[A Case of Unilateral Interstitial Lung Disease in a Patient Treated with Oxaliplatin, 5-Fluorouracil, and Leucovorin].

Respiratory symptoms are rarely reported as side effects of oxaliplatin, 5-fluorouracil, and Leucovorin(FOLFOX)therapy. We report a case of a patient with FOLFOX-induced unilateral interstitial pneumonia. The patient was a 68-year-old man who underwent ileocecal resection of cecum cancer. FOLFOX regimen was started as an adjuvant chemotherapy. After the administration of 11 courses, he visited our hospital with fever, dyspnea, and anorexia. We diagnosed this as FOLFOX- induced unilateral interstitial pneumonia through a blood test, chest radiograph, computed tomography, and bronchoscopy. Treatment was started with 30 mg of prednisolone, and the dosage was gradually decreased. The patient responded well to the treatment and was discharged from the hospital without any complications on the 33th day after admission.

Postoperative diaphragmatic hernia with upside-down stomach: a case report.

A 31-year-old man presented to our hospital's Emergency Department with sudden epigastric pain and vomiting. He had undergone endoscopic resection via the retroperitoneal route for a retroperitoneal tumor located in the left diaphragmatic crus of the esophageal hiatus at another hospital 8 months previously. Radiography and computed tomography showed inversion of the stomach beyond the diaphragm into the thoracic cavity, with the gastroesophageal junction serving as the fulcrum point. This finding led to a diagnosis of postoperative diaphragmatic hernia accompanied by an upside-down stomach (UDS). The prolapsed stomach in the thoracic cavity was reduced to the abdominal cavity using laparoscopic surgery. The postoperative course was favorable, and the patient was discharged from the hospital on postoperative day 7. No recurrence has been observed in the past 5 years. The pathological condition of a UDS observed in esophageal hiatal hernias may be found in postoperative diaphragmatic hernias. Laparoscopic surgery for a postoperative diaphragmatic hernia with a UDS is considered a useful surgical procedure. Laparoscopic surgery can simultaneously confirm the viability of the herniated organs, reduce the organs to the abdominal cavity, and close and reinforce the diaphragm.

Calcium sparks enhance the tissue fluidity within epithelial layers and promote apical extrusion of transformed cells.

In vertebrates, newly emerging transformed cells are often apically extruded from epithelial layers through cell competition with surrounding normal epithelial cells. However, the underlying molecular mechanism remains elusive. Here, using phospho-SILAC screening, we show that phosphorylation of AHNAK2 is elevated in normal cells neighboring RasV12 cells soon after the induction of RasV12 expression, which is mediated by calcium-dependent protein kinase C. In addition, transient upsurges of intracellular calcium, which we call calcium sparks, frequently occur in normal cells neighboring RasV12 cells, which are mediated by mechanosensitive calcium channel TRPC1 upon membrane stretching. Calcium sparks then enhance cell movements of both normal and RasV12 cells through phosphorylation of AHNAK2 and promote apical extrusion. Moreover, comparable calcium sparks positively regulate apical extrusion of RasV12-transformed cells in zebrafish larvae as well. Hence, calcium sparks play a crucial role in the elimination of transformed cells at the early phase of cell competition.

De novo non-synonymous CTR9 variants are associated with motor delay and macrocephaly: human genetic and zebrafish experimental evidence.

CTR9 is one of five genes that form the PAF1 complex, which binds to RNA polymerase II and plays critical roles in transcriptional elongation and transcription-coupled histone modifications including histones H3K4me3 and H3K36me3. In this study, de novo CTR9 non-synonymous variants (p.(Glu15Asp) and p.(Pro25Arg)) were detected in two unrelated patients with macrocephaly, motor delay, and intellectual disability. A pull-down assay showed that the mutant CTR9 proteins had stronger affinities to the PAF1 protein than the wild-type protein. Functional analyses using zebrafish showed that the knockout of the ctr9 gene caused motor defects and enlargement of the telencephalon, which is homologous to the mammalian cerebrum. The rescue experiment, in which the human CTR9 mutants were introduced into ctr9-knockout zebrafish, failed to maintain the swimming posture of the ctr9-knockout fish, suggesting that the human CTR9 mutant proteins do not function normally in vivo. In addition, the overexpression of human CTR9 mutant mRNA caused telencephalon enlargement in zebrafish larvae, suggesting that the human CTR9 mutant proteins interfered with normal endogenous CTR9 function. We concluded that the two missense variants in CTR9 (p.(Glu15Asp) and p.(Pro25Arg)) cause a new syndrome involving macrocephaly, motor delay and intellectual disability through the loss of the normal function of CTR9 and the inhibition of the normal intrinsic CTR9 function of the contralateral allele.

Development of pups born to rats established as a model of underweight Japanese women and the onset of impaired glucose tolerance.

An increasing number of Japanese women of childbearing age are underweight (BMI <18.5), but the association between this and the increased number of low-birth-weight babies born remains unclear. Here, a rat model was established to mimic the undernutrition (85% of the energy required for those with normal activity levels) experienced by such women and to evaluate the associated impaired glucose tolerance. The undernourished Wistar rat group showed increased serum corticosterone level reflecting stress, and greater adrenal weight and size. It also showed greater insulin resistance, higher expression of FOXO-1, a transcription factor related to muscle atrophy, and lower expression of p-Akt, an insulin-dependent signaling factor. Overall, this work shows the key role of undernutrition during pregnancy as a cause of impaired glucose tolerance and increased diabetes risk in offspring. The findings of this study may inform preemptive measures to prevent the development of metabolic syndrome in offspring of undernourished mothers.

A Clockwork Bleb: cytoskeleton, calcium, and cytoplasmic fluidity.

When the plasma membrane (PM) detaches from the underlying actin cortex, the PM expands according to intracellular pressure and a spherical membrane protrusion called a bleb is formed. This bleb retracts when the actin cortex is reassembled underneath the PM. Whereas this phenomenon seems simple at first glance, there are many interesting, unresolved cell biological questions in each process. For example, what is the membrane source to enlarge the surface area of the PM during rapid bleb expansion? What signals induce actin reassembly for bleb retraction, and how is cytoplasmic fluidity regulated to allow rapid membrane deformation during bleb expansion? Furthermore, emerging evidence indicates that cancer cells use blebs for invasion, but little is known about how molecules that are involved in bleb formation, expansion, and retraction are coordinated for directional amoeboid migration. In this review, we discuss the molecular mechanisms involved in the regulation of blebs, which have been revealed by various experimental systems.

STIM-Orai1 signaling regulates fluidity of cytoplasm during membrane blebbing.

The cytoplasm in mammalian cells is considered homogeneous. In this study, we report that the cytoplasmic fluidity is regulated in the blebbing cells; the cytoplasm of rapidly expanding membrane blebs is more disordered than the cytoplasm of retracting blebs. The increase of cytoplasmic fluidity in the expanding bleb is caused by a sharp rise in the calcium concentration. The STIM-Orai1 pathway regulates this rapid and restricted increase of calcium in the expanding blebs. Conversely, activated ERM protein binds to Orai1 to inhibit the store-operated calcium entry in retracting blebs, which results in decreased in cytoplasmic calcium, rapid reassembly of the actin cortex.

Incisional hernia after extreme lateral interbody fusion on the lumbar spine: A case report.

INTRODUCTION: Extreme lateral interbody fusion is a minimally invasive lateral transpsoas approach for spine surgery. We herein report a case of an incisional hernia after an extreme lateral interbody fusion on the lumbar spine that was successfully treated by laparoscopic surgery with intraperitoneal onlay mesh repair. PRESENTATION OF CASE: A 78-year-old woman was referred to our hospital with a complaint of left abdominal bulge and pain. She had undergone an extreme lateral interbody fusion for a lumbar spinal canal stenosis from L1 to L4 a year prior. Abdominal computerized tomography showed a left lumbar incisional hernia, and laparoscopic surgery was performed. The hernia orifice was sutured closed and covered with mesh. The patient was discharged five days after the operation with no complications. DISCUSSION: When performing XLIF for a spinal disorder, the muscles should be separated bluntly along their fibers to prevent muscle atrophy, and the incised fascia should be securely sutured closed. Abdominal wall incisional hernias can occur after spinal surgeries such as extreme lateral interbody fusion. CONCLUSION: Laparoscopic repair for abdominal wall incisional hernia after spine surgery is safe and feasible.

Laparoscopic treatment for adult inguinal hernia with cryptorchidism: A case report.

INTRODUCTION: Cryptorchidism or undescended testis is the most common disorder of male children, which is often diagnosed and treated during childhood. Adult patients with cryptorchidism are uncommon. Herein we report the case of adult inguinal hernia with cryptorchidism successfully treated by laparoscopic surgery simultaneously. PRESENTATION OF CASE: We report a case of 68 year-old-man who was admitted to our hospital with a complaint of bulge and pain in the right groin area from 2 weeks before. CT or MRI revealed a right inguinal hernia and an undescended testis in the right inguinal canal. He was diagnosed with right inguinal hernia accompanied by cryptorchidism. Laparoscopic transabdominal preperitoneal repair (TAPP) and orchiectomy were performed simultaneously. Postoperative period was uneventful and he was discharged home on the 1st postoperative day. Pathological examination of the specimen was reported as atrophic testis with no malignancy. There has been no recurrence during a follow-up. DISCUSSION: To our Knowledge, the case report of adult inguinal hernia with cryptorchidism treated by laparoscopic surgery is rare. All cases recommended the feasibility of laparoscopic surgery. CONCLUSION: Adult inguinal hernia with cryptorchidism is a rare condition. TAPP and simultaneous laparoscopic orchiectomy for inguinal hernia with cryptorchidism were safe and feasible. It could be the first surgical option for the treatment of such adult patients.

Coordinated changes in cell membrane and cytoplasm during maturation of apoptotic bleb.

Apoptotic cells form membrane blebs, but little is known about how the formation and dynamics of membrane blebs are regulated. The size of blebs gradually increases during the progression of apoptosis, eventually forming large extracellular vesicles called apoptotic bodies that have immune-modulating activities. In this study, we investigated the molecular mechanism involved in the differentiation of blebs into apoptotic blebs by comparing the dynamics of the bleb formed during cell migration and the bleb formed during apoptosis. We revealed that the enhanced activity of ROCK1 is required for the formation of small blebs in the early phase of apoptosis, which leads to the physical disruption of nuclear membrane and the degradation of Lamin A. In the late phase of apoptosis, the loss of asymmetry in phospholipids distribution caused the enlargement of blebs, which enabled translocation of damage-associated molecular patterns to the bleb cytoplasm and maturation of functional apoptotic blebs. Thus, changes in cell membrane dynamics are closely linked to cytoplasmic changes during apoptotic bleb formation.

[A Case of Primary Breast Cancer and Gastric Cancer Metastasis to the Skin-Usefulness of Immunohistochemistry in Differentiating Primary Breast Cancer from Metastatic Breast Cancer].

We herein report the case of a 76-year-old female patient who had undergone gastrectomy for advanced gastric cancer (histologically tubular adenocarcinoma)before 5 months, presenting with abdominal skin tumor. A skin biopsy revealed tubular adenocarcinoma. Positron emission tomography-computed tomographic scanning detected right breast tumor. A partial mastectomy of the right breast and local resection of abdominal skin tumor were performed and both tumors depicted similar histology of tubular adenocarcinoma in routine pathological examination. Immunohistochemically, positive for CDX2 and MUC5AC in previously resected gastric cancer and skin tumor tissues, whereas negative for both antigens in breast cancer. Thus, the final pathological diagnosis demonstrated skin metastasis originating from gastric cancer and primary breast cancer(invasive ductal carcinoma)histologically mimicking gastric cancer. We emphasize difficulties in diagnosis of this situation and that immunohistochemistry is helpful to distinguish primary breast cancer from gastric cancer metastasizing to the breast.

The impact of exercise and vitamin D supplementation on physical function in community-dwelling elderly individuals: A randomized trial.

BACKGROUND: We investigated the impact of exercise and vitamin D supplementation on physical function and locomotor dysfunction in community-dwelling elderly individuals. METHODS: In total, 148 community-dwelling elderly individuals (aged ≥60 years) who were not taking osteoporosis medications participated in a 24-week intervention. The participants were randomly divided into an exercise group, vitamin D group, and exercise and vitamin D group. The participants and outcome-assessing staff were not blinded to group assignment. Exercise comprised three daily sets each of single-leg standing (1 min/leg/set) and squatting (5-6 repetitions/set); vitamin D supplementation was 1000 IU/day. Participants were contacted every 2 weeks to check on their condition and encourage continued participation. The primary outcome was lower limb muscle strength and mass; secondary outcomes were several physical function measurements, serum 25-hydroxyvitamin D levels, and results of a self-assessment questionnaire completed pre- and post-intervention. RESULTS: We analyzed data from 45, 42, and 43 participants in the exercise, vitamin D, and exercise and vitamin D groups, respectively, who completed the intervention. Locomotive syndrome, which involves reduced mobility due to locomotive organ impairment, was diagnosed in 99 participants (76.2%). Many physical function measurements improved in all groups. Lower limb muscle mass increased significantly in all three groups, with no significant differences between the groups in the degree of change. The average serum 25-hydroxyvitamin D of all vitamin D-supplemented participants increased from 28.1 ng/ml to 47.3 ng/ml after vitamin D supplementation. CONCLUSIONS: Both exercise and vitamin D supplementation independently improved physical function and increased muscle mass in community-dwelling elderly individuals. Moreover, the combination of exercise and vitamin D supplementation might further enhance these positive effects. CLINICAL TRIAL REGISTRY: UMIN Clinical Trial, UMIN000028229.

Membrane bleb: A seesaw game of two small GTPases.

The plasma membrane is generally associated with underling actin cytoskeleton. When the plasma membrane detaches from actin filaments, it is expanded by the intracellular pressure and the spherical membrane protrusion which lacks underlying actin cortex, termed bleb, is formed. Bleb is widely used for migration across species; however, the molecular mechanism underlying membrane blebbing remains largely unknown. Our recent study revealed that 2 small GTPases, Rnd3 and RhoA, are important regulators of membrane blebbing. In the expanding blebs, Rnd3 is recruited to the plasma membrane and inhibits RhoA activity by activating RhoGAP. On the other hand, RhoA is activated at the retracting membrane and removes Rnd3 from plasma membrane by the activity of ROCK (Rho-associated protein kinase). ROCK is also important for the rapid reassembly of actin cortex and retraction of membrane blebs by activating Ezrin. We propose that a Rnd3 and RhoA cycle underlies the core machinery of continuous membrane blebbing.

A RhoA and Rnd3 cycle regulates actin reassembly during membrane blebbing.

The actin cytoskeleton usually lies beneath the plasma membrane. When the membrane-associated actin cytoskeleton is transiently disrupted or the intracellular pressure is increased, the plasma membrane detaches from the cortex and protrudes. Such protruded membrane regions are called blebs. However, the molecular mechanisms underlying membrane blebbing are poorly understood. This study revealed that epidermal growth factor receptor kinase substrate 8 (Eps8) and ezrin are important regulators of rapid actin reassembly for the initiation and retraction of protruded blebs. Live-cell imaging of membrane blebbing revealed that local reassembly of actin filaments occurred at Eps8- and activated ezrin-positive foci of membrane blebs. Furthermore, we found that a RhoA-ROCK-Rnd3 feedback loop determined the local reassembly sites of the actin cortex during membrane blebbing.

Immunoreactive insulin in diabetes mellitus patient sera detected by ultrasensitive ELISA with thio-NAD cycling.

To minimize patient suffering, the smallest possible volume of blood should be collected for diagnosis and disease monitoring. When estimating insulin secretion capacity and resistance to insulin in diabetes mellitus (DM), increasing insulin assay immunosensitivity would reduce the blood sample volume required for testing. Here we present an ultrasensitive ELISA coupled with thio-NAD cycling to measure immunoreactive insulin in blood serum. Only 5 µL of serum was required for testing, with a limit of detection (LOD) for the assay of 10(-16) moles/assay. Additional recovery tests confirmed this method can detect insulin in sera. Comparisons between a commercially available immunoreactive insulin kit and our ultrasensitive ELISA using the same commercially available reference demonstrated good data correlation, providing further evidence of assay accuracy. Together, these results demonstrate our ultrasensitive ELISA could be a powerful tool in the diagnosis and treatment of not only DM but also many other diseases in the future.

The effects of self-directed home exercise with serial telephone contacts on physical functions and quality of life in elderly people at high risk of locomotor dysfunction.

Exercise is essential for maintaining quality of life (QOL) in elderly individuals. However, adherence to exercise programs is low. Here, we assessed the effectiveness of a self-directed home exercise program with serial telephone contacts to encourage exercise adherence among elderly individuals at high risk of locomotor dysfunction. We recruited community-dwelling adults (ｧ65 years) in Niigata, Japan, who were targets of the long-term care prevention project for locomotor dysfunction but did not participate in the government-sponsored prevention programs. The study was conducted from November 2011 to October 2012. Participants received exercise instruction and performed exercises independently for 3 months with serial telephone contacts. The single-leg stance and five-times sit-to-stand tests were used to assess physical function. The SF-8 was used to measure health-related QOL. Ninety-seven participants were enrolled in the study, representing 2.5% of eligible people;87 completed the intervention. Scores from physical function tests were significantly improved by the intervention, as were 7 of eight SF-8 subscales. Adherence was 85.4% for the single-leg standing exercise and 82.1% for squatting. Thus, self-directed home exercise with serial telephone contacts improved physical function and health-related QOL, representing a promising model for preventing the need for long-term care due to locomotor dysfunction.

Tocilizumab dramatically ameliorated life-threatening diarrhea due to secondary amyloidosis associated with rheumatoid arthritis.

Severe diarrhea improved dramatically with administration of the humanized anti-interleukin-6 receptor antibody tocilizumab (TCZ) in a patient with secondary reactive amyloidosis, which was associated with rheumatoid arthritis (RA). A 53-year-old woman with RA went into hypovolemic shock because of severe watery diarrhea associated with gastrointestinal amyloidosis. The high-dose prednisolone therapy and glucocorticoid pulse therapy did not improve her intractable diarrhea. After TCZ administration, the life-threatening diarrhea lessened in about 6 h, and her vital signs became stable the next day. Perforation of the small intestine, however, occurred 2 days after TCZ administration. Whether TCZ could have been involved in the perforation in such a short time is unknown. Surgery was successful, and the patient recovered. TCZ may work immediately in diarrhea associated with secondary amyloidosis.