprogramming of glucose metabolism occurs in many human tumor types, and one of these, gluconeogenesis, is known to exhibit anti-tumor effects in hepatocellular carcinoma (HCC). The transcription factor NFYA regulates gluconeogenesis in the normal liver tissue, but the function of the NFYA-gluconeogenesis axis in cancer and the functional differences of NFYA splicing variants in the regulation of gluconeogenesis is still unclear. Here, we demonstrate that NFYAv2, the short-form variant, upregulates the transcription of a gluconeogenic enzyme PCK1. We further reveal that its regulation induces high ROS levels and energy crisis in HCC and promotes cell death. These indicate that the NFYAv2-gluconeogenesis axis has enhanced anti-tumor effects in HCC, suggesting that the axis may be a potential therapeutic target for HCC. Furthermore, Nfyav1-deficient mice, spontaneously overexpressing Nfyav2, had no increasing gluconeogenesis in the liver. Taken together, our results reveal NFYAv2-gluconeogenesis axis has anti-tumor effects and the potential for NFYAv2 to be a safer therapeutic target for HCC.

Epidemiology of bloodstream infections and surface swab cultures in burn patients.

Aim: For infection control in burn patients, it is essential to understand the epidemiology of bloodstream infection (BSI) and the local microbiological situation. There are few studies on blood and swab culture results among burn patients in Japan. The purpose of this study was to investigate the epidemiology of BSI and swab cultures in burn patients. Methods: Data from 355 burn patients over 13 years from 2008 were analyzed retrospectively. Bloodstream infection was defined as the isolation of bacteria or fungi from two or more blood cultures. The characteristics of burn patients and microorganisms detected from various cultures were analyzed. Results: The mortality rate among burn patients with BSI was 37.8%, which was more than twice that among burn patients without BSI. The univariate analysis showed that inhalation injury, total burn surface area (TBSA), and mortality were associated with BSI. The multivariate logistic analysis indicated that TBSA was an independent risk factor for BSI. The most frequently isolated organism from blood and swab cultures were Candida species and Pseudomonas aeruginosa, respectively. Seventy-five percent of the microorganisms isolated from blood were detected previously in swab cultures performed within 1 week from blood cultures. Conclusions: The prognosis of burn patients with BSI was poor, and TBSA was an independent risk factor for BSI. The predominant organisms isolated from blood and swab cultures were Candida species and P. aeruginosa, respectively. Surveillance wound swab cultures could be utilized for monitoring the local microbiological situation in burn patients.

Melanin-producing medullary thyroid carcinoma with transformation to melanoma: A case report.

Only one case of melanoma arising from melanin-producing medullary thyroid carcinoma (MTC) has been reported previously. In the present study, a second such case was reported and compared with the previous one. The patient was an 86-year-old male who presented with a right anterior neck mass. Ultrasound revealed a nodule measuring 49x48x40 mm in the right lobe of the thyroid. The levels of serum calcitonin (2,298 pg/ml) and carcinoembryonic antigen (CEA; 27.0 ng/ml) were markedly elevated. Aspiration cytology revealed suspected malignant anaplastic thyroid carcinoma and total thyroidectomy without neck nodal dissection was performed. On gross observation, the nodule was well encapsulated, soft, solid and black. Light microscopy indicated that the nodule was composed mainly of large, occasionally huge, pleomorphic cells with a solid or alveolar growth pattern. On immunohistochemistry, these cells were positive for melan-A and S-100 protein, and negative for thyroid transcription factor 1, calcitonin, chromogranin A and CEA. In the subcapsular area, melanin-producing MTC was intimately intermingled with the pleomorphic cells. No primary site of the melanoma was detectable in other organs. At three years after surgery, the patient died due to metastasis of the melanoma to the brain. The previously reported case had no detectable recurrence or distant metastasis up to 11 years after surgery. In comparison with that case, the present case had a similar morphology but the outcome was poorer. Thus, the prognosis of melanoma that transforms from MTC appears to remain uncertain.

Extensor hallucis longus muscle contracture after distal tibial physeal injury: A report of two cases.

Few studies have reported about isolated contracture in the extensor hallucis longus (EHL) muscle, but none of the EHL muscle contracture after distal tibial physeal injury. Two such cases in 16- and 14-year-old boys who underwent surgeries for distal physeal injury of the tibia at a previous hospital are presented. Extension contracture of the hallux appeared 1-2 months post-surgery. Physical examinations revealed that the extension contracture of the first metatarsophalangeal joint was aggravated in plantar flexion of the ankle due to a tenodesis effect, and magnetic resonance imaging showed atrophy and signal changes in the anterior compartment muscles. This was diagnosed as EHL muscle contracture due to anterior compartment syndrome (ACS) after distal tibial physeal injury. The EHL tendon transfers were performed in both cases, with favorable short-term results. Therefore, the EHL tendon transfer might be preferable in case of the EHL muscle contracture due to partial ACS.

Effect of acute coagulopathy before fluid administration in mortality for burned patients.

BACKGROUND: The presence of acute coagulopathy and its effect on prognosis in burn patients are unclear. No studies are extant verifying early coagulopathy before fluid administration in burn patients. The current study focused on arrival coagulopathy before volume resuscitation was begun in earnest. METHODS: Data from 137 burn patients transported directly to the hospital without fluid administration from January 2006 to December 2019 were analyzed retrospectively. RESULTS: The non-survival group had significantly increased age, total burn surface area (TBSA) burned, various scoring systems, prothrombin time-international normalized ratio (PT-INR), activated partial thromboplastin time (APTT), the presence of coagulopathy, and lactate levels compared to the survival group. In the logistic regression analysis, the incidence of coagulopathy was independently associated with mortality. The coagulopathy group had significant increases in TBSA burned, various scoring systems, PT-INR, APTT, lactate levels, and the mortality than the noncoagulopathy group. The prognostic burn index (PBI) was significantly correlated with PT-INR and APTT. We also found a significant correlation between the serum lactate and the PT-INR, APTT, and PBI. CONCLUSIONS: Acute coagulopathy of burn patients might be present on arrival to the hospital before fluid replacement which is an independent risk factor for in-hospital mortality.

Reevaluation for prognostic value of prognostic burn index in severe burn patients.

AIM: The prognostic burn index (PBI), which consists of half partial-thickness burn surface area plus full-thickness burn surface area and age, has been widely used to predict mortality in Japan. However, the prognostic value of PBI has not been investigated sufficiently. The purpose of the present study is to clinically reevaluate the PBI in severe burn patients. METHODS: Data of 69 severe burn patients admitted to the burn center at Kyorin University Hospital (Tokyo, Japan) from January 2008 to December 2017 were analyzed retrospectively. The primary outcome in this study was in-hospital mortality. RESULTS: The overall in-hospital mortality rate was 34.8%. There were significant differences in age, the presence of inhalation injury, total burned surface area, full-thickness burn area, burn index, and PBI between survivors and non-survivors. In logistic regression analysis, PBI was independently associated with mortality, while the presence of inhalation injury was not. A PBI above the threshold of 105 was significantly associated with in-hospital mortality. The area under the receiver operating characteristic curve for PBI was 0.85 (95% confidence interval, 0.73-0.93). CONCLUSION: The PBI could be a good prognostic indicator. A PBI above the threshold of 105 was associated with mortality among severe burn patients treated in burn-care facilities.

Chest Compression Depth and Rate　- Effect on Instructor Visual Assessment of Chest Compression Quality.

BACKGROUND: The aim of the present study was to determine whether instructors could accurately assess chest compression quality visually, considering the association between chest compression depth and rate. Methods and Results: In this prospective, observational study, the quality of chest compressions performed by a simulated actor in a video was visually assessed by certified instructors. The film consisted of 14 case scenarios, each including a combination of depth (2 patterns: adequate, 5-6 cm; and inadequate, <5 cm) and rate (7 categories: compressions 90-150 times/min in increments of 10 times/min). The participants evaluated whether the compression depth was adequate, deep, or inadequate; and whether the compression rate was appropriate, fast, or slow. Of 198 instructors, 56% of participants misidentified adequate depth as deep at a chest compression rate of 120/min (the tendency toward this response increased as chest compression rate increased), and 64.1% of participants incorrectly determined 130/min to be appropriate. On generalized linear mixed-effects model analysis, perceived chest compression depth and rate were significant factors for a correct response (P<0.01, both). A significant interaction between chest compression depth and rate was observed (P<0.01). CONCLUSIONS: In the visual assessment of chest compression quality, recognition of chest compression depth was closely associated with compression rate. Misidentification of adequate chest compression depth as deep increased as the compression rate increased.

The Clinical Significance of Serum 1,3-ß-D-Glucan For the Diagnosis of Candidemia in Severe Burn Patients.

Although the serum 1,3-ß-D-glucan test has been used as an early diagnostic marker of candidemia, there are few studies regarding the association of serum 1,3-ß-D-glucan levels with candidemia in severe burn patients. The purpose of this study was to elucidate the clinical significance of 1,3-ß-D-glucan for the diagnosis of candidemia in severe burn patients. Data from 51 severe burn patients whose serum levels of 1,3-ß-D-glucan had been measured for the suspicion of invasive fungal infection were analyzed retrospectively. The primary outcome in this study was the detection of candidemia. The levels of 1,3-ß-D-glucan (pg/ml) in candidemia and noncandidemia groups ranged from 41.1 to 600.0 with a median of 90.6 and from 5.0 to 41.3 with a median of 6.8, respectively. A significant difference in the levels of 1,3-ß-D-glucan was observed between the two groups. The optimal cutoff value was 40 pg/ml, with a sensitivity of 100% and a specificity of 95%, whereas the conventional cutoff value (11 pg/ml) resulted in a sensitivity of 100% and a specificity of 68%. The 1,3-ß-D-glucan test was found to be useful for detecting candidemia in severe burn patients, and the cutoff value might be set to 40 pg/ml to detect it more accurately.

Surgical treatment for lumbar hyperlordosis after resection of a spinal lipoma associated with spina bifida: A case report.

RATIONALE: A hyperlordosis deformity of the lumbar spine is relatively rare, and surgical treatment has not been comprehensively addressed. In this case report, we describe the clinical presentation, surgical treatment, and medium-term follow-up of a patient presenting with a progressive lumbar hyperlordosis deformity after resection of a spinal lipoma associated with spina bifida. PATIENT CONCERNS: The patient was a 20-year-old woman presenting with a progressive hyperlordosis deformity of the lumbar spine associated with significant back pain (visual analog pain score of 89/100 mm), but with no neurological symptoms. DIAGNOSES: The lumbar lordosis (LL), measured on standing lateral view radiographs, was 114°, with a sagittal vertical axis (SVA) of -100 mm. The patient had undergone excision of a lipoma, associated with spina bifida of the lumbar spine, at 7 months of age.She was first evaluated at our hospital at 18 years of age for progressive spinal deformity and lumbago. INTERVENTIONS: An in situ fusion, from T5 to S1, using pedicle screws with bone graft obtained from the iliac crest, was performed. OUTCOMES: Postoperatively, the LL decreased to 93°, and the SVA decreased to -50 mm. The decision to not correct the hyperlordosis deformity fully was intentional. Seven years and 1 month postsurgery, the patient had no limitations in standing and walking and reported a pain score of 8/100 mm; there was no evidence of a loss of correction. LESSONS: Lumbar hyperlordosis after resection of a spinal lipoma associated with spina bifida is rare. Posterior fixation provided an effective treatment in this case. As the lumbar hyperlordosis deformity is often high, correction can be difficult. In this case, although the correction and fusion were performed in situ, there was no progression of either the deformity or the lumbago. Early detection remains an essential component of effective treatment, allowing correction when the spinal deformity is easily reversible.

Establishment of Imaging Spectroscopy of Nuclear Gamma-Rays based on Geometrical Optics.

Since the discovery of nuclear gamma-rays, its imaging has been limited to pseudo imaging, such as Compton Camera (CC) and coded mask. Pseudo imaging does not keep physical information (intensity, or brightness in Optics) along a ray, and thus is capable of no more than qualitative imaging of bright objects. To attain quantitative imaging, cameras that realize geometrical optics is essential, which would be, for nuclear MeV gammas, only possible via complete reconstruction of the Compton process. Recently we have revealed that "Electron Tracking Compton Camera" (ETCC) provides a well-defined Point Spread Function (PSF). The information of an incoming gamma is kept along a ray with the PSF and that is equivalent to geometrical optics. Here we present an imaging-spectroscopic measurement with the ETCC. Our results highlight the intrinsic difficulty with CCs in performing accurate imaging, and show that the ETCC surmounts this problem. The imaging capability also helps the ETCC suppress the noise level dramatically by ~3 orders of magnitude without a shielding structure. Furthermore, full reconstruction of Compton process with the ETCC provides spectra free of Compton edges. These results mark the first proper imaging of nuclear gammas based on the genuine geometrical optics.

Spontaneous improvement of cervical kyphosis in eosinophilic granuloma: a case report.

We describe the case of a spontaneous improvement of the cervical kyphosis in eosinophilic granuloma with long-term follow-up. A collapse of the C5 vertebral body was confirmed by cervical spine radiography and computed tomography. The patient wore a sterno-occipitalmandibular immobilizer brace for 6 months, and remodeling of the vertebral body was confirmed 18 months after onset. Seven years have passed since the onset of symptoms, and the patient's cervical spine has maintained normal alignment. Management of eosinophilic granuloma of the pediatric cervical spine is still controversial. Conservative treatment suffices as adequate management of cervical eosinophilic granuloma, even with kyphotic deformity.

Atypical femoral fracture after receiving antiresorptive drugs in breast cancer patients with bone metastasis.

BACKGROUND: Atypical femoral fracture (AFF) occurs with minor trauma in patients receiving antiresorptive drugs such as bisphosphonate and denosumab. We hypothesized that patients with bone metastasis who receive higher doses of antiresorptive drugs tend to experience AFF more frequently. This study aimed to investigate the prevalence rate of AFF in patients receiving antiresorptive drugs for bone metastasis of breast cancer. METHODS: Based on the database from our hospital, patients with breast cancer between March and September 2014 were investigated. Thirty-two patients with bone metastasis who received higher doses of antiresorptive drugs were included for analysis and defined as the metastasis (M) group. For the control (C) group, 32 patients in the same period with breast cancer without bone metastasis who did not undergo antiresorptive drug therapy were included. We evaluated the localized periosteal thickening of the lateral cortex (beaking) and femoral neck-shaft angle in CT scout view, the periods from induction of antiresorptive drugs to the appearance of beaking, and the occurrence rate of complete fracture. The 2 groups were compared. RESULTS: Of the 64 limbs in 32 patients of the M group, 8 limbs in 6 patients showed beaking at the subtrochanteric area (12.5%). After the occurrence of beaking, 5 limbs in 3 patients eventually had a complete fracture with minor trauma (7.8%). On the other hand, no beaking was observed in the C group. CONCLUSIONS: The frequency of AFF in patients with breast cancer receiving bisphosphonate and/or denosumab for bone metastasis was high. More attention should be paid to the occurrence of AFF in these patients than osteoporotic patients.

Independent risk factors for a complicated hospital course in intensive care unit overdose patients.

Aim: The purpose of the present study was to identify risk factors associated with a complicated hospital course in overdose patients admitted to the intensive care unit. Methods: A total of 335 overdose patients were retrospectively studied in the surgical and medical intensive care unit of an academic tertiary hospital. Factors possibly associated with a complicated hospital course were evaluated. Complicated hospital course was defined as the occurrence of pneumonia, rhabdomyolysis, decubitus ulcer, nerve palsy, prolonged intubation, prolonged hospitalization, or death. Results: Of the 335 overdose patients, 93 (27.8%) had a complicated hospital course. Complicated hospital course was found to be associated with a high number of ingested pills (median, 135 [interquartile range, 78-240] versus 84 [53-134] tablets, P < 0.0001), low Glasgow Coma Scale score on admission (7 [3-11] versus 13 [8-15], P < 0.0001), and a high serum lactate level on admission (1.8 [1.0-3.0] versus 1.4 [0.9-2.0] mg/dL, P < 0.01) on univariate analysis of these factors in patients with and without a complicated hospital course. The independent risk factors for a complicated hospital course identified on multivariate analysis were a high number of ingested pills (≥100 tablets), low admission Glasgow Coma Scale score (<9), and high serum lactate on admission (≥2.0 mg/dL). The probability of a complicated hospital course for patients with 0, 1, 2, or all 3 independent risk factors were 7%, 22%, 40%, and 81%, respectively. Conclusion: The total number of ingested pills, admission Glasgow Coma Scale score, and serum lactate level on admission are predictive of a complicated hospital course in overdose patients admitted to the intensive care unit.

Biological differential diagnosis of follicular thyroid tumor and Hürthle cell tumor on the basis of telomere length and hTERT expression.

BACKGROUND: The most difficult thyroid tumors to diagnose by histology are follicular carcinomas (FTCs) and Hürthle cell carcinomas (HCCs). Telomere alteration and human telomerase reverse transcriptase (hTERT) expression have been observed in most human cancers and are known to be a feature of malignancy. The purpose of this study was to clarify whether hTERT protein expression and telomere alteration could be applicable biological markers for distinguishing FTC from HCC. METHODS: We investigated a total of 78 thyroid tumor cases, including 14 FTCs, 47 follicular adenomas (FTAs), 5 HCCs, and 12 Hürthle cell adenomas (HCAs). hTERT protein expression was examined by immunohistochemistry, and telomere length was determined by tissue quantitative fluorescence in situ hybridization. RESULTS: Positivity for hTERT protein expression was observed in 86 % of FTCs and 49 % of FTAs. Telomeres in FTCs were significantly shorter than those in FTAs. All HCCs and HCAs (100 %) expressed hTERT protein. Telomeres in HCCs were significantly shorter than those in HCAs. CONCLUSIONS: Our results suggest that hTERT protein expression and telomere shortening would be applicable as biological markers to distinguish FTC from FTA. Previous studies have suggested that follicular tumor and Hürthle cell tumor should be classified biologically as distinct tumors. All Hürthle cell tumors expressed hTERT protein and HCCs had markedly shortened telomeres, suggesting that follicular tumor and Hürthle cell tumor might be biologically distinct entities.

Hamate hook non-union treated with a break-away screw: a case report.

Hamate hook non-union is a relatively rare, but on the increase. We encountered a 25-year-old male baseball instructor with hamate hook non-union, and treated it with debridement of the fractured region and osteosynthesis using a break-away screw. Splint fixation was applied for three weeks after surgery, and active/passive range of motion exercises were actively performed thereafter. Bone union was noted three months after surgery. Transient ulnar paralysis resolved, and the patient could return to the same sports activity as that before injury six months after surgery. Since break-away screws are capable of loading a strong pressure on the fractured region and these screws can be inserted by preparing only a surgical field for guide wire insertion, requiring no soft tissue dissection to prepare a region for applying fixation materials, break-away screws are useful for the fixation of small bone fragments and osteosynthesis in a deep surgical field.

Amplification of the human epidermal growth factor receptor 2 gene in differentiated thyroid cancer correlates with telomere shortening.

The human epidermal growth factor receptor 2 (HER2) proto-oncogene plays an important role in the development and progression of breast and gastric cancer. Monitoring of the HER2 status and treatment with trastuzumab was performed initially in breast cancer, and subsequently in gastric cancer. However, the HER2 status of thyroid cancer remains unexplored. Telomere alteration and telomerase activity have been observed in most human cancers and are known to be a feature of malignancy. The aims of this study were to clarify the HER2 status of thyroid cancer and to examine any correlations to various characteristics of malignancy. We investigated 69 cases of differentiated thyroid cancers with reference to: i) telomere length as measured using tissue quantitative fluorescence in situ hybridization (Q-FISH), ii) expression of human telomerase reverse transcriptase (hTERT) as determined by immunohistochemistry (IHC), and iii) overexpression of the HER2 protein as determined by IHC and amplification of the HER2 gene as determined by fluorescence in situ hybridization (FISH). The telomeres of thyroid cancers, especially follicular carcinomas, were significantly shorter compared to those of adjacent normal tissues. Positivity for hTERT expression and HER2 amplification were observed in approximately 70 and 22% of thyroid cancers, respectively. Our data demonstrated that telomeres in HER2-positive cancers were significantly shorter compared to those in HER2-negative cancers. These results suggest that highly malignant differentiated thyroid cancer can be detected by monitoring HER2 status and telomere shortening, and that trastuzumab therapy may be effective for refractory thyroid cancer.

Report from the Japanese registry of CPR for in-hospital cardiac arrest (J-RCPR).

BACKGROUND: In-hospital cardiopulmonary arrest (CPA) is an important issue, but data in Japan are limited. METHODS AND RESULTS: To investigate in-hospital CPA, we conducted a prospective multicenter observational registry of in-hospital CPA and resuscitation in Japan (J-RCPR). During January 2008 to December 2009, patients were registered from 12 participating hospitals. All patients, visitors and employees within the facility campus who experience a cardiopulmonary resuscitation event defined as either a pulseless or a pulse with inadequate perfusion requiring chest compressions and/or defibrillation of ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) were registered. Data were collected in 6 major categories of variables: facility data, patient demographic data, pre-event data, event data, outcome data, and quality improvement data. Data for 491 adults were analyzed. The prevalence of pulseless VT/VF as first documented rhythm was 28.1%, asystole was 29.5% and pulseless electrical activity was 41.1%. Immediate causes of event were arrhythmia 30.6%, acute respiratory insufficiency 26.7%, and hypotension 15.7%. Return of spontaneous circulation was 64.7%; the proportion of survival 24h after CPA was 49.8%, the proportion of survival to hospital discharge was 27.8% and proportion of favorable neurological outcome at 30 days was 21.4%. CONCLUSIONS: This is the first report of the registry for in-hospital CPA in Japan and shows that the registry provides important observational data.