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Adjudication of inpatient AKI in the Systolic Blood Pressure Intervention Trial (SPRINT) was based on billing codes and admission and discharge notes. The purpose of this study was to evaluate the effect of intensive versus standard BP control on creatinine-based inpatient and outpatient AKI, and whether AKI was associated with cardiovascular disease (CVD) and mortality.We linked electronic health record (EHR) data from 47 clinic sites with trial data to enable creatinine-based adjudication of AKI. Cox regression was used to evaluate the effect of intensive BP control on the incidence of AKI, and the relationship between incident AKI and CVD and all-cause mortality.A total of 3644 participants had linked EHR data. A greater number of inpatient AKI events were identified using EHR data (187 on intensive versus 155 on standard treatment) as compared with serious adverse event (SAE) adjudication in the trial (95 on intensive versus 61 on standard treatment). Intensive treatment increased risk for SPRINT-adjudicated inpatient AKI (HR, 1.51; 95% CI, 1.09 to 2.08) and for creatinine-based outpatient AKI (HR, 1.40; 95% CI, 1.15 to 1.70), but not for creatinine-based inpatient AKI (HR, 1.20; 95% CI, 0.97 to 1.48). Irrespective of the definition (SAE or creatinine based), AKI was associated with increased risk for all-cause mortality, but only creatinine-based inpatient AKI was associated with increased risk for CVD.Creatinine-based ascertainment of AKI, enabled by EHR data, may be more sensitive and less biased than traditional SAE adjudication. Identifying ways to prevent AKI may reduce mortality further in the setting of intensive BP control.

Hemodialysis (HD) at home has gained increasing popularity in recent years because of regulatory and financial issues. Creation and maintenance of a well-functioning, cannulatable vascular access is essential for performance of home HD (HHD). A vascular access team-based approach to creation, maintenance, and troubleshooting of vascular access can facilitate removing barriers to cannulation at home related to fear of pain and bleeding associated with large bore needles. Frequent cannulation of HD access is associated with more frequent access complications, especially infections. Thus, proper cannulation of arteriovenous access requires careful training of rope ladder and buttonhole techniques to avoid infectious and traumatic complications that can lead to dire consequences. Development of better methods of creating buttonholes and single needles for dialysis can facilitate HHD. A culture of self-cannulation at dialysis centers can also promote HHD.

Background Early diagnosis is important for the timely treatment of gallbladder carcinoma (GBC) patients and may lead to increased survival outcomes. Here, we have applied serological proteome analysis (SERPA), an immunoproteomics approach, for the detection of ‘tumor-associated antigens (TAAs) that elicit humoral response’ in early stage GBC patients. Methods Total protein from pooled tumor tissue of GBC patients (n = 7) was resolved by two-dimensional gel electrophoresis (2-DE) followed by immunoblotting using pooled blood plasma from healthy volunteers (n = 11) or gallstone disease (GSD) cases (n = 11) or early stage GBC (Stage I and II) (n = 5) or GBC stage IIIA (n = 9). 2-D gel and immunoblot images were acquired and analyzed using PDQuest software to identify immunoreactive spots in GBC cases in comparison to controls. Proteins from immunoreactive spots were identified by liquid chromatography- tandem mass spectrometric analysis (LC-MS/MS). Autoantibody levels for two of the functionally relevant proteins were investigated in individual plasma samples (52 cases and 89 controls) by dot blot assay using recombinant proteins. Results Image analysis using PDQuest software identified 25 protein spots with significantly high or specific immunoreactivity in GBC cases. Mass spectrometric analysis of 8 corresponding protein spots showing intense immunoreactivity (based on densitometric analysis) in early stage GBC or GBC stage IIIA cases led to the identification of 27 proteins. Some of the identified proteins include ANXA1, HSPD1, CA1, CA2, ALDOA and CTSD. Among the two proteins, namely ANXA1 and HSPD1 verified using a cohort of samples, significantly elevated autoantibody levels against ANXA1 were observed in early stage GBC cases in comparison to healthy volunteers or GSD cases (unpaired t-test, p Conclusions The study suggests that the ANXA1 autoantibody levels against ANXA1 may be potentially employed for early stage detection of GBC patients. Other proteins could also be explored and verified in a large cohort of clinical samples.

Context Congenital generalized lipodystrophy, type 1 (CGL1), due to biallelic pathogenic variants in AGPAT2, is characterized by the near total loss of body fat from the face, trunk, and extremities. Patients develop premature diabetes, hypertriglyceridemia, hepatic steatosis, and polycystic ovary syndrome. However, sparing of the facial fat and precocious pubertal development has not been previously reported in CGL1. Case Description We report a 21-year-old woman of European descent with CGL1 who had sparing of the facial fat and premature thelarche at birth with premature pubarche and menstrual bleeding at age 3 years. Her serum 17-OH progesterone level rose to 1000 ng/dL (30.26 nmol/L) after cosyntropin stimulation test, suggestive of nonclassical congenital adrenal hyperplasia (NCAH) due to 21-hydroxylase deficiency. Hydrocortisone replacement therapy from age 3.5 to 10 years resulted in cessation of menstruation and growth of pubic hair, and a reduction of breast size. Sanger and whole-exome sequencing revealed compound heterozygous variants c.493-1G>C; p.(Leu165_Gln196del), and c.del366_588+534; p.(Leu123Cysfs*55) in AGPAT2 plus c.806G>C; p.(Ser269Thr) and c.844G>T; p.(Val282Leu) in CYP21A2. She developed diabetes at age 13 requiring high-dose insulin and had 7 episodes of acute pancreatitis due to extreme hypertriglyceridemia in the next 5 years. Metreleptin therapy was initiated at age 18 and after 3 years, she had remission of diabetes and hypertriglyceridemia; however, menstrual irregularity and severe hirsutism did not improve. Conclusion Concomitant NCAH in this CGL1 patient was associated with precocious pubertal development and sparing of facial fat. Metreleptin therapy drastically improved her hyperglycemia and hyperlipidemia but not menstrual irregularity and hirsutism.

End-stage kidney disease patients who are candidates for surgical arteriovenous fistula creation commonly experience obstacles to a functional surgical arteriovenous fistula, including protracted wait time for creation, poor maturation, and surgical arteriovenous fistula dysfunction that can result in significant patient morbidity. The recent approval of two endovascular devices designed to create a percutaneous arteriovenous fistula enables arteriovenous fistula creation to be placed in the hands of interventionalists, thereby increasing the number of arteriovenous fistula providers, reducing wait times, and allowing the patient to avoid surgery. Moreover, current studies demonstrate that patients with percutaneous arteriovenous fistula experience improved time to arteriovenous fistula maturation. Yet, in order to realize the potential advantages of percutaneous arteriovenous fistula creation within our hemodialysis patient population, it is critical to select appropriate patients, ensure adequate patient and dialysis unit education, and provide sufficient instruction in percutaneous arteriovenous fistula cannulation and monitoring. In this White Paper by the American Society of Diagnostic and Interventional Nephrology, experts in interventional nephrology, surgery, and interventional radiology convened and provide recommendations on the aforementioned elements that are fundamental to a functional percutaneous arteriovenous fistula.

Multiple genetic loci have been reported for progeroid syndromes. However, the molecular defects in some extremely rare forms of progeria have yet to be elucidated. Here, we report a 21-year-old man of Chinese ancestry who has an autosomal recessive form of progeria, characterized by severe dwarfism, mandibular hypoplasia, hyperopia, and partial lipodystrophy. Analyses of exome sequencing data from the entire family revealed only 1 rare homozygous missense variant (c.86CT; p.Pro29Leu) in TOMM7 in the proband, while the parents and 2 unaffected siblings were heterozygous for the variant. TOMM7, a nuclear gene, encodes a translocase in the outer mitochondrial membrane. The TOMM complex makes up the outer membrane pore, which is responsible for importing many preproteins into the mitochondria. A proteomic comparison of mitochondria from control and proband-derived cultured fibroblasts revealed an increase in abundance of several proteins involved in oxidative phosphorylation, as well as a reduction in abundance of proteins involved in phospholipid metabolism. We also observed elevated basal and maximal oxygen consumption rates in the fibroblasts from the proband as compared with control fibroblasts. We concluded that altered mitochondrial protein import due to biallelic loss-of-function TOMM7 can cause severe growth retardation and progeroid features.

Dysregulation of metabolism and utilization of iron can lead to the development and maintenance of anemia of CKD. Anemia is prevalent among patients with CKD. The markers of iron sufficiency or availability of iron are far from perfect which results in inaccurate diagnosis and treatment of anemia with poor outcomes. Hepcidin, a 25 amino acid peptide produced by the hepatocytes, has emerged as the key regulator of uptake and release of iron in the tissues to maintain a steady supply of iron to erythron and other tissues while avoiding higher levels of iron that could be detrimental to the organs. Hepcidin itself is regulated by the supply of iron, the need for erythropoiesis, and the state of inflammation. Alterations in hepcidin levels are associated with restricted erythropoiesis, anemia, and iron overload. Discovery of hepcidin and elucidation of its mechanism of action and consequences of its upregulation and suppression have unraveled important insight into many hematologic disorders including anemia of CKD. This knowledge has also unlocked unique opportunities to modulate hepcidin via agonists and antagonists of hepcidin and its feedback pathways to treat clinical conditions. Many such agents are being developed and have potential therapeutic utility in future.

In ultrasonic imaging, reduction of lateral sidelobes can result in an improved image with less distortion and fewer artifacts. In general, apodization is used to lower sidelobes in exchange for increasing the width of the main lobe, and thus decreasing lateral resolution. Null subtraction imaging (NSI) is a nonlinear image processing technique that uses different receive apodizations on copies of the same RF data to maintain low sidelobe levels while simultaneously improving lateral resolution. The images created with three different apodization functions are combined to form an image with low sidelobe levels and apparent improvements in lateral resolution compared to conventional rectangular apodization. To evaluate the performance of this technique for different imaging tasks, experiments were performed on an ATS539 phantom containing wire targets to assess lateral resolution and cylindrical anechoic and hyperechoic targets to assess contrast. NSI images were compared against rectangular apodized images and minimum variance beamformed images. In experiments, the apparent lateral resolution was observed to improve by a factor of more than $35\times $ when compared to rectangular apodization. Image quality was assessed by the estimation of lateral resolution (−6-dB receive beamwidth), main-lobe-to-sidelobe ratio, and contrast-to-noise ratio (CNR). Imaging with NSI using a focal number of 2 (f/2), the −6-dB beamwidth on receive as measured from a small wire target in the ATS phantom was $0.03\lambda $ compared to $2.79\lambda $ for rectangular apodization. Sidelobes were observed to decrease by 32.9 dB with NSI compared to rectangular apodization. However, the ability to observe the contrast of anechoic and hyperechoic targets reduced when utilizing the NSI scheme, i.e., the CNR decreased from −3.05 to −1.01 for anechoic targets and 1.65 to 0.45 for the hyperechoic targets.

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.

Background Most of the reported risk score models for coronavirus disease 2019 (COVID-19) mortality are based on the levels of inflammatory markers, comorbidities or various treatment modalities, and there is a paucity of risk score models based on clinical symptoms and comorbidities. Methods To address this need, age, clinical symptoms and comorbidities were used to develop a COVID-19 scoring system (CSS) for early prediction of mortality in severe COVID-19 patients. The CSS was developed with scores ranging from 0 to 9. A higher score indicates higher risk with good discrimination quality presented by Mann Whitney U test and area under receiver operating characteristic curve (AUROC). Results Patient age of ≥60 y, cough, breathlessness, diabetes and any other comorbidity (with or without diabetes) are significant and independent risk factors for non-survival among COVID-19 patients. The CSS showed good sensitivity and specificity (i.e. 74.1% and 78.5% at CSS≥5, respectively), with an overall diagnostic accuracy of 82.8%, which was close to the diagnostic accuracy detected in the validation cohort (81.9%). In the validation cohort, high (8–9), medium (5–7) and low (0–4) CSS groups had 54.80%, 28.60% and 6.5% observed mortality, respectively, which was very close to the predicted mortality (62.40%, 27.60% and 5.2%, respectively, by scoring cohort). Conclusions The CSS shows a positive relationship between a higher score and proportion of mortality and, as its validation showed, it is useful for the prediction of risk of mortality in COVID-19 patients at an early stage, so that referral for triage and admission can be predetermined even before admission to hospital.

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.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.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.Laparoscopic surgery for post-cholecystectomy BBS with an LRYHJ or LHD is feasible and safe and compares favourably with the open approach.

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.

Summary Background Closure of an abdominal stoma, a common elective operation, is associated with frequent complications; one of the commonest and impactful is incisional hernia formation. We aimed to investigate whether biological mesh (collagen tissue matrix) can safely reduce the incidence of incisional hernias at the stoma closure site. Methods In this randomised controlled trial (ROCSS) done in 37 hospitals across three European countries (35 UK, one Denmark, one Netherlands), patients aged 18 years or older undergoing elective ileostomy or colostomy closure were randomly assigned using a computer-based algorithm in a 1:1 ratio to either biological mesh reinforcement or closure with sutures alone (control). Training in the novel technique was standardised across hospitals. Patients and outcome assessors were masked to treatment allocation. The primary outcome measure was occurrence of clinically detectable hernia 2 years after randomisation (intention to treat). A sample size of 790 patients was required to identify a 40% reduction (25% to 15%), with 90% power (15% drop-out rate). This study is registered with ClinicalTrials.gov, NCT02238964. Findings Between Nov 28, 2012, and Nov 11, 2015, of 1286 screened patients, 790 were randomly assigned. 394 (50%) patients were randomly assigned to mesh closure and 396 (50%) to standard closure. In the mesh group, 373 (95%) of 394 patients successfully received mesh and in the control group, three patients received mesh. The clinically detectable hernia rate, the primary outcome, at 2 years was 12% (39 of 323) in the mesh group and 20% (64 of 327) in the control group (adjusted relative risk [RR] 0·62, 95% CI 0·43–0·90; p=0·012). In 455 patients for whom 1 year postoperative CT scans were available, there was a lower radiologically defined hernia rate in mesh versus control groups (20 [9%] of 229 vs 47 [21%] of 226, adjusted RR 0·42, 95% CI 0·26–0·69; p

Importance There are concerns with translating results from the Systolic Blood Pressure Intervention Trial (SPRINT) into clinical practice because the standardized protocol used to measure blood pressure (BP) may not be consistently applied in routine clinical practice. Objectives To evaluate the concordance between BPs obtained in routine clinical practice and those obtained using the SPRINT protocol and whether concordance varied by target trial BP. Design, setting, and participants This observational prognostic study linking outpatient vital sign information from electronic health records (EHRs) with data from 49 of the 102 SPRINT sites was conducted from November 8, 2010, to August 20, 2015, among 3074 adults 50 years or older with hypertension without diabetes or a history of stroke. Statistical analysis was performed from May 21, 2019, to March 20, 2020. Main outcomes and measures Blood pressures measured in routine clinical practice and SPRINT. Results Participant-level EHR data was obtained for 3074 participants (2482 men [80.7%]; mean [SD] age, 68.5 [9.1] years) with 3 or more outpatient and trial BP measurements. In the period from the 6-month study visit to the end of the study intervention, the mean systolic BP (SBP) in the intensive treatment group from outpatient BP recorded in the EHR was 7.3 mm Hg higher (95% CI, 7.0-7.6 mm Hg) than BP measured at trial visits; the mean difference between BP recorded in the outpatient EHR and trial SBP was smaller for participants in the standard treatment group (4.6 mm Hg [95% CI, 4.4-4.9 mm Hg]). Bland-Altman analyses demonstrated low agreement between outpatient BP recorded in the EHR and trial BP, with wide agreement intervals ranging from approximately -30 mm Hg to 45 mm Hg in both treatment groups. In addition, the difference between BP recorded in the EHR and trial BP varied widely by site. Conclusions and relevance Outpatient BPs measured in routine clinical practice were generally higher than BP measurements taken in SPRINT, with greater mean SBP differences apparent in the intensive treatment group. There was a consistent high degree of heterogeneity between the BPs recorded in the EHR and trial BPs, with significant variability over time, between and within the participants, and across clinic sites. These results highlight the importance of proper BP measurement technique and an inability to apply 1 common correction factor (ie, approximately 10 mm Hg) to approximate research-quality BP estimates when BP is not measured appropriately in routine clinical practice. Trial registration SPRINT ClinicalTrials.gov Identifier: NCT01206062.

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.

The International Summit on Laparoscopic Pancreatic Resection (ISLPR) was held in Coimbatore, India, on 7th and 8th of October 2016 and thirty international experts who regularly perform laparoscopic pancreatic resections participated in ISPLR from four continents, i.e., South and North America, Europe and Asia. Prior to ISLPR, the first conversation among the experts was made online on August 26th, 2016 and the structures of ISPLR were developed. The aims of ISPLR were; i) to identify indications and optimal case selection criteria for minimally invasive pancreatic resection (MIPR) in the setting of both benign and malignant diseases; ii) standardization of techniques to increase the safety of MIPR; iii) identification of common problems faced during MIPR and developing associated management strategies; iv) development of clinical protocols to allow early identification of complications and develop the accompanying management plan to minimize morbidity and mortality. As a process for interactive discussion, the experts were requested to complete an online questionnaire consisting of 65 questions about the various technical aspects of laparoscopic pancreatic resections. Two further web-based meetings were conducted prior to ISPLR. Through further discussion during ISPLR, we have created productive statements regarding the topics of Disease, Implementation, Patients, Techniques, and Instrumentations (DIPTI) and hereby publish them as “Coimbatore Summit Statements”.

BackgroundLaparoscopic surgery has traditionally been contraindicated for the management of gall bladder cancer (GBC). This study was undertaken to determine the safety and feasibility of a laparoscopic radical cholecystectomy (LRC) for GBC and compare it with an open radical cholecystectomy (ORC).MethodsRetrospective analysis of primary GBC patients (with limited liver infiltration) and incidental GBC (IGBC) patients (detected after a laparoscopic cholecystectomy) who underwent LRC between June 2011 and October 2013. Patients who fulfilled the study criteria and underwent ORC during the same period formed the control group.ResultsDuring the study period, 147 patients with GBC underwent a radical cholecystectomy. Of these, 24 patients (primary GBC– 20, IGBC – 4) who underwent a LRC formed the study group (Group A). Of the remaining 123 patients who underwent ORC, 46 matched patients formed the control group (Group B). The median operating time was higher in Group A (270 versus 240 mins, P= 0.021) and the median blood loss (ml) was lower (200 versus 275 ml, P= 0.034). The post-operative morbidity and mortality were similar (P= 1.0). The pathological stage of the tumour in Group A was T1b (n = 1), T2 (n = 11) and T3 (n = 8), respectively. The median lymph node yield was 10 (4–31) and was comparable between the two groups (P=0.642). During a median follow-up of 18 (6–34) months, 1 patient in Group A and 3 in Group B developed recurrence. No patient developed a recurrence at a port site.ConclusionLRC is safe and feasible in selected patients with GBC, and the results were comparable to ORC in this retrospective comparison.

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. The present study aims to compare physicians’ perspectives on the influence of spirituality and religion (S/R) on health between Brazil, India, and Indonesia. 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. 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. 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.

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.

Background: Favorable outcomes of laparoscopic surgery for gallbladder cancer (GBC) have been reported; yet consensus on the indications and surgical techniques for laparoscopic surgery for GBC is lacking. Objective: To evaluate the current status of laparoscopic surgery for GBC by analyzing the results of a survey of experts and by reviewing the relevant published literature. Methods: Before an expert meeting was held on September 10, 2016 in Seoul, Korea, an international survey was undertaken of expert surgeons in the field of GBC surgery. Results: The majority of surgeons who responded agreed that laparoscopic surgery has an acceptable role for suspicious or early GBC, and that laparoscopic extended cholecystectomy has a value comparable to that of open surgery in selected patients with GBC. However, the selection criteria for laparoscopic surgery for overt GBC and the details of the surgical techniques varied among surgeons. Conclusions: This survey and literature review revealed that laparoscopic surgery for GBC is performed in highly selected cases. However, the favorable outcomes in the published reports and the positive view of experienced surgeons for this operative procedure suggest a high likelihood that laparoscopic surgery will be more frequently performed for GBC in the future.

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.

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. Therefore, we 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.

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.

Background Involvement of the 16b1 (interaortocaval) lymph node (LN) in gallbladder cancer (GBC) is considered to represent metastatic disease. Although this is universally accepted, the role of routine frozen-section histopathological examination (HPE) of the 16b1 LN in the management of GBC has not been previously reported. Methods A prospective study (August 2009–November 2011) using routine biopsy of 16b1 LNs and frozen-section HPE prior to radical resection in patients deemed operable on preoperative evaluation and staging laparoscopy was carried out. Results Of the 451 GBC patients assessed, 251 (55.7%) were deemed operable on preoperative imaging. Of these, 68 (27.1%) were found to have disseminated disease on staging laparoscopy/laparotomy. Of the 183 patients in whom 16b1 LN biopsy was performed, 34 (18.6%) had evidence of metastases on frozen-section HPE and the planned surgical resection was abandoned (Group A). Of the remaining 149 patients (Group B), 142 (95.3%) underwent curative resection and seven (4.7%) were found to be unresectable as a result of locoregionally advanced disease. A comparison of findings in Group A with those in Group B showed no significant difference in the clinical stage of the tumour. The proportions of patients with jaundice, elevated carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 levels were significantly higher in Group A than in Group B (P = 0.008, P = 0.012 and P = 0.023, respectively). Conclusions Routine 16b1 LN biopsy prevented non-therapeutic radical resection and its associated morbidity in 18.6% of patients deemed resectable on preoperative imaging and staging laparoscopy. The yield was higher in patients with jaundice and elevated preoperative tumour marker levels.

Mass-forming xanthogranulomatous cholecystitis (XGC), an uncommon inflammatory pathology of gallbladder (GB), masquerades as gallbladder cancer (GBC) and diagnosis is often a histological surprise. A retrospective analysis of prospectively collected database of patients with GB mass operated between August 2009 and September 2012 was conducted to determine clinical, radiological, and intraoperative findings that might aid in the preoperative diagnosis of mass-forming XGC and ascertain their optimal management strategy. Of the 566 patients with GB mass and suspected GBC, 239 were found to be inoperable on preoperative workup and 129 patients had unresectable disease on staging laparoscopy/laparotomy. Of the 198 with resectable disease, 31 were reported as XGC on final histopathology (Group A), while 167 were GBC (Group B). Of these 31 patients, six with an intraoperative suspicion of benign pathology underwent cholecystectomy with segments IVb and V resection, and frozen section histopathology. Twenty-five underwent radical cholecystectomy, with (n = 10) or without (n = 15) adjacent organ resection. In comparison, anorexia and weight loss were significantly more in Group B (p = 0.001 and

Topical capsaicin and eutectic mixture of local anesthetics (EMLA) have been found to be equally effective in minimizing the pain of venipuncture. After the injection of capsaicin, both tertiary amine local anesthetics and their quaternary ammonium derivatives can elicit a prolonged and predominantly sensory/nociceptor selective block. We hypothesized that the combined application of capsaicin and ELMA will be more effective than their individual effect, and lower concentrations of individual drugs in this mixture may also be associated with reduced side effects.One hundred twenty patients were randomized into 4 equal groups. The control group received plain lubricant cream; the EMLA group received EMLA cream; the capsaicin group received Myolaxin ointment (containing oleoresin capsaicin equivalent to capsaicin 0.075% w/w, methylsalicylate IP 20% w/w, menthol IP 10% w/w, camphor USP 5% w/w, and eucalyptus oil IP 5% w/w); and the EMLA + capsaicin group received EMLA cream and Myolaxin ointment mixed in equal amounts. An anesthesiologist applied the cream to a 10-cm(2) area (site of venous cannulation) on the dorsum of the nondominant hand of the patient 1 hour before venipuncture and covered the area with an occlusive transparent dressing. Venipuncture was performed with an 18-gauge cannula after removing the dressing. Venipuncture pain was graded by the patient on a 0 to 10 visual analog scale, where 0 means no pain and 10 means worst imaginable pain. P values (after correction for multiple comparisons) of0.05 were considered significant.The incidence of no pain on venous cannulation (primary end point) was 0% in the control group (0/30). The incidence of no pain were significantly higher in the EMLA group (32%, 9/28, 95% corrected confidence interval for the difference 12%-57%, P = 0.0025), capsaicin group (30%, 9/30, 10%-53%, P = 0.0031), and EMLA + capsaicin groups (47%, 14/30, 25%-69%, P0.0001). Severity of venipuncture pain as assessed by visual analog scale median (interquartile range) was lower in the EMLA + capsaicin group 1 (2) compared with other groups 3 (1), 1.5 (3), and 1.5 (3) for control, EMLA, and capsaicin, respectively (P0.001, P = 0.04, and P = 0.04, respectively).We observed that the combination of capsaicin and EMLA in a low concentration is as effective in managing venous cannulation as when applied as an individual drug alone. Larger studies with varying concentration of capsaicin and EMLA are recommended to more fully evaluate the potential advantages.

The results of cardiomyotomy in patients of achalasic megaesophagus with axis deviation are not satisfactory, and several authors have advocated an esophagectomy in these patients. We describe the technical details and outcomes of a novel technique of laparoscopic esophagogastroplasty for end-stage achalasia. Patients with end-stage achalasia, characterized by tortuous megaesophagus were selected. The surgery was performed in supine position using five abdominal ports. The steps included mobilization of the gastroesophageal junction and lower intrathoracic esophagus, straightening and anchoring the pulled intrathoracic esophagus into the abdomen, and a side-side esophagogastroplasty. Four patients with megaesophagus due to end-stage achalasia underwent this procedure. The average duration of surgery was 177.5 (range, 120–240) min. All patients could be ambulated on the first postoperative day. Oral feeding was initiated by the third postoperative day, and all patients had significant improvements in their dysphagia scores. All patients had excellent cosmetic results and were discharged by the fifth postoperative day. An upper gastrointestinal contrast study done at 6 weeks after surgery did not show any hold up of contrast, and there was decrease in the convolutions and diameter of the esophagus. At a mean follow-up of 10.5 (range, 3–15) months, all patients are euphagic without significant symptoms of gastroesophageal reflux. Laparoscopic esophagogastroplasty is an effective option for relieving dysphagia in megaesophagus due to achalasia with axis deviation and is a reasonable alternative before subjecting to a major and potentially morbid esophagectomy.

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.

Introduction Chronic central venous catheters (CVC) for dialysis lose patency and deliver lower blood flow over time, often due to fibrous sheathing that covers the lumen tips. The CentrosFLO central venous catheter has a shape that directs the arterial and venous tips away from the walls of the vena cava and right atrium, making sheathing of the tips less likely. Methods A prospective, multicenter, single arm, non-controlled, observational study was conducted at eight sites in the United States. All consenting dialysis patients receiving CentrosFLO catheters through the right or left internal jugular veins were accepted in the study, as long as the catheter was expected to be used for 45 days and was not an over-the-wire replacement for a previous CVC. Data were automatically collected on initial and average dialysis blood flow rate and initial arterial and venous pressures, for up to 26 weeks of dialysis therapy. Findings 75 patients were enrolled. Kaplan-Meier analysis indicated that 87% of patients maintained blood flow rate over 300 mL/min throughout 26 weeks of follow-up. There was no decline in average dialysis blood flow rate and no significant change in hydraulic resistance of the arterial or venous lumens of the catheters during the study. Discussion The CentrosFLO catheter demonstrates long term patency with good flow rates on dialysis, which, by comparison with previous studies, shows a clinically significant improvement in blood flow rate vs. other catheters. Stable hydraulic resistance of the catheter lumens showed no evidence of tip encroachment by fibrous sheaths.

Over the past several years, many more isoforms for the same enzymes, specifically for 1-acylglycerol-3-phosphate O-acyltransferases (AGPATs), have been cloned and studied. In this review, we summarize their biochemical features and discuss their functional role.The most significant role of these AGPATs appeared from our observation of AGPAT2 in the biology of adipose tissue (adipocytes) in humans and mice. Other isoforms are shown to be implicated in lung, reproductive and cardiac muscle function and in the cause of cancer. In-vitro substrate specificities of these AGPATs also suggest the in-vivo role of these AGPATs in remodeling of several of the glycerophospholipids.Despite significant progress in understanding the role of these AGPATs, much is still to be discovered in terms of how each of these AGPATs function in the presence or absence of other AGPATs and what their functional role might be.

ObjectivesTraditionally, a gallbladder removed for presumed benign disease has been sent for histopathological examination (HPE), but this practice has been the subject of controversy. This study was undertaken to compare patients in whom gallbladder cancer (GBC) was diagnosed after cholecystectomy on HPE with GBC patients in whom the gallbladder was not sent for HPE and who therefore presented late with symptoms.MethodsA retrospective analysis of prospectively collected data for 170 GBC patients diagnosed after cholecystectomy was conducted. All patients presented to one centre during 2000–2011. These patients were divided into two groups based on the availability of histopathology reports: Group A included patients who presented early with HPE reports (n=93), and Group B comprised patients who presented late with symptoms and without HPE reports (n=77).ResultsThe median time to presentation in Group A was significantly lower than in Group B (29days vs. 152days; P

Hydatid disease of the liver is endemic in India and is a common health problem. Although various treatment options have been described ranging from pharmacotherapy to radiological interventions and surgical procedures (both conservative and radical), the best treatment option in an individual case continues to be debated. We did a retrospective analysis of patients with hydatid disease of the liver who were managed at our centre between January 2000 and December 2009. All cysts were classified as per the Gharbi’s classification. The various treatment options used to treat hydatid cysts of the liver included percutaneous aspiration, injection and reaspiration (PAIR) or PAIR with drainage (PAIR-D) and surgery (both conservative and radical). The immediate and long-term outcomes following such management were analysed. During the study period, 128 patients with hydatid cyst of the liver were managed with PAIR/PAIR-D (n = 52), radical/excisional surgery (n = 61) and conservative surgery (n = 33). In ten patients, the PAIR procedure was abandoned due to either bile or pultaceous material aspirated after the initial puncture and these patients subsequently underwent surgical management. The PAIR was unsuccessful in eight of the 42 patients in whom it was attempted and these subsequently underwent surgery. The mean intraoperative blood loss and the duration of surgery were comparable in patients who underwent either conservative or radical surgery (p = 0.35 and 0.19, respectively). Postoperative bile leaks and cavity abscesses were significantly higher in patients who underwent conservative surgery (p = 0.032 and p = 0.001, respectively). Five patients (one following a radical operation and four following a conservative surgery, p = 0.05) developed recurrence in a mean follow-up period of 28 months and these were managed medically. Several treatment options are available for the management of hydatid disease of the liver and the treatment modality chosen should be tailored to the individual patient. While percutaneous drainage (with PAIR/PAIR-D) is reserved for more favourable cases of type I and II cysts, the others are best managed surgically. Complete excision (cystopericstectomy or resection) of the hydatid cyst is the preferred approach and 61 of the 94 patients who were managed surgically were suitable for it. Although excisional surgery minimizes the risk of long-term recurrence and cavity-related complications, it may be hazardous in cysts located close to major biliovascular channels. In these cases (considering that it is benign disease), a drainage operation is preferable. Both conservative and radical surgery can be safely performed laparoscopically.

The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA). In this study, we show enzymatic properties, tissue distribution, and subcellular localization of human AGPAT3 and AGPAT5. In cells overexpressing these isoforms, the proteins were detected in the nuclear envelope and the endoplasmic reticulum. AGPAT5-GFP fusion protein was localized in the mitochondria of both Chinese hamster ovary and human epithelial cervical cancer cells. Using lysates of AD293 cells infected with AGPAT3 and AGPAT5 recombinant adenovirus, we show that AGPAT3 and AGPAT5 proteins have AGPAT activity. Both the isoforms have similar apparent V(max) of 6.35 and 2.42 nmol/min/mg protein, respectively, for similar LPA. The difference between the two isoforms is in their use of additional lysophospholipids. AGPAT3 shows significant esterification of lysophosphatidylinositol (LPI) in the presence of C20:4 fatty acid, whereas AGPAT5 demonstrates significant acyltransferase activity toward lysophosphatidylethanolamine (LPE) in the presence of C18:1 fatty acid. The AGPAT3 mRNA is ubiquitously expressed in human tissues with several-fold differences in the expression pattern compared with the closely related AGPAT4. In summary, we show that in the presence of different fatty acids, AGPAT3 and AGPAT5 prefer different lysophospholipids as acyl acceptors. More importantly, localization of overexpressed AGPAT5 (this study) as well as GPAT1 and 2 (previous studies) in mitochondria supports the idea that the mitochondria might be capable of synthesizing some of their own glycerophospholipids.

We performed homozygosity mapping in two recently reported pedigrees from Portugal and Mexico with an autosomal-recessive autoinflammatory syndrome characterized by joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP). This revealed only one homozygous region spanning 2.4 Mb (5818 SNPs) on chromosome 6p21 shared by all three affected individuals from both families. We directly sequenced genes involved in immune response located in this critical region, excluding the HLA complex genes. We found a homozygous missense mutation c.224C>T (p.Thr75Met) in the proteasome subunit, beta-type, 8 (PSMB8) gene in affected patients from both pedigrees. The mutation segregated in an autosomal-recessive fashion and was not detected in 275 unrelated ethnically matched healthy subjects. PSMB8 encodes a catalytic subunit of the 20S immunoproteasomes called β5i. Immunoproteasome-mediated proteolysis generates immunogenic epitopes presented by major histocompatibility complex (MHC) class I molecules. Threonine at position 75 is highly conserved and its substitution with methionine disrupts the tertiary structure of PSMB8. As compared to normal lymphoblasts, those from an affected patient showed significantly reduced chymotrypsin-like proteolytic activity mediated by immunoproteasomes. We conclude that mutations in PSMB8 cause JMP syndrome, most probably by affecting MHC class I antigen processing.

Restrictive dermopathy (RD) results in stillbirth or early neonatal death. RD is characterized by prematurity, intrauterine growth retardation, fixed facial expression, micrognathia, mouth in the 'o' position, rigid and tense skin with erosions and denudations and multiple joint contractures. Nearly all 25 previously reported neonates with RD had homozygous or compound heterozygous null mutations in the ZMPSTE24 gene. Here, we report three new cases of RD; all died within 3 weeks of birth. One of them had a previously reported homozygous c.1085dupT (p.Leu362PhefsX19) mutation, the second case had a novel homozygous c.1020GA (p.Trp340X) null mutation in ZMPSTE24, but the third case, a stillborn with features of RD except for the presence of tapering rather than rounded, bulbous digits, harbored no disease-causing mutations in LMNA or ZMPSTE24. In the newborn with a novel ZMPSTE24 mutation, unique features included butterfly-shaped thoracic 5 vertebra and the bulbous appearance of the distal clavicles. Skin biopsies from both the stillborn fetus and the newborn with c.1020GA ZMPSTE24 mutation showed absence of elastic fibers throughout the dermis. This report provides evidence of genetic heterogeneity among RD and concludes that there may be an additional locus for RD which remains to be identified.

The conversion of lysophosphatidic acid (LPA) to phosphatidic acid is carried out by the microsomal enzymes 1-acylglycerol-3-phosphate-O-acyltransferases (AGPATs). These enzymes are specific for acylating LPA at the sn-2 (carbon 2) position on the glycerol backbone and are important, because they provide substrates for the synthesis of phospholipids and triglycerides. At least, mutations in one isoform, AGPAT2, cause near complete loss of adipose tissue in humans. We cloned a cDNA predicted to be an AGPAT isoform, AGPAT11. This cDNA has been recently identified also as lysophosphatidylcholine acyltransferase 2 (LPCAT2) and lyso platelet-activating factor acetyltransferase. When AGPAT11/LPCAT2/lyso platelet-activating factor acetyltransferase cDNA was expressed in CHO and HeLa cells, the protein product localized to the endoplasmic reticulum. In vitro enzymatic activity using lysates of Human Embryonic Kidney-293 cells infected with recombinant AGPAT11/LPCAT2/lyso platelet-activating factor-acetyltransferase cDNA adenovirus show that the protein has an AGPAT activity but lacks glycerol-3-phosphate acyltransferase enzymatic activity. The AGPAT11 efficiently uses C18:1 LPA as acyl acceptor and C18:1 fatty acid as an acyl donor. Thus, it has similar substrate specificities for LPA and acyl-CoA as shown for AGPAT9 and 10. Expression of AGPAT11 mRNA was significantly upregulated in human breast, cervical, and colorectal cancer tissues, indicating its adjuvant role in the progression of these cancers. Our enzymatic assays strongly suggest that the cDNA previously identified as LPCAT2/lyso platelet-activating factor-acetyltransferase cDNA has AGPAT activity and thus we prefer to identify this clone as AGPAT11 as well.

A 43-year-old woman presented with right upper abdominal pain, on and off for 3–4 years. One year prior to her presentation, a space-occupying lesion was found in the right lobe of the liver, which was suspected to be hemangioma, as the patient had history of combined oral contraceptive pill use for the last 15 years. On examination, she was thinly built and had pallor; abdominal examination revealed tender hepatomegaly 3 cm below the costal margin, smooth surface, sharp regular edge with left lobe enlargement, and no bruit. All routine biochemical and hematologic investigations were normal, except hemoglobin of 7.6 gm/dl. On triple-phase CT scan, there were hypodense ill-defined lobulated area in right lobe of liver; similar lesions were also seen in segments V and VII of liver along with a few sub-diaphragmatic and para-aortic nodes. Liver biopsy showed features suggestive of hemangioendothelioma, and immunohistochemistry showed CD 31 and CD 34 positivity but negative for estrogen receptors. Laparoscopy revealed presence of multiple deposits on left lobe of liver and ascites. Tumor was unresectable, and the patient was found to be a candidate for liver transplant. Chemoembolization was tried as a palliation awaiting transplant, but the procedure was unsuccessful due to the hypovascular nature of the tumor. The patient died within 4 months of diagnosis due to liver failure, awaiting liver transplant, as a suitable donor was not available. A clinical suspicion based on demographics, risk factors and imaging, familiarity with the pathologic findings, and utilization of advanced imaging techniques may allow early diagnosis of these tumors and hence their appropriate management.

The adipocytes synthesize and store triglycerides as lipid droplets surrounded by various proteins and phospholipids at its surface. Recently, the molecular basis of some of the genetic syndromes of lipodystrophies has been elucidated and some of these genetic loci have been found to contribute to lipid droplet formation in adipocytes. The two main types of genetic lipodystrophies are congenital generalized lipodystrophy (CGL) and familial partial lipodystrophy (FPL). So far, three CGL loci: 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2), Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) and caveolin 1 (CAV1) and four FPL loci: lamin A/C (LMNA), peroxisome proliferator-activated receptor gamma (PPARG), v-AKT murine thymoma oncogene homolog 2 (AKT2) and zinc metalloprotease (ZMPSTE24), have been identified. AGPAT2 plays a critical role in the synthesis of glycerophospholipids and triglycerides required for lipid droplet formation. Another protein, seipin (encoded by BSCL2 gene), has been found to induce lipid droplet fusion. CAV1 is an integral component of caveolae and might contribute towards lipid droplet formation. PPARgamma and AKT2 play important role in adipogenesis and lipid synthesis. In this review, we discuss and speculate about the contribution of various lipodystrophy genes and their products in the lipid droplet formation.

Anemia of chronic kidney disease due to deficiency of erythropoietin is common and has clinical consequences. Erythropoiesis stimulating agents including darbepoetin alfa (DA) are effective in correcting anemia. DA is generally well tolerated and has side effect profile similar to recombinant human erythropoietin. It has a long half-life permitting infrequent dosing. DA has been tested extensively in preclinical and clinical studies and significant experience has accumulated in clinical practice. Global safety profile of DA must consider recent data indicating worse survival, poor cardiovascular outcomes and thrombotic risks of targeting near normal hemoglobin levels and administering high doses of erythropoiesis stimulating agents. Strategies to achieve and maintain a reasonable, individualized target hemoglobin level with minimal variations in hemoglobin level are needed.

Context: Mandibuloacral dysplasia (MAD) is a rare autosomal recessive progeroid syndrome due to mutations in genes encoding nuclear lamina proteins, lamins A/C (LMNA) or prelamin A processing enzyme, and zinc metalloproteinase (ZMPSTE24).Objective: The aim of the study was to investigate the underlying genetic and molecular basis of the phenotype of a 7-yr-old girl with MAD belonging to a consanguineous pedigree and with severe progeroid features and lipodystrophy.Design and Patient: The patient developed mandibular hypoplasia during infancy and joint stiffness, skin thinning, and mottled hyperpigmentation at 15 months. Progressive clavicular hypoplasia, acroosteolysis, and severe loss of hair from the temporal and occipital areas were noticed at 3 yr. At 5 yr, cranial sutures were still open and lipodystrophy of the limbs was prominent. GH therapy from the ages of 3–7 yr did not improve the short stature. Severe joint contractures resulted in abnormal posture and decreased mobility. We studied her skin fibroblasts for nuclear morphology and immunoblotting and determined the in vitro effects of various pharmacological interventions on fibroblasts.Results: LMNA gene sequencing revealed a homozygous missense mutation, c.1579C>T, p.Arg527Cys. Immunoblotting of skin fibroblast lysate with lamin A/C antibody revealed no prelamin A accumulation. Immunofluorescence staining of the nuclei for lamin A/C in fibroblasts revealed marked nuclear morphological abnormalities. This abnormal phenotype could not be rescued with inhibitors of farnesyl transferase, geranylgeranyl transferase, or histone deacetylase.Conclusion: Severe progeroid features in MAD could result from LMNA mutation, which does not lead to accumulation of prenylated lamin A or prelamin A.

Congenital generalized lipodystrophy (CGL) is a rare auto-somal recessive disorder characterized by extreme paucity of adipose tissue from birth, and early onset of metabolic complications related to insulin resistance. Mutations in three genes, 1-acylglycerol 3-phosphate-O-acyltransferase 2 (AGPAT2), Berardinelli Seip Congenital Lipodystrophy 2 (BSCL2), and Caveolin-1 (CAV1) are associated with the three subtypes of this disorder, CGL1, CGL2 and CGL3, respectively. We report two siblings of Hispanic origin who displayed characteristic features of CGL such as generalized loss of subcutaneous fat from birth, acanthosis nigricans, acromegaloid habitus, umbilical prominence, hepatosplenomegaly, hypoleptinemia, dyslipidemia, and insulin resistance. However, no disease causing variants were detected in the DNA sequence of AGPAT2, BSCL2 or CAV1 genes. Further, whole body magnetic resonance imaging (MRI) in the two siblings revealed marked loss of subcutaneous, intraabdominal and intrathoracic fat like in other patients with CGL, but preservation of bone marrow fat which is invariably lost in all patients with CGL1 and CGL2, but not in the patient reported with CGL3. They also had generalized muscle weakness during infancy and early childhood associated with a nearly fivefold increase in serum creatine kinase (CK) levels, but with normal muscle biopsy and electrophysiologic studies. Both patients were also found to have atlantoaxial dislocation requiring surgical intervention. Thus, this pedigree represents a novel subtype of CGL characterized by generalized loss of body fat but with preservation of bone marrow fat, congenital muscular weakness and cervical spine instability. The genetic basis of this novel subtype remains to be determined.

Background Splenic vein thrombosis leading to sinistral portal hypertension and variceal bleeding is a complication of chronic pancreatitis. The management of these patients without variceal bleeding remains controversial. Methods A total of 157 patients with chronic pancreatitis were managed consecutively in our center between January 1996 and December 2005. Thirty-four patients with chronic pancreatitis were diagnosed to have splenic vein thrombosis. Results The incidence of splenic vein thrombosis in patients with chronic pancreatitis was 22%. Fifteen percent of patients with chronic pancreatitis and splenic vein thrombosis presented with gastroesophageal variceal bleeding. Nine patients underwent splenectomy along with pancreatic procedures and 21 patients underwent pancreatic procedures only. Adding splenectomy to the pancreatic procedure did not lead to increased morbidity or mortality. Conclusion Splenectomy should be added to the pancreatic procedure in patients who have evidence of portal hypertension on preoperative evaluation, especially if gastric varices are found.

Patients with advanced chronic kidney disease are at a high risk of cardiovascular events. Patients with end-stage renal disease have a particularly high morbidity and mortality, in part attributed to the complications and dysfunction related to vascular access in this population. Creation of an arteriovenous access for HD is considered standard of care for most patients and has distinct advantages including less likelihood of infections, less need for intervention, and positive impact on survival as compared with usage of a catheter. However, creation of an arteriovenous shunt incites a series of events that significantly impacts cardiovascular and neurohormonal health in both positive and negative ways. This article will review the short- and long-term effects of dialysis access on cardiovascular, neurohormonal, and pulmonary systems as well as a brief review of their effect on survival on HD. Presence of other comorbidities in a patient with dialysis access can amplify these effects, and these considerations are of paramount importance in individualizing the approach to not only the choice of vascular access but also the modality of kidney replacement therapy.

Lack of adipose tissue, either complete or partial, is the hallmark of disorders known as lipodystrophies. Patients with lipodystrophies suffer from metabolic complications similar to those associated with obesity, including insulin resistance, type 2 diabetes, hypertriglyceridemia, and hepatic steatosis. The loss of body fat in inherited lipodystrophies can be caused by defects in the development and/or differentiation of adipose tissue as a consequence of mutations in a number of genes, including PPARG (encoding a nuclear hormone receptor), AGPAT2 (encoding an enzyme involved in the biosynthesis of triglyceride and phospholipids), AKT2 (encoding a protein involved in insulin signal transduction), and BSCL2 (encoding seipin, whose role in the adipocyte biology remains unclear). The loss of body fat can also be caused by the premature death of adipocytes due to mutations in lamin A/C, nuclear lamina proteins, and ZMPSTE24, which modifies the prelamin A post-translationally. In this review, we focus on the molecular basis of inherited lipodystrophies as they relate to adipocyte biology and their associated phenotypic manifestations.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder normally caused by a spontaneous heterozygous mutation in the LMNA gene that codes for the nuclear lamina protein lamin A. Several enzymes are involved in the processing of its precursor, prelamin A, to the mature lamin A. A functional knockout of one of the enzymes involved in prelamin A processing, the zinc metalloprotease ZMPSTE24, causes an even more severe disorder with early neonatal death described as restrictive dermatopathy (RD). This work describes a HGPS patient with a combined defect of a homozygous loss-of-function mutation in the ZMPSTE24 gene and a heterozygous mutation in the LMNA gene that results in a C-terminal elongation of the final lamin A. Whereas the loss of function mutation of ZMPSTE24 normally results in lethal RD, the truncation of LMNA seems to be a salvage alteration alleviating the clinical picture to the HGPS phenotype. The mutations of our patient indicate that farnesylated prelamin A is the deleterious agent leading to the HGPS phenotype, which gives further insights into the pathophysiology of the disorder.

We present an anatomic variation of type IIIA thumb hypoplasia in which a tendinous interconnection between the flexor pollicis longus and the extensor pollicis longus occurred on the ulnar aspect of the thumb. Interconnection between extrinsic flexor and extensor systems is well known in type IIIA thumb hypoplasia and has been reported on the radial side (pollex abductus). In our patient the ulnar location of the interconnection remained unrecognized until recurrence of the deformity in adolescence.

Selective loss of body fat is the hallmark of patients with lipodystrophies. Among genetic lipodystrophies, fat loss is observed either from birth, as in congenital generalized lipodystrophy, or later in life, as in familial partial lipodystrophy. The extent of fat loss also varies among subtypes of lipodystrophies. Patients develop hyperinsulinemia, acanthosis nigricans, hypertriglyceridemia, diabetes mellitus, and hepatic steatosis. Defects in several genes, such as those encoding an enzyme (AGPAT2), a nuclear receptor (PPARγ), a nuclear lamina protein (LMNA) and its processing endoprotease (ZMPSTE24), a kinase (AKT2), and a protein of unknown function (BSCL2), have been found in patients with genetic lipodystrophies. Additional loci remain to be discovered. We discuss features of autosomal recessive and dominant types of lipodystrophies and therapeutic interventions available for these patients.