Xanthogranulomatous cholecystitis with histologic features suggestive of IgG4 related cholecystitis - A morphologic overlap with IgG4 related disease.

AIMS: Both xanthogranulomatous cholecystitis (XGC) and IgG4-related cholecystitis (IgG4-CC) are rare chronic fibroinflammatory tumefactive diseases of the gallbladder, which cause a strong confusion with resectable malignancy in view of their mass forming tendency with extension into the liver. We aim to study the histopathologic features of xanthogranulomatous cholecystitis with regard to IgG4-related cholecystitis in extended cholecystectomy specimens. METHODS AND RESULTS: Sixty cases of extended cholecystectomy with liver wedge resection, diagnosed as XGC on histopathology from January 2018 to December 2021 were retrieved from the archives. Representative sections were reviewed by two pathologists independently. Immunohistochemistry was performed for IgG4 and IgG4/IgG was derived. The cases were dichotomized in two groups on the basis of IgG4 positive plasma cells. Six cases with >50 IgG4 positive plasma cells had storiform fibrosis, IgG4/IgG ratio >0.40 and extra-cholecystic extension. Of these, 50 % had obliterative phlebitis and 66.7 % had perineural plasma cell wrapping. CONCLUSIONS: A small subset of XGC cases (~10 %) had morphologic overlap with IgG4-CC, but should not be overcalled as the diagnosis of IgG4-RD requires an integrative approach based on clinical, serologic and imaging criteria and not solely on histopathology.

Discovery of MDV6058 (PF-06952229), a selective and potent TGFßR1 inhibitor: Design, synthesis and optimization.

Compound 1 is a potent TGF-ß receptor type-1 (TGFßR1 or ALK5) inhibitor but is metabolically unstable. A solvent-exposed part of this molecule was used to analogue and modulate cell activity, liver microsome stability and mouse pharmacokinetics. The evolution of SAR that led to the selection of 2 (MDV6058 / PF-06952229) as a preclinical lead compound is described.

Bi-allelic POLR3A Loss-of-Function Variants Cause Autosomal-Recessive Wiedemann-Rautenstrauch Syndrome.

Wiedemann-Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome, is a rare disorder of unknown etiology. It has been proposed to be autosomal-recessive and is characterized by variable clinical features, such as intrauterine growth restriction and poor postnatal weight gain, characteristic facial features (triangular appearance to the face, convex nasal profile or pinched nose, and small mouth), widened fontanelles, pseudohydrocephalus, prominent scalp veins, lipodystrophy, and teeth abnormalities. A previous report described a single WRS patient with bi-allelic truncating and splicing variants in POLR3A. Here we present seven additional infants, children, and adults with WRS and bi-allelic truncating and/or splicing variants in POLR3A. POLR3A, the largest subunit of RNA polymerase III, is a DNA-directed RNA polymerase that transcribes many small noncoding RNAs that regulate transcription, RNA processing, and translation. Bi-allelic missense variants in POLR3A have been associated with phenotypes distinct from WRS: hypogonadotropic hypogonadism and hypomyelinating leukodystrophy with or without oligodontia. Our findings confirm the association of bi-allelic POLR3A variants with WRS, expand the clinical phenotype of WRS, and suggest specific POLR3A genotypes associated with WRS and hypomyelinating leukodystrophy.

Identification and structure-activity relationship studies of small molecule inhibitors of the human cathepsin D.

Cathepsin D, an aspartyl protease, is an attractive therapeutic target for various diseases, primarily cancer and osteoarthritis. However, despite several small molecule cathepsin D inhibitors being developed, that are highly potent, most of them show poor microsomal stability, which in turn limits their clinical translation. Herein, we describe the design, optimization and evaluation of a series of novel non-peptidic acylguanidine based small molecule inhibitors of cathepsin D. Optimization of our hit compound 1a (IC50 = 29 nM) led to the highly potent mono sulphonamide analogue 4b (IC50 = 4 nM), however with poor microsomal stability (HLM: 177 and MLM: 177 µl/min/mg). To further improve the microsomal stability while retaining the potency, we carried out an extensive structure-activity relationship screen which led to the identification of our optimised lead 24e (IC50 = 45 nM), with an improved microsomal stability (HLM: 59.1 and MLM: 86.8 µl/min/mg). Our efforts reveal that 24e could be a good starting point or potential candidate for further preclinical studies against diseases where Cathepsin D plays an important role.

Laparoscopic versus open surgery for the management of post-cholecystectomy benign biliary strictures.

BACKGROUND AND AIM: Surgical management by a bilioenteric anastomosis is the standard for the repair of post-cholecystectomy benign biliary strictures (BBS). This is traditionally done as an open operation. There are a few reports describing the procedure by a laparoscopic technique. The aim of the present study was to describe our experience of laparoscopic bilio-enteric anastomosis [Roux-en-Y hepaticojejunostomy (LRYHJ)/laparoscopic hepaticoduodenostomy (LHD)] in the management of post-cholecystectomy BBS and compare the outcomes with our patients operated by the open approach. METHODS: Retrospective analysis of prospective data of post-cholecystectomy BBS patients treated by laparoscopic bilio-enteric anastomosis. The outcomes were compared with patients who underwent an open repair. RESULTS: Between January 2016 and February 2019, 63 patients underwent surgery for post-cholecystectomy BBS. Twenty-nine patients who underwent laparoscopic bilio-enteric anastomosis (LRYHJ-13, LHD-16) were compared with 34 patients who underwent an open repair. The median age (40 vs 39) years, type of index surgery [laparoscopic cholecystectomy (13 vs 15), laparoscopic converted to open cholecystectomy (10 vs 16), and open cholecystectomy (6 vs 3)], type of injury low stricture (7 vs 5) and high stricture (22 vs 29), preoperative biliary fistula (23 vs 30), and time from injury to repair (6 vs 7 months) were similar in the 2 groups. The median duration of surgery was also similar (210 vs 200 min, p = 0.937); however, the median intraoperative blood loss (50 mL vs 200 mL, p = 0.001), time to resume oral diet (2 vs 4 days p = 0.023),** and median duration of postoperative hospital stay (6 vs 8 days, p = 0.001) were significantly less in the laparoscopy group. Overall morbidity rate (within 30 days post-surgery) was significantly higher in the open repair group (38% vs 20%). In a subgroup analysis of the laparoscopic repair group, the operative time in patients who underwent an LHD was significantly less than LRYHJ (190 vs 230 min, p = 0.034). The other parameters like the mean intraoperative blood loss, time to initiate oral diet, duration of postoperative hospital stay, and incidence of postoperative bile leak were similar. Patients undergoing open repair had a median follow-up of 26 months with two developing anastomotic stenosis and those undergoing laparoscopic repair had a median follow-up for 9 months with one developing anastomotic stenosis. CONCLUSION: Laparoscopic surgery for post-cholecystectomy BBS with an LRYHJ or LHD is feasible and safe and compares favourably with the open approach.

Insights into lipid accumulation in skeletal muscle in dysferlin-deficient mice.

Loss of dysferlin (DYSF) protein in humans results in limb-girdle muscular dystrophy 2B, characterized by progressive loss of muscles in the distal limbs with impaired locomotion. The DYSF-null (Bla/J) mouse develops severe steatotic muscles upon aging. Here, we report a marked increase in adipocytes, especially in the psoas and gluteus muscles but not in the soleus and tibialis anterior muscles in aged Bla/J mice compared with WT mice. There was a robust upregulation in the mRNA expression of enzymes involved in lipogenesis and triacylglycerol (TAG) synthesis pathways in the steatotic skeletal muscles. Lipidomic analysis of the steatotic skeletal muscles revealed an increase in several molecular species of TAG, although it is unclear whether it was at the expense of phosphatidylcholine and phosphatidylserine. The adipocytes in steatotic muscles were extramyocellular, as determined by the increased expression of caveolin 1 (a cellular marker for adipocytes) and lipid-droplet protein, perilipin 1. This increase in adipocytes occured as a consequence of the loss of myocytes.

Innovations in vascular access for hemodialysis.

Worldwide, hemodialysis remains the prevalent dialysis modality for more than 2 million patients who require well-functioning vascular access for this procedure. Creation of an arteriovenous fistula for long-term hemodialysis was the first innovation since the Scribner shunt and was followed by the development of an arteriovenous graft and catheter. Bioengineered vessels were developed during the last century, but this field has been energized by recent technology relating to the creation of human vessels. Novel endovascular techniques for creating an arteriovenous fistula may resolve some of the logistical issues involved in obtaining a timely arteriovenous fistula. Treatment of access stenosis, infection, and thrombosis has remained suboptimal, and innovative technologies are evolving. Many new approaches are now targeting the biological and mechanical aspects of vascular access, such as creation and maturation of arterial and venous anastomoses, development of a biological conduit for outflow, and negotiating the problems of central vein stenosis. Importantly, processes of access care that have long focused on arteriovenous fistulas are now recognizing the new paradigm, providing a complementary niche to arteriovenous grafts and dialysis catheters in the algorithm for individualized access placement. Cumulatively, to the credit of the multidisciplinary team approach, the long overdue focus on the very existential issue of vascular access for hemodialysis is being approached with newfound evidence-based enthusiasm as the vexing challenges related to regulations and reimbursement in hemodialysis persist. Patient choice and experience, often missed and ignored in the challenging management of an end-stage organ failure, need to stay central as we focus on patient-centered care of vascular access.

Avoiding problems in tunneled dialysis catheter placement.

Tunneled dialysis catheters (TDCs) remain the predominant vascular access for initiation of hemodialysis (HD) worldwide. TDCs are also utilized in a significant number of prevalent patients for continuation of dialysis and during the periods of complications related to arteriovenous (AV) accesses. TDC placement is a routine procedure, but can be associated with mechanical and infectious complications related to placement. Imaging guidance with ultrasound and fluoroscopy has made the placement of TDC safer and more successful. Adequate operator training, careful technique, utilization of a checklist, and barrier precautions are essential to avoid problems related to TDC placement.

Laparoscopic Surgery for Gallbladder Cancer: An Expert Consensus Statement.

BACKGROUND: Despite the increasing number of reports on the favorable outcomes of laparoscopic surgery for gallbladder cancer (GBC), there is no consensus regarding this surgical procedure. OBJECTIVE: The study aimed to develop a consensus statement on the application of laparoscopic surgery for GBC based on expert opinions. METHODS: A consensus meeting among experts was held on September 10, 2016, in Seoul, Korea. RESULTS: Early concerns regarding port site/peritoneal metastasis after laparoscopic surgery have been abated by improved preoperative recognition of GBC and careful manipulation to avoid bile spillage. There is no evidence that laparoscopic surgery is associated with decreased survival compared with open surgery in patients with early-stage GBC if definitive resection during/after laparoscopic cholecystectomy is performed. Although experience with laparoscopic extended cholecystectomy for GBC has been limited to a few experts, the postoperative and survival outcomes were similar between laparoscopic and open surgeries. Laparoscopic reoperation for postoperatively diagnosed GBC is technically challenging, but its feasibility has been demonstrated by a few experts. CONCLUSIONS: Laparoscopic surgery for GBC is still in the early phase of the adoption curve, and more evidence is required to assess this procedure.

Vascular access of last resort.

Exhausted vasculature is not uncommon in patients receiving long-term hemodialysis treatment. Certain patients exhaust their peripheral veins and do not retain the venous capital necessary for fistula creation. Others suffer from severe peripheral arterial disease and despite the presence of adequate venous capital are not able to receive an arteriovenous access successfully. Most importantly, in the case of occluded central veins, the creation of an arteriovenous access in the arms or thighs would be futile, even if peripheral veins and/or arteries were available. Because renal transplant is not readily available, such patients virtually face death in the absence of dialysis therapy. Hence, it is critically important that vascular access options be available to successfully receive renal replacement therapy. This article describes accesses of last resort and provides information vital to nephrologists for discussion with their patients and to surgeons in choosing an optimal option.

Complications of Vascular Access: Superior Vena Cava Syndrome.

Stenosis or occlusion of central veins in hemodialysis patients is common, especially with previous intravascular catheter or device use. Superior vena cava (SVC) obstruction is emerging as a frequent chronic complication of central vein cannulation that not only jeopardizes the availability of vascular access for hemodialysis, but can become a life-threatening emergency. Clinical features of SVC syndrome can be subtle or dramatic, including facial swelling and shortness of breath, which require expeditious attention and intervention. The approach to SVC syndrome involves judicious use of imaging techniques to define the cause and location. Early management with endovascular intervention with angioplasty and stent placement is the usual first choice. The occlusion can often be recanalized using new techniques such as radiofrequency wire and then salvaged with stents, providing prompt resolution of symptoms. Limitations to interventions include requirement of cutting-edge equipment, expertise, expense, and the usually temporary nature of the resolution. Surgery is considered the treatment of last resort for refractory cases. SVC syndrome can be prevented by minimizing catheter and intravascular device use through early recognition of patients with chronic kidney disease, early referral for education about all choices for kidney replacement modalities, and early placement of arteriovenous access prior to the onset of dialysis therapy.

Juvenile-onset generalized lipodystrophy due to a novel heterozygous missense LMNA mutation affecting lamin C.

The LMNA gene contains 12 exons and encodes lamins A and C by alternative splicing within exon 10. While mutations in lamin A specific residues cause several diseases including lipodystrophy, progeria, muscular dystrophy, neuropathy, and cardiomyopathy, only three families with mutations in lamin C-specific residues are reported with cardiomyopathy, neuropathy, and muscular dystrophy so far. We now report two brothers with juvenile-onset generalized lipodystrophy due to a lamin C-specific mutation. The proband, a 23-year-old Caucasian male was reported to have generalized lipodystrophy at 3 weeks of age, developed diabetes, hypertriglyceridemia, hypertension and liver problems and died with complications of cirrhosis, and kidney failure. His younger brother, a 37-year-old Caucasian male developed generalized lipodystrophy around 2 years of age and was diagnosed with diabetes, hypertriglyceridemia, fatty liver, and hypertension at 36 years of age. Their father also died of end stage renal disease at age 52 years. Exome sequencing of the proband revealed an extremely rare missense heterozygous variant c.1711_1712CG>TC; p.(Arg571Ser) in LMNA which was confirmed by Sanger sequencing in both the patients. Interestingly, the mutation had no effect on mRNA splicing or relative expression of lamin A or C mRNA and protein in the lymphoblasts. Our observations suggest that mutant lamin C disrupts its interaction with other cellular proteins resulting in generalized lipodystrophy due to defective development and maintenance of adipose tissue.

Design, synthesis and optimization of bis-amide derivatives as CSF1R inhibitors.

Signaling via the receptor tyrosine kinase CSF1R is thought to play an important role in recruitment and differentiation of tumor-associated macrophages (TAMs). TAMs play pro-tumorigenic roles, including the suppression of anti-tumor immune response, promotion of angiogenesis and tumor cell metastasis. Because of the role of this signaling pathway in the tumor microenvironment, several small molecule CSF1R kinase inhibitors are undergoing clinical evaluation for cancer therapy, either as a single agent or in combination with other cancer therapies, including immune checkpoint inhibitors. Herein we describe our lead optimization effort that resulted in the identification of a potent, cellular active and orally bioavailable bis-amide CSF1R inhibitor. Docking and biochemical analysis allowed the removal of a metabolically labile and poorly permeable methyl piperazine group from an early lead compound. Optimization led to improved metabolic stability and Caco2 permeability, which in turn resulted in good oral bioavailability in mice.

Mogat1 deletion does not ameliorate hepatic steatosis in lipodystrophic (Agpat2-/-) or obese (ob/ob) mice.

Reducing triacylglycerol (TAG) in the liver continues to pose a challenge in states of nonalcoholic hepatic steatosis. MonoacylglycerolO-acyltransferase (MOGAT) enzymes convert monoacylglycerol (MAG) to diacylglycerol, a precursor for TAG synthesis, and are involved in a major pathway of TAG synthesis in selected tissues, such as small intestine. MOGAT1 possesses MGAT activity in in vitro assays, but its physiological function in TAG metabolism is unknown. Recent studies suggest a role for MOGAT1 in hepatic steatosis in lipodystrophic [1-acylglycerol-3-phosphateO-acyltransferase (Agpat)2(-/-)] and obese (ob/ob) mice. To test this, we deletedMogat1in theAgpat2(-/-)andob/obgenetic background to generateMogat1(-/-);Agpat2(-/-)andMogat1(-/-);ob/obdouble knockout (DKO) mice. Here we report that, despite the absence ofMogat1in either DKO mouse model, we did not find any decrease in liver TAG by 16 weeks of age. Additionally, there were no measureable changes in plasma glucose (diabetes) and insulin resistance. Our data indicate a minimal role, if any, of MOGAT1 in liver TAG synthesis, and that TAG synthesis in steatosis associated with lipodystrophy and obesity is independent of MOGAT1. Our findings suggest that MOGAT1 likely has an alternative function in vivo.

Spirituality, Religiosity, and Health: a Comparison of Physicians' Attitudes in Brazil, India, and Indonesia.

BACKGROUND: One of the biggest challenges in the spirituality, religiosity, and health field is to understand how patients and physicians from different cultures deal with spiritual and religious issues in clinical practice. PURPOSE: The present study aims to compare physicians' perspectives on the influence of spirituality and religion (S/R) on health between Brazil, India, and Indonesia. METHOD: This is a cross-sectional, cross-cultural, multi-center study carried out from 2010 to 2012, examining physicians' attitudes from two continents. Participants completed a self-rated questionnaire that collected information on sociodemographic characteristics, S/R involvement, and perspectives concerning religion, spirituality, and health. Differences between physicians' responses in each country were examined using chi-squared, ANOVA, and MANCOVA. RESULTS: A total of 611 physicians (194 from Brazil, 295 from India, and 122 from Indonesia) completed the survey. Indonesian physicians were more religious and more likely to address S/R when caring for patients. Brazilian physicians were more likely to believe that S/R influenced patients' health. Brazilian and Indonesians were as likely as to believe that it is appropriate to talk and discuss S/R with patients, and more likely than Indians. No differences were found concerning attitudes toward spiritual issues. CONCLUSION: Physicians from these different three countries had very different attitudes on spirituality, religiosity, and health. Ethnicity and culture can have an important influence on how spirituality is approached in medical practice. S/R curricula that train physicians how to address spirituality in clinical practice must take these differences into account.

Minimally invasive oesophagectomy in prone versus lateral decubitus position: A comparative study.

BACKGROUND: Thoracoscopic oesophageal mobilisation during a minimally invasive oesophagectomy (MIE) is most commonly performed with the patient placed in the lateral decubitus position (LDP). The prone position (PP) for thoracoscopic oesophageal mobilisation has been proposed as an alternative. MATERIALS AND METHODS: This was a retrospective, comparative study designed to compare early outcomes following a minimally invasive thoracolaparoscopic oesophagectomy for oesophageal cancer in LDP and in PP. RESULTS: During the study period, between January 2011 and February 2014, 104 patients underwent an oesophagectomy for cancer. Of these, 42 were open procedures (transhiatal and transthoracic oesophagectomy) and 62 were minimally invasive. The study group included patients who underwent thoracolaparoscopic oesophagectomy in LDP (n = 23) and in PP (n = 25). The median age of the study population was 55 (24-71) years, and there were 25 males. Twenty-one (21) patients had tumours in the middle third of the oesophagus, 24 in the lower third, and 3 arising from the gastro-oesophageal junction. The most common histology was squamous cell cancer (85.4%). The median duration of surgery was similar in the two groups; however, the estimated median intraoperative blood loss was less in the PP group [200 (50-400) mL vs 300 (100-600) mL; P = 0.01)]. In the post-operative period, 26.1% patients in the LDP group and 8% in the PP group (8%) developed respiratory complications. The incidence of other post-operative complications, including cervical oesophagogastric anastomosis, hoarseness of voice and chylothorax, was not different in the two groups. The T stage of the tumour was similar in the two groups, with the majority (37) having T3 disease. A mean of 8 lymph nodes (range 2-33) were retrieved in the LDP group, and 17.5 (range 5-41) lymph nodes were retrieved in the PP group (P = 0.0004). The number of patients with node-positive disease was also higher in the PP group (19 vs 10, P = 0.037). CONCLUSION: MIE in the PP is an effective alternative to LDP. The exposure obtained is excellent even without the need for a complete lung collapse, thereby obviating the need for a double-lumen endotracheal tube. A more meticulous dissection can be performed resulting in a higher lymph nodal yield.

Hepatic gluconeogenesis is enhanced by phosphatidic acid which remains uninhibited by insulin in lipodystrophic Agpat2-/- mice.

In this study we examined the role of phosphatidic acid (PA) in hepatic glucose production (HGP) and development of hepatic insulin resistance in mice that lack 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2). Liver lysophosphatidic acid and PA levels were increased ∼2- and ∼5-fold, respectively, in male Agpat2(-/-) mice compared with wild type mice. In the absence of AGPAT2, the liver can synthesize PAs by activating diacylglycerol kinase or phospholipase D, both of which were elevated in the livers of Agpat2(-/-) mice. We found that PAs C16:0/18:1 and C18:1/20:4 enhanced HGP in primary WT hepatocytes, an effect that was further enhanced in primary hepatocytes from Agpat2(-/-) mice. Lysophosphatidic acids C16:0 and C18:1 failed to increase HGP in primary hepatocytes. The activation of HGP was accompanied by an up-regulation of the key gluconeogenic enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. This activation was suppressed by insulin in the WT primary hepatocytes but not in the Agpat2(-/-) primary hepatocytes. Thus, the lack of normal insulin signaling in Agpat2(-/-) livers allows unrestricted PA-induced gluconeogenesis significantly contributing to the development of hyperglycemia in these mice.

Whole exome sequencing identifies de novo heterozygous CAV1 mutations associated with a novel neonatal onset lipodystrophy syndrome.

Despite remarkable progress in identifying causal genes for many types of genetic lipodystrophies in the last decade, the molecular basis of many extremely rare lipodystrophy patients with distinctive phenotypes remains unclear. We conducted whole exome sequencing of the parents and probands from six pedigrees with neonatal onset of generalized loss of subcutaneous fat with additional distinctive phenotypic features and report de novo heterozygous null mutations, c.424C>T (p.Q142*) and c.479_480delTT (p.F160*), in CAV1 in a 7-year-old male and a 3-year-old female of European origin, respectively. Both the patients had generalized fat loss, thin mottled skin and progeroid features at birth. The male patient had cataracts requiring extraction at age 30 months and the female patient had pulmonary arterial hypertension. Dermal fibroblasts of the female patient revealed negligible CAV1 immunofluorescence staining compared to control but there were no differences in the number and morphology of caveolae upon electron microscopy examination. Based upon the similarities in the clinical features of these two patients, previous reports of CAV1 mutations in patients with lipodystrophies and pulmonary hypertension, and similar features seen in CAV1 null mice, we conclude that these variants are the most likely cause of one subtype of neonatal onset generalized lipodystrophy syndrome.

Correlations of portal pressure in post-cholecystectomy benign biliary stricture.

AIM: Presence of portal hypertension (PH) adversely affects perioperative and long-term outcome in patients with post-cholecystectomy benign biliary stricture (PCBBS). Identification of factors related to the development of PH will help to prevent this complication. METHODS: From September 2010 to December 2012, 30 patients with PCBBS were studied prospectively for correlation of portal pressure (PP) with injury repair interval (IRI), biliary pressure (BP), severity of hepatic fibrosis (FS), severity of hepatic inflammation (IS) and obstructive biliary pathology score (OBPS). Appropriate statistical methods employed and P ≤ 0.05 (two-sided) was considered statistically significant. RESULTS: Mean PP, mean BP and median IRI were 19.4 ± 4.74 mmHg, 20.1 ± 3.99 mmHg and 145 days, respectively. Spearman's rank correlation coefficients (P-value) of PP with IRI, FS, IS and OBPS were 0.564 (0.001), 0.502 (0.004), 0.752 (0.0001) and 0.242 (0.19), respectively. Pearson correlation of PP with BP was r = 0.383 (r(2) = 0.146, P = 0.03). Spearman's rank correlation coefficients (P-value) of FS with IS and OBPS were 0.561 (0.003) and 0.371 (0.04), respectively. Spearman's rank correlation coefficient of serum bilirubin with OBPS was 0.550 (P = 0.001). Incidence of PH was 33.3% and mean fall of PP following biliary repair was 6.2 ± 1.98 mmHg (P < 0.0001). CONCLUSION: PP in patients with PCBBS has a good correlation with IS, and a fair correlation with both FS and IRI whereas PP was not directly related to BP and OBPS; further prospective trials are mandatory to confirm this correlation, and to evaluate mechanism of fall in PP following biliary decompression.