Rapid Onset of De Novo Rectal Prolapse Following Colpocleisis.

INTRODUCTION: The aim of this video case series is to demonstrate our experience of the clinical findings and the surgical management of the rapid onset de novo rectal prolapse (RP) following colpocleisis METHODS: This is a case series of three patients who developed de novo RP within 1 month after colpocleisis, which was repaired by laparoscopic ventral mesh rectopexy (LVMR). The video shows the physical, radiological, and intraoperative findings of these patients. A retrospective review of our surgical cases of RP was also performed to analyze the onset timing of de novo RP after various pelvic organ prolapse (POP) procedures. RESULTS: The pathological condition of all three patients' RP was evacuation enterocele, and LVMR was feasible without postoperative complications or recurrences. In the retrospective case review of 158 RP surgeries in our institution (June 2015 to September 2023), 18 cases (11.4%) occurred following POP surgery. De novo RP following colpocleisis developed significantly earlier than those following other procedures (average: 6.1 vs 66.4 months, p = 0.010). CONCLUSIONS: Although de novo RP following colpocleisis is relatively rare, this complication could have a detrimental effect on patients' quality of life. Preoperative informed consent may be advisable before planning colpocleisis.

Effect of soft tissue tension around the knee joint on medio-lateral patellar position.

Patellofemoral pain (PFP) is one of the most common sports injuries of the knee joint and has a high persistence and recurrence rate. Medio-lateral patellar position in the knee extension position during contraction is associated with PFP. However, soft tissue tension that most influences the medio-lateral patellar position in the knee extension position during contraction in vivo is unclear. We aimed to clarify the relationship between medio-lateral patellar position and soft tissue tension around the knee joint. Twelve patients with PFP and 20 healthy participants were included. Medio-lateral patellar position and tension of the rectus femoris, vastus lateralis (VL), vastus medialis, iliotibial band (ITB), lateral patellofemoral ligament, and medial patellofemoral ligament were measured during contraction and rest. The tensions of the VL and ITB during contraction and the medio-lateral patellar position at rest were significantly associated with medio-lateral patellar position during contraction (ß = 0.449, 0.354, and 0.393, respectively). In addition, the tension of ITB was significantly associated with the medio-lateral patellar position at rest (ß = 0.646). These relationships were not affected by the presence of PFP. These findings suggest that the patellar position during contraction became more lateral as the tension in the VL and ITB increased, regardless of the presence of PFP. These results may facilitate the prevention and treatment of PFP.

Iliac vein variation in the sacral promontory on three-dimensional computed tomography angiography: a prospective observational study before laparoscopic sacrocolpopexy.

INTRODUCTION AND HYPOTHESIS: Venous injury may occur during exposure of the anterior longitudinal ligament at the anterior sacral promontory (SP). We aimed to quantitatively measure the extent of the vascular window (VW) in front of the SP in patients with internal iliac vein (IIV) variations using preoperative three-dimensional computed tomography angiography (3DCTA). We hypothesized that patients with IIV variations would have a narrow VW. METHODS: This prospective observational study included patients scheduled for laparoscopic sacrocolpopexy (LSC) between July 2022 and April 2023 who underwent preoperative 3DCTA. The primary endpoint was the VW measurement in the standard and variant IIV groups using 3DCTA before LSC. The secondary endpoint was the difference between the two IIV groups adjusted for age, body mass index, hypertension, and diabetes using an analysis of covariance (ANCOVA) model. Multiple regression analysis was performed to analyze the effect of factors on the distance from the SP to great vascular bifurcations. RESULTS: There were 20 cases of IIV variation (20.2%). VW was 28.8 ± 12.4 mm in the variant group and 39.6 ± 12.6 mm in the standard group (p = 0.001). In the ANCOVA model, IIV variations affected VW (coefficient, -11.8; 95% confidence interval [CI], -18.4 to -5.08, p < 0.001). Multivariate analysis revealed that the aorta-SP distance decreased with age (coefficient, -0.44; 95% CI, -0.77 to -0.11, p = 0.009). CONCLUSIONS: One in five women has a vascular variant at the SP that restricts the "safe" zone of fixation to < 3 cm.

Erdheim-Chester Disease With BRAF V600E Mutation and Central Diabetes Insipidus Successfully Treated With Glucocorticoid.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterized by xanthoma/xanthogranuloma infiltration in various organs and a broad spectrum of clinical presentations, including bone lesions, central diabetes insipidus and renal failure. BRAF V600E mutation is seen in almost half of the cases of ECD; the BRAF inhibitor vemurafenib is recommended treatment in the United States and the European Union. However, the indication for vemurafenib in Japan is limited to unresectable malignant melanoma with BRAF mutation. Although glucocorticoids, interferon, chemotherapy, and radiation therapy are treatment options, no standard therapy for ECD has yet been established in Japan. We describe here a patient with central diabetes insipidus and retroperitoneal lesions who was successfully treated with prednisolone. Glucocorticoid therapy is therefore a plausible alternative for ECD with BRAF V600E mutation when the BRAF inhibitor vemurafenib cannot be used.

Unmasked insulinoma occasioned by severe hypoglycemic coma immediately postpartum: a case report.

BACKGROUND: Insulinoma in women during pregnancy and postpartum is very rare; approximately 65% of cases are diagnosed early in pregnancy and ~ 35% immediately after delivery, few being found in middle or late pregnancy, likely due to increased insulin resistance seen after early-stage pregnancy. We successfully treated a case of insulinoma in which severe hypoglycemic coma immediately after delivery occasioned detailed investigation and diagnosis. CASE PRESENTATION: Our patient experienced hypoglycemic coma in the 3rd month of pregnancy (initially considered due to her hyperemesis gravidarum) that improved spontaneously during the gestational period. No abnormalities of plasma glucose or body weight were found in regular checkups during her pregnancy; however, recurrence of hypoglycemic coma after delivery led us to suspect insulinoma. While contrast enhanced computer tomography and endoscopic ultrasonography (EUS) initially failed to detect a tumor in the pancreas, selective arterial calcium stimulation test revealed an insulin-secreting tumor localized in the pancreatic body. She then underwent spleen-preserving distal pancreatectomy; a 10-mm tumor positive for chromogranin A, synaptophysin and insulin was identified. CONCLUSIONS: Although pregnancy can mask insulinoma-associated symptoms and make diagnosis challenging, hypoglycemic episodes during early pregnancy, which were observed in this case, are suggestive of insulinoma. Importantly, in this case, accurate preoperative localization of the tumor enabled prompt curative surgery after delivery. Thus, clinical vigilance for the occurrence of insulinoma and its localization is appropriate for pregnant women suffering severe hypoglycemia.

Effectiveness of countermeasure for polypharmacy by multidisciplinary team review in patients with diabetes mellitus.

AIMS/INTRODUCTION: Polypharmacy in diabetes patients is related to worse clinical outcomes. The aim of this study was to evaluate the usefulness of our countermeasure for polypharmacy, which combines a pharmacist check followed by a multidisciplinary team review in diabetic patients with polypharmacy. METHODS: A single-center, retrospective observational study was conducted at Gifu University Hospital. Study participants included diabetic patients taking six or more drugs on admission to the diabetes ward between July 2021 and June 2022. Drugs which were discontinued by the present countermeasure were examined, and the number of drugs being taken by each patient was compared between admission and discharge. RESULTS: 102 of 308 patients were taking six or more drugs on admission. The drugs being taken by these patients were evaluated by pharmacists using a checklist for polypharmacy. Eighty-four drugs which were evaluated as inappropriate or potentially inappropriate medications by pharmacists were discontinued following the multidisciplinary team review. The median and mean number of drugs taken by the 102 patients significantly decreased from 9.0 (IQR: 8-12) and 9.26 ± 2.64 on admission to 9.0 (IQR: 6-10) and 8.42 ± 2.95 on discharge (P = 0.0002). We followed up with these patients after discontinuation of the drugs and confirmed that their clinical status had not deteriorated. CONCLUSION: The present countermeasure for polypharmacy, which combines a pharmacist check based on a checklist for evaluating polypharmacy followed by a multidisciplinary team review, was useful for reducing the number of inappropriate or potentially inappropriate medications taken by diabetes patients with polypharmacy.

Two cases of systemic lupus erythematosus after administration of severe acute respiratory syndrome coronavirus 2 vaccine.

Although there is a great demand for increased coronavirus disease 2019vaccination worldwide, rare side effects of the vaccines in susceptible individuals are attracting attention. We recently treated two patients who developed systemic lupus erythematosus after administration of a severe acute respiratory syndrome coronavirus 2 vaccine from Pfizer-BioNTech or Moderna. While causal relationships between vaccination and adverse events are difficult to discern due to both confounding and masking factors, our findings suggest that attention to possible adjuvant-related autoimmune diseases in certain individuals receiving severe acute respiratory syndrome coronavirus 2 vaccines is appropriate.

Association of dipeptidyl peptidase-4 inhibitor use and risk of pancreatic cancer in individuals with diabetes in Japan.

AIMS/INTRODUCTION: This study was designed and carried out to investigate the association of dipeptidyl peptidase-4 inhibitor (DPP-4i) use with pancreatic cancer (PC) in individuals with diabetes in Japan. MATERIALS AND METHODS: The JMDC Claims Database, which contains the medical and prescription information of Japanese employment-based health insurance programs, was used. The primary outcome was duration to the first occurrence of PC (International Classification of Diseases 10th Revision code C25), both all and hospitalized, from prescription of DPP-4is or other oral glucose-lowering agents (GLAs). RESULTS: Individuals with diabetes who received DPP-4is (n = 61,430) or other oral GLAs (n = 83,304) were analyzed. Follow-up periods (median [interquartile range]) were 17 months (8-33) for DPP-4is and 14 months (7-28) for other oral GLAs. Kaplan-Meier curve analysis to determine the duration of first use of DPP4i or other oral GLA to diagnosis of PC disclosed no differences between the two groups in duration to all or hospitalized PC (log-rank test: all, P = 0.7140; hospitalized, P = 0.3446). Cox proportional hazards models showed that use of DPP-4is did not affect the PC risk adjusted for medications, age, sex and risk comorbidities (all, hazard ratio 1.1, 95% confidence interval 0.8-1.3, P = 0.6518; hospitalized, hazard ratio 1.1, 95% confidence interval 0.8-1.4, P = 0.6662). Similar results were obtained when individuals with ≥2 years oral GLA treatment and those with medical checkup data (e.g., smoking or drinking habit) available were analyzed. CONCLUSION: This database study shows that there is not a significant PC risk due to DPP-4i treatment in individuals with diabetes in Japan, but larger studies with longer follow up are required to confirm these findings.

Advances in insulin therapy from discovery to ß-cell replacement.

Insulin therapy using insulin purified from porcine or bovine pancreas revolutionized diabetes therapy in the 1920s. A series of advances including cloning human insulin cDNA enabled the development of recombinant human insulin with improved features. Insulin treatment for diabetes may well be upended by ß-cell replacement therapy in the coming decades.

Semaglutide is effective in type 2 diabetes and obesity with schizophrenia.

Background: Prevention and treatment of type 2 diabetes and obesity are problematic for individuals with schizophrenia partly because atypical antipsychotics and mental distress themselves increase appetite, thus promoting subsequent body weight gain and deterioration of glycemic control. Glucagon-like peptide-1 (GLP-1) receptor agonists have been gaining attention for their glucose-lowering and body weight-reducing effects in obese individuals with type 2 diabetes generally, but their effects in those also having schizophrenia have not been adequately addressed. Case presentation: This case was a 50-year-old obese woman having type 2 diabetes and schizophrenia. Although she was receiving oral anti-diabetes treatment, her HbA1c remained inadequately controlled (8.0-9.0%) partly due her difficulty in following instructions on heathy diet and exercise. In addition, she was repeatedly hospitalized due to suicide attempts by overdosing on her anti-psychotic and anti-diabetes drugs. Her HbA1c was elevated to as high as 10.2% despite the use of multiple anti-diabetes drugs including the GLP-1 receptor agonist dulaglutide, and she was hospitalized in our department. We chose the GLP-1 receptor agonist semaglutide to replace dulaglutide along with a multidisciplinary team approach that included a cognitive-behavioral therapist. The patient perceived that her hunger was suppressed when she started receiving semaglutide 0.5 mg. After discharge, semaglutide was remarkably more effective than dulaglutide in that it reduced and maintained the patient's HbA1c and body weight for 6 months after initiation of the drug. Conclusion: The GLP-1 receptor agonist semaglutide can be effective in maintaining appropriate control of glycemia and body weight in diabetes and obesity with schizophrenia.

A case of familial hypocalciuric hypercalcemia type 1 due to CASR p.Pro55Leu mutation.

BACKGROUND: Familial hypocalciuric hypercalcemia (FHH) is a rare autosomal dominant disease, which requires differential diagnosis from relatively common primary hyperparathyroidism (PHPT) in order to avoid unnecessary surgery. CASE PRESENTATION: A 16-year-old female had been followed by the department of psychosomatic medicine at our institution. Throughout the follow-up period, her plasma calcium levels were high, plasma Pi levels were relatively low, and plasma intact PTH was relatively high. She was referred to our department to determine the cause of her hypercalcemia. Her 24 h urinary calcium excretion was as low as 100 mg/day, and calcium creatinine clearance ratio was below 0.01. Moreover, she had a family history of hypercalcemia (proband, her brother, and her father). The genetic testing for her family revealed that she, her brother, and her father were definitively diagnosed with FHH type 1 due to the heterozygous calcium-sensing receptor mutation (NM_00388:4:c.164C > T:p.Pro55Leu). CONCLUSION: We experienced a 16-year-old female with FHH, in whom genetic testing identified the heterozygous calcium-sensing receptor mutation (NM_00388:4:c.164C > T:p.Pro55Leu) as pathogenic, permitting a definitive diagnosis of FHH type 1. The genetic testing for calcium sensing receptor is beneficial to distinguish asymptomatic primary hyperparathyroidism from FHH.

Graves' Disease after Administration of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccine in a Type 1 Diabetes Patient.

Although there is a great demand for increased coronavirus disease 2019 (COVID-19) vaccination worldwide, rare side effects of the vaccine in susceptible individuals are attracting attention. We recently treated a patient with type 1 diabetes who had HLA-A*240201/A*020101, B*5401/B*5601, DRB1*0405/DRB1*0405, DPB1*0501/DPB1*0501 and DQB1*0401/DQB1*040 and developed Graves' disease soon after the administration of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. While causal relationships between vaccinations and adverse events are difficult to discern due to both confounding and masking factors, our findings suggest that attention to possible adjuvant-related endocrinological diseases in certain individuals receiving SARS-CoV-2 vaccines is appropriate.

Cyclic Thiosulfonates for Thiol-Mediated Uptake: Cascade Exchangers, Transporters, Inhibitors.

Thiol-mediated uptake is emerging as a powerful method to penetrate cells. Cyclic oligochalcogenides (COCs) have been identified as privileged scaffolds to enable and inhibit thiol-mediated uptake because they can act as dynamic covalent cascade exchangers, i.e., every exchange produces a new, covalently tethered exchanger. In this study, our focus is on the essentially unexplored COCs of higher oxidation levels. Quantitative characterization of the underlying dynamic covalent exchange cascades reveals that the initial ring opening of cyclic thiosulfonates (CTOs) proceeds at a high speed even at a low pH. The released sulfinates exchange with disulfides in aprotic but much less in protic environments. Hydrophobic domains were thus introduced to direct CTOs into hydrophobic pockets to enhance their reactivity. Equipped with such directing groups, fluorescently labeled CTOs entered the cytosol of living cells more efficiently than the popular asparagusic acid. Added as competitive agents, CTOs inhibit the uptake of various COC transporters and SARS-CoV-2 lentivectors. Orthogonal trends found with different transporters support the existence of multiple cellular partners to account for the diverse expressions of thiol-mediated uptake. Dominant self-inhibition and high activity of dimers imply selective and synergistic exchange in hydrophobic pockets as distinguishing characteristics of thiol-mediated uptake with CTOs. The best CTO dimers with hydrophobic directing groups inhibit the cellular entry of SARS-CoV-2 lentivectors with an IC50 significantly lower than the previous best CTO, below the 10 µM threshold and better than ebselen. Taken together, these results identify CTOs as an intriguing motif for use in cytosolic delivery, as inhibitors of lentivector entry, and for the evolution of dynamic covalent networks in the broadest sense, with reactivity-based selectivity of cascade exchange emerging as a distinguishing characteristic that deserves further attention.

Pnictogen-Centered Cascade Exchangers for Thiol-Mediated Uptake: As(III)-, Sb(III)-, and Bi(III)-Expanded Cyclic Disulfides as Inhibitors of Cytosolic Delivery and Viral Entry.

Dynamic covalent exchange cascades with cellular thiols are of interest to deliver substrates to the cytosol and to inhibit the entry of viruses. The best transporters and inhibitors known today are cyclic cascade exchangers (CAXs), producing a new exchanger with every exchange, mostly cyclic oligochalcogenides, particularly disulfides. The objective of this study was to expand the dynamic covalent chalcogen exchange cascades in thiol-mediated uptake by inserting pnictogen relays. A family of pnictogen-expanded cyclic disulfides covering As(III), Sb(III), and Bi(III) is introduced. Their ability to inhibit thiol-mediated cytosolic delivery is explored with fluorescently labeled CAXs as transporters. The promise of inhibiting viral entry is assessed with SARS-CoV-2 lentiviral vectors. Oxygen-bridged seven-membered 1,3,2-dithiabismepane rings are identified as privileged scaffolds. The same holds for six-membered 1,3,2-dithiarsinane rings made from asparagusic acid and para-aminophenylarsine oxide, which are inactive or toxic when used alone. These chemically complementary Bi(III) and As(III) cascade exchangers inhibit both thiol-mediated cytosolic delivery and SARS-CoV-2 lentivector uptake at concentrations of 10 µM or lower. Crystal structures, computational models, and exchange kinetics support that lentivector entry inhibition of the contracted dithiarsinane and the expanded dithiabismepane rings coincides with exchange cascades that occur without the release of the pnictogen relay and benefit from noncovalent pnictogen bonds. The identified leads open perspectives regarding drug delivery as well as unorthodox approaches toward dynamic covalent inhibition of cellular entry.

Graves' Disease with Thymic Hyperplasia: The Response of the Thyroid Function, Thyrotropin Receptor Autoantibody, and Thymic Size to Thiamazole Treatment.

We treated a 22-year-old woman suffering from Graves' disease and thymic hyperplasia. She was referred to our institution for a close investigation of thyrotoxicosis and thymic mass. Thyroid tests and magnetic resonance imaging resulted in a diagnosis of Graves' disease and thymic hyperplasia. The thyroid function and thyroid-stimulating hormone receptor antibody (TRAb) were normalized one and five months after thiamazole initiation, respectively. The thymic size began to decrease after 1 month and was further decreased after 5 months; it was normalized after 12 months. The correlation between TRAb titers and the thymic size (R2=0.99) suggested that the patient's autoimmunity might have contributed to the thymic hyperplasia.

Total Synthesis of Resiniferatoxin Enabled by Photocatalytic Decarboxylative Radical Cyclization.

Resiniferatoxin (1) is a complex daphnane diterpenoid with a highly oxygenated 5/7/6-membered ABC-ring system. Here we report a new synthetic route to 1 that requires 27 steps from a starting d-ribose derivative. The carbon spacer and A-ring are sequentially attached to the C-ring by radical allylation and Stille coupling reactions, respectively. An Ir(III)-catalyzed photoinduced decarboxylative radical reaction then forged the sterically hindered bond between the tetra- and trisubstituted carbons to cyclize the central seven-membered B-ring.

Hypoglycemic coma in an elderly adult switched from twice-daily vildagliptin to once-daily glimepiride to improve drug adherence.

BACKGROUND: Elderly adults with diabetes are at increased risk of severe hypoglycemia and hypoglycemic coma due to various conditions including decline in cognitive function, reduced activity of daily living (ADL) and reduced renal function; special cautions are, therefore, recommended to avoid these life-threatening events. CASE PRESENTATION: A 92-year-old female was admitted to our institution because of severe coma. Upon arrival, her serum C-peptide was 1.64 ng/mL despite low plasma glucose (24 mg/dL) and serum glimepiride (40.85 ng/mL). She had past history of compression fracture of her lumbar spine, which substantially affected her ADL. Her score on the dementia assessment sheet for community-based integrated care system-8 items (DASC-8) was 26 points. She had been receiving 12 oral medications for diabetes, essential hypertension, chronic gastritis and constipation from her nearby clinic. Her physician-in-charge had found that she was not taking her medications properly and simplified her prescription regimen to 3 oral medications with vildagliptin 50 mg twice daily replaced by glimepiride 3 mg once daily and asked her son to assist in taking the drugs 6 days before her admission to our hospital. While her consciousness level was improved to some extent, she was transferred to a long-term care bed hospital because it had become too difficult to care for her at home. CONCLUSIONS: It is important to note that anti-diabetes drugs should be carefully selected based on each patient's cognitive function and ADL, and that the reasoning should be shared with the general practitioners involved to avoid severe hypoglycemic events. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-021-00510-9.

Differences in lower limb muscle strength and balance ability between sarcopenia stages depend on sex in community-dwelling older adults.

AIM: This study aimed to compare motor function between sarcopenia stages with respect to sex in community-dwelling older adults. METHODS: The participants, comprising 2107 community-dwelling older adults (738 men and 1369 women), were classified into 4 groups and the groups were operationally defined-normal, low muscle mass, low physical function, and sarcopenia groups. Lower limb muscle strength and balance ability were assessed for evaluating motor function. To compare motor function between sarcopenia stages, an analysis of covariance adjusted for age and body mass index was performed. RESULTS: Lower limb muscle strengths were significantly lower not only in the sarcopenia group but also in the low muscle mass and low physical function groups than that in the normal group in both men and women. Low hip abductor muscle strength was observed in the low physical function group compared to the low muscle mass group in women, but not in men. Timed Up and Go test results in the sarcopenia and low function groups was lower than in the normal and low muscle mass groups for men and women. One-leg standing in the low physical function group was lower than that in the normal group, only for women. CONCLUSIONS: Reduced motor function was observed not only in older people with sarcopenia but also in older people with only low muscle mass or low physical function, and the decline in lower limb muscle strength and balance ability in the low function group were greater in older women than in older men.

Glucokinase-maturity onset diabetes mellitus in the young suggested by factory-calibrated glucose monitoring data: a case report.

Glucokinase has an important role in regulating glycolysis as a glucose sensor in liver and pancreatic ß cells. Glucokinase-maturity onset diabetes in young (GCK-MODY also known as MODY2) is caused by autosomal dominant gene mutation of the GCK gene; it is characterized by mild fasting hyperglycemia and small 2-h glucose increment during 75 g-oral glucose tolerance test (OGTT) as well as near-normal postprandial glucose variabilities. A 10-year-old girl with family history of diabetes visited her physician after being found positive for urinary glucose by school medical checkup. She received a diagnosis of diabetes based on the laboratory data: 75 g-OGTT (mild fasting hyperglycemia and small 2-h glucose increment) and factory-calibrated glucose monitoring (mild elevation of average glucose level and near-normal glycemic variability), which raised suspicion of GCK-MODY. She was then referred to our institution for genetic examination, which revealed a GCK heterozygous mutation (NM_000162: exon10: c.1324G>T: p.E442X) in the proband as well as in her mother and maternal grandmother, who had been receiving anti-diabetes medications without knowing that they had GCK-MODY specifically. GCK-MODY cases show incidence of microvascular and macrovascular diseases similar to that of normal subjects, and their glucose levels are adequately controlled without anti-diabetes drug use. Thus, early and definitive diagnosis of MODY2 by genetic testing is important to avoid unnecessary medication.

Flipper Probes for the Community.

This article describes four fluorescent membrane tension probes that have been designed, synthesized, evaluated, commercialized and applied to current biology challenges in the context of the NCCR Chemical Biology. Their names are Flipper-TR®, ER Flipper-TR®, Lyso Flipper-TR®, and Mito Flipper-TR®. They are available from Spirochrome.