Sulfide oxidation promotes hypoxic angiogenesis and neovascularization.

Angiogenic programming in the vascular endothelium is a tightly regulated process for maintaining tissue homeostasis and is activated in tissue injury and the tumor microenvironment. The metabolic basis of how gas signaling molecules regulate angiogenesis is elusive. Here, we report that hypoxic upregulation of ·NO in endothelial cells reprograms the transsulfuration pathway to increase biogenesis of hydrogen sulfide (H2S), a proangiogenic metabolite. However, decreased H2S oxidation due to sulfide quinone oxidoreductase (SQOR) deficiency synergizes with hypoxia, inducing a reductive shift and limiting endothelial proliferation that is attenuated by dissipation of the mitochondrial NADH pool. Tumor xenografts in whole-body (WBCreSqorfl/fl) and endothelial-specific (VE-cadherinCre-ERT2Sqorfl/fl) Sqor-knockout mice exhibit lower mass and angiogenesis than control mice. WBCreSqorfl/fl mice also exhibit decreased muscle angiogenesis following femoral artery ligation compared to control mice. Collectively, our data reveal the molecular intersections between H2S, O2 and ·NO metabolism and identify SQOR inhibition as a metabolic vulnerability for endothelial cell proliferation and neovascularization.

Electronic Nicotine Delivery Systems and Cardiovascular/Cardiometabolic Health.

The use of electronic nicotine delivery systems, specifically electronic cigarettes (e-cig), has risen dramatically within the last few years; the demographic purchasing these devices is now predominantly adolescents that are not trying to quit the use of traditional combustible cigarettes, but rather are new users. The composition and appearance of these devices has changed since their first entry into the market in the late 2000s, but they remain composed of a battery and aerosol delivery system that is used to deliver breakdown products of propylene glycol/vegetable glycerin, flavorings, and potentially nicotine or other additives. Manufacturers have also adjusted the type of nicotine that is used within the liquid to make the inhalation more palatable for younger users, further affecting the number of youth who use these devices. Although the full spectrum of cardiovascular and cardiometabolic consequences of e-cig use is not fully appreciated, data is beginning to show that e-cigs can cause both short- and long-term issues on cardiac function, vascular integrity and cardiometabolic issues. This review will provide an overview of the cardiovascular, cardiometabolic, and vascular implications of the use of e-cigs, and the potential short- and long-term health effects. A robust understanding of these effects is important in order to inform policy makers on the dangers of e-cigs use.

Genomic description of acquired fluconazole- and echinocandin-resistance in patients with serial Candida glabrata isolates.

Candida glabrata is one of the most common causes of systemic candidiasis, often resistant to antifungal medications. To describe the genomic context of emerging resistance, we conducted a retrospective analysis of 82 serially collected isolates from 33 patients from population-based candidemia surveillance in the United States. We used whole-genome sequencing to determine the genetic relationships between isolates obtained from the same patient. Phylogenetic analysis demonstrated that isolates from 29 patients were clustered by patient. The median SNPs between isolates from the same patient was 30 (range: 7-96 SNPs), while unrelated strains infected four patients. Twenty-one isolates were resistant to echinocandins, and 24 were resistant to fluconazole. All echinocandin-resistant isolates carried a mutation either in the FKS1 or FKS2 HS1 region. Of the 24 fluconazole-resistant isolates, 17 (71%) had non-synonymous polymorphisms in the PDR1 gene, which were absent in susceptible isolates. In 11 patients, a genetically related resistant isolate was collected after recovering susceptible isolates, indicating in vivo acquisition of resistance. These findings allowed us to estimate the intra-host diversity of C. glabrata and propose an upper boundary of 96 SNPs for defining genetically related isolates, which can be used to assess donor-to-host transmission, nosocomial transmission, or acquired resistance. IMPORTANCE In our study, mutations associated to azole resistance and echinocandin resistance were detected in Candida glabrata isolates using a whole-genome sequence. C. glabrata is the second most common cause of candidemia in the United States, which rapidly acquires resistance to antifungals, in vitro and in vivo.

Rapid magnetically directed assembly of pre-patterned capillary-scale microvessels.

Capillary scale vascularization is critical to the survival of engineered 3D tissues and remains an outstanding challenge for the field of tissue engineering. Current methods to generate micro-scale vasculature such as 3D printing, two photon hydrogel ablation, angiogenesis, and vasculogenic assembly face challenges in rapidly creating organized, highly vascularized tissues at capillary length-scales. Within metabolically demanding tissues, native capillary beds are highly organized and densely packed to achieve adequate delivery of nutrients and oxygen and efficient waste removal. Here, we adopt two existing techniques to fabricate lattices composed of sacrificial microfibers that can be efficiently and uniformly seeded with endothelial cells (ECs) by magnetizing both lattices and ECs. Ferromagnetic microparticles (FMPs) were incorporated into microfibers produced by solution electrowriting (SEW) and fiber electropulling (FEP). By loading ECs with superparamagnetic iron oxide nanoparticles (SPIONs), the cells could be seeded onto magnetized microfiber lattices. Following encapsulation in a hydrogel, the capillary templating lattice was selectively degraded by a bacterial lipase that does not impact mammalian cell viability or function. This work introduces a novel approach to rapidly producing organized capillary networks within metabolically demanding engineered tissue constructs which should have broad utility for the fields of tissue engineering and regenerative medicine.

Clinical presentations of adult and pediatric SARS-CoV-2-positive cases in a community cohort, Nashville, Tennessee.

Compared to adults, the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) illness in children has been lower and less severe. However, reports comparing SARS-CoV-2 infection among children and adults are limited. As part of our longitudinal cohort study of adults and children with SARS-CoV-2 infection and their household contacts in Nashville, Tennessee, we compared the clinical characteristics and outcomes of SARS-CoV-2 infections between children and adults. Children were more likely to be asymptomatically infected and had a shorter illness duration compared to adults. The differences observed in clinical presentation across ages may inform symptom-specific testing, screening, and management algorithms.

Quantum limits of position-sensitive photodiodes.

The split photodiode and the lateral effect photodiode are two popular detectors for measuring beam displacement. For small displacements of a Gaussian beam, which is the case of interest here, they are often seen as equivalent and used interchangeably, giving a signal proportional to the displacement. We show theoretically and experimentally that in the limit of low technical noise, where the signal to noise ratio is dominated by the shot noise of the light, the lateral effect photodiode produces a better signal to noise ratio than the split photodiode, owing to its optimum spatial detector response. This quantum advantage can be practically exploited in spite of the intrinsic thermal noise of the lateral effect photodiode.

Model Based Design of a Low Cost and Compliant Low Profile Prosthetic Foot.

This paper describes the design of a simple and low-cost compliant low-profile prosthetic foot based on a cantilevered beam of uniform strength. The prosthetic foot is developed such that the maximum stress experienced by the beam is distributed approximately evenly across the length of the beam. Due to this stress distribution, the prosthetic foot exhibits compliant behavior not achievable through standard design approaches (e.g., designs based on simple cantilevered beams). Additionally, due to its simplicity and use of flat structural members, the foot can be manufactured at low cost. An analytical model of the compliant behavior of the beam is developed that facilitates rapid design changes to vary foot size and stiffness. A characteristic prototype was designed and constructed to be used in both a benchtop quasi-static loading test as well as a dynamic walking test for validation. The model predicted the rotational stiffness of the prototype with 5% error. Furthermore, the prototype foot was tested alongside two commercially available prosthetic feet (a low profile foot and an energy storage and release foot) in level walking experiments with a single study participant. The prototype foot displayed the lowest stiffness of the three feet (6.0, 7.1, and 10.4 Nm/deg for the prototype foot, the commercial low profile foot, and the energy storage and release foot, respectively). This foot design approach and accompanying model may allow for compliant feet to be developed for individuals with long residual limbs.

Tremor in triventricular hydrocephalus secondary to an aqueductal web with stenosis and response to third ventricular ventriculostomy.

We demonstrate a case report of triventricular hydrocephalus due to an aqueductal web and stenosis which presented itself clinically solely with bilateral hand tremors in an adolescent male. The patient underwent Endoscopic third ventriculostomy (ETV) and the subsequent improvement in cerebrospinal fluid (CSF) flow resulted in complete resolution of his tremor. We propose a mechanism involving compression of the rubrospinal tract (or stretching of the frontal premotor area) and advise cranial imaging in cases of hand tremor to exclude this as a potential cause. Neurosurgical review and potential CSF diversion if triventriclar hydrocephalus is established should be considered as positive clinical outcome can be achieved.

Surgical procedures for male infertility: an update.

PURPOSE OF REVIEW: The aim of this review is to provide an overview of surgical treatment options for male infertility including varicocelectomy, treatment of ejaculatory duct obstruction, vasovasostomy, and sperm extraction, and to review recent advances in techniques and technologies that may improve operative outcomes. RECENT FINDINGS: Microscopic subinguinal varicocelectomy has been shown to have the highest success rates with lowest rates of complications, and may be facilitated by the use of Doppler, indocyanine green angiography, and the 4K3D operating video microscope. The standard treatment for ejaculatory duct obstruction by transurethral resection of the ejaculatory ducts has changed little over time, but vesiculoscopy may allow for temporary dilation of an obstruction to allow for natural conception, while also offering diagnostic capabilities. Use of the robotic platform has gained popularity for vasectomy reversals but controversy remains regarding the cost-effectiveness of this option. Recently, a reinforcing suture technique has been described for vasovasostomy to minimize anastomotic breakdown and reversal failure. Finally, gray-scale and color-enhanced ultrasound may improve ability to predict successful sperm retrieval during extraction procedures. SUMMARY: Though the fundamentals of surgical treatment options for male infertility have changed little with time, technological advancements have contributed to improved surgical outcomes over recent years.

Applying the RE-AIM implementation framework to evaluate fall prevention interventions in community dwelling adults with cognitive impairment: a review and secondary analysis.

BACKGROUND: Cognitive impairment (CI) is a risk factor for falls due to environmental or living settings, balance, gait and vision impairments, as well as medications. While previous systematic reviews have focused on the effectiveness of fall prevention programs in adults with cognitive impairment, very limited information is available on their implementation. This review examines what aspects of fall prevention interventions for community-dwelling adults with CI have been reported using the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to support successful implementation. METHODS: We examined the included studies from our systematic review, which searched 7 databases for primary and secondary fall prevention interventions involving community-dwelling adults ≥50 years with mild to moderate CI. Reviewers screened citations and extracted data for study characteristics and the 5 dimensions (62 criteria) of the RE-AIM framework. RESULTS: Twelve randomized or clinical controlled trials (RCTs/CCTs) consisting of 8 exercise interventions, 3 multifactorial interventions, and 1 medication treatment were included in the review. Only 4 of 62 criteria were reported by all 12 included studies and 29 criteria were not reported by any of the studies. Five of the included studies reported on 20 or more of the 62 possible RE-AIM criteria and 3 of these studies self-identified as "feasibility" studies. While Reach was the best-reported construct by the included studies, followed by Effectiveness and Implementation, the criteria within the Adoption and Maintenance constructs were rarely mentioned by these studies. In general, there was also wide variation in how each of the criteria were reported on by study authors. CONCLUSION: Based on the reporting of RE-AIM components in this review, we are unable to make connections to successful intervention components and thus practice-based recommendations for fall prevention in those with CI. The lack of detail regarding implementation approaches greatly limits the interpretation and comparisons across studies to fully inform future research efforts.

Fall prevention in community-dwelling adults with mild to moderate cognitive impairment: a systematic review and meta-analysis.

BACKGROUND: Cognitive impairment (CI) increases an individual's risk of falls due to the role cognition plays in gait control. Older adults with dementia fall 2-3 times more than cognitively healthy older adults and 60-80% of people with dementia fall annually. Practitioners require evidence-based fall prevention best practices to reduce the risk of falls in cognitively impaired adults living in the community. METHODS: We conducted a systematic review and meta-analysis to identify the effectiveness of primary and secondary fall prevention interventions in reducing falls and fear of falling, and improving gait, balance, and functional mobility. We searched 7 databases for fall prevention interventions involving community-dwelling adults ≥50 years with mild to moderate CI. Reviewers screened citations, extracted data, and assessed risk of bias and certainty of evidence (GRADE). We assessed statistical and methodological heterogeneity and performed a meta-analysis of studies including subgroup analysis based on intervention and risk of bias groupings. RESULTS: Five hundred nine community-dwelling adults (mean age 67.5 to 84.0 years) with mild to moderate CI from 12 randomized or clinical controlled trials (RCTs/CCTs) were included in this review. Eight studies were exercise interventions, 3 were multifactorial, and 1 provided medication treatment. Fall prevention interventions had significant effects of medium magnitude on fear of falling (standardized mean difference (SMD) -0.73 [- 1.10, - 0.36]), balance (SMD 0.66 [0.19, 1.12]), and functional mobility measured as Timed Up and Go test (SMD -0.56 [- 0.94, - 0.17]) and significant effects of small magnitude on gait control (SMD 0.26 [0.08, 0.43]) all with moderate certainty of evidence. The meta-analysis showed no significant effects for falls (number of events or falls incidence). Sub-analysis showed that exercise and low risk of bias studies remained significant for balance and perceived risk of falls. CONCLUSION: The effect of fall prevention interventions on direct outcomes, such as falls, remains unclear in cognitively impaired individuals. Exercise interventions are effective at improving fall risk factors, however, high quality studies with longer follow-up and adequate sample sizes are needed to determine their effectiveness on falls directly. There remains a gap in terms of effective fall prevention interventions for older adults with CI.

Simulation of Legionnaires' disease prospective spatiotemporal cluster detection, Allegheny County, Pennsylvania, USA.

Legionnaires' disease (LD) incidence in the USA has quadrupled since 2000. Health departments must detect LD outbreaks quickly to identify and remediate sources. We tested the performance of a system to prospectively detect simulated LD outbreaks in Allegheny County, Pennsylvania, USA. We generated three simulated LD outbreaks based on published outbreaks. After verifying no significant clusters existed in surveillance data during 2014-2016, we embedded simulated outbreak-associated cases into 2016, assigning simulated residences and report dates. We mimicked daily analyses in 2016 using the prospective space-time permutation scan statistic to detect clusters of ⩽30 and ⩽180 days using 365-day and 730-day baseline periods, respectively. We used recurrence interval (RI) thresholds of ⩾20, ⩾100 and ⩾365 days to define significant signals. We calculated sensitivity, specificity and positive and negative predictive values for daily analyses, separately for each embedded outbreak. Two large, simulated cooling tower-associated outbreaks were detected. As the RI threshold was increased, sensitivity and negative predictive value decreased, while positive predictive value and specificity increased. A small, simulated potable water-associated outbreak was not detected. Use of a RI threshold of ⩾100 days minimised time-to-detection while maximizing positive predictive value. Health departments should consider using this system to detect community-acquired LD outbreaks.

Demographic factors in Swedish adults undergoing root filling and subsequent extraction of a maxillary first molar: a comparative study.

AIM: To study the demographics of Swedish adults who had received a root filling, followed by extraction during the following 5-6 years in comparison with subjects who had undergone a corresponding root filling with an uneventful outcome. METHODOLOGY: The root filled maxillary first molar was chosen as the comparison model. The Swedish Social Insurance Agency provided data on all teeth reported as root filled in Sweden during 2009. A comparison group, equally large as the study group, was constructed by randomly selecting subjects with root filled maxillary first molars, which had not subsequently been extracted, that is, an uneventful outcome. Demographic data on the subjects were obtained from Statistics Sweden: country of birth, disposable income, educational level, age, civil status and gender. Chi-square, t-tests and logistic regression were used for statistical analyses. RESULTS: In the year 2009, 36 139 maxillary first molar teeth were reported to have been root filled, 4362 (12.1%) of which were then recorded as extracted during the following 5-6 year period. Only minor intergroup differences were noted: 86.5% of the study group were Swedish-born, compared with 84.4% of the comparison group (P = 0.007). Women comprised 53.2% of the study group and 50.5% (P = 0.01) of the comparison group. There was an association between extractions and gender as well as age; men had a lower odds ratio (OR) for extraction OR, 0.87; confidence interval (CI), 0.80-0.95. For every additional year, the chance for extraction was higher OR, 1.01; CI, 1.01-1.01. No other significant differences were detected. CONCLUSIONS: There was only little or no demographic differences between the study group, comprising Swedish adults who had undergone root filling of one of their maxillary first molars in 2009 and subsequent extraction during the following 5-6 years, and the comparison group, with uneventful outcomes after a corresponding root filling.

Risk factors associated with taeniosis-cysticercosis in rural farming communities in Gauteng Province, South Africa.

The aim of this study was to determine which of the livestock management and human practices known to be risk factors associated with taeniosis-cysticercosis occur in Gauteng Province. A questionnaire survey was conducted in two regions of Gauteng Province, Germiston and Pretoria. Results revealed that almost 20% of the interviewed farmers do not have toilets, most of them let their animals roam freely during the day for grazing and scavenging, and 47% use streams as the water source for their animals. This may create an infection opportunity through ingestion of Taenia-contaminated herbage or water. Furthermore, 26% mentioned that their animals might have access to human excreta. More than 70% of farmers in the province slaughter cattle and pigs for their own consumption without inspecting meat for cysticercosis. Only a few of the interviewed farmers in both regions were aware of the taeniosis-cysticercosis complex. Backyard slaughtering, consumption of uninspected meat by the public, poor livestock management, and limited sanitation in rural communities of Gauteng Province are identified as risk factors associated with the occurrence of Taenia saginata and Taenia solium infections in the province. Taenia saginata and T. solium are considered to have a global distribution; therefore, these risk factors may be applicable globally, not just in Gauteng Province. Programs on public awareness with regard to transmission and prevention of Taenia infections as well as more detailed studies on risk factors of taeniosis-cysticercosis are recommended.

Interferon-gamma released from omental adipose tissue of insulin-resistant humans alters adipocyte phenotype and impairs response to insulin and adiponectin release.

BACKGROUND: Inflammatory factors derived from adipose tissue have been implicated in mediating insulin resistance in obesity. We sought to identify these using explanted human adipose tissue exposed to innate and adaptive immune stimuli. METHODS: Subcutaneous and omental adipose tissue from obese, insulin-resistant donors was cultured in the presence of macrophage and T-cell stimuli, and the conditioned medium tested for its ability to inhibit insulin-stimulated glucose uptake into human Simpson-Golabi-Behmel Syndrome (SGBS) adipocytes. The nature of the inhibitory factor in conditioned medium was characterized physicochemically, inferred by gene microarray analysis and confirmed by antibody neutralization. RESULTS: Conditioned medium from omental adipose tissue exposed to a combination of macrophage- and T-cell stimuli inhibited insulin action and adiponectin secretion in SGBS adipocytes. This effect was associated with a pronounced change in adipocyte morphology, characterized by a decreased number of lipid droplets of increased size. The bioactivity of conditioned medium was abolished by trypsin treatment and had a molecular weight of 46 kDa by gel filtration. SGBS adipocytes exposed to a bioactive medium expressed multiple gene transcripts regulated by interferon-gamma (IFN-γ). Recombinant human IFN-γ recapitulated the effects of the bioactive medium and neutralizing antibody against IFN-γ but not other candidate factors abrogated medium bioactivity. CONCLUSIONS: IFN-γ released from inflamed omental adipose tissue may contribute to the metabolic abnormalities seen in human obesity.

Clinical outcomes of melanoma brain metastases treated with stereotactic radiation and anti-PD-1 therapy.

BACKGROUND: The anti-programmed death-1 (anti-PD-1) therapy nivolumab has significant clinical activity in patients with metastatic melanoma. However, little is known about the safety and outcomes in patients receiving anti-PD-1 therapy and stereotactic radiation for the treatment of brain metastases (BMs). PATIENTS AND METHODS: Data were analyzed retrospectively from two prospective nivolumab protocols enrolling 160 patients with advanced resected and unresectable melanoma at a single institution. Patients were included if BMs were diagnosed and treated with stereotactic radiation within 6 months of receiving nivolumab. The primary end point of this study was neurotoxicity; secondary end points included BM control and survival. RESULTS: Twenty-six patients with a total of 73 BMs treated over 30 sessions were identified. Radiation was administered before, during and after nivolumab in 33 lesions (45%), 5 lesions (7%), and 35 lesions (48%), respectively. All BMs were treated with stereotactic radiosurgery (SRS) in a single session except 12 BMs treated with fractionated stereotactic radiation therapy, nine of which were in the postoperative setting. One patient experienced grade 2 headaches following SRS with symptomatic relief with steroid treatment. No other treatment-related neurologic toxicities or scalp reactions were reported. Eight (11%) local BM failures with a ≥20% increase in volume were noted. Of these lesions, hemorrhage was noted in 4, and edema was noted in 7. Kaplan-Meier estimates for local BM control following radiation at 6 and 12 months were 91% and 85%, respectively. Median overall survival (OS) from the date of stereotactic radiation and nivolumab initiation was 11.8 and 12.0 months, respectively, in patients receiving nivolumab for unresected disease (median OS was not reached in patients treated in the resected setting). CONCLUSIONS: In our series, stereotactic radiation to melanoma BMs is well tolerated in patients who received nivolumab. BM control and OS appear prolonged compared with standard current treatment. Prospective evaluation is warranted.

Clinical outcomes of melanoma brain metastases treated with stereotactic radiosurgery and anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitor, or conventional chemotherapy.

BACKGROUND: The effect of immunologic and targeted agents on intracranial response rates in patients with melanoma brain metastases (MBMs) is not yet clearly understood. This report analyzes outcomes of intact MBMs treated with single-session stereotactic radiosurgery (SRS) and anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors(i), BRAFi, or conventional chemotherapy. PATIENTS AND METHODS: Patients were included if MBMs were treated with single-session SRS within 3 months of receiving systemic therapy. The primary end point of this study was distant MBM control. Secondary end points were local MBM control defined as a >20% volume increase on follow-up MRI, systemic progression-free survival, overall survival (OS) from both SRS and cranial metastases diagnosis, and neurotoxicity. Images were reviewed alongside two neuro-radiologists at our institution. RESULTS: Ninety-six patients were treated to 314 MBMs over 119 SRS treatment sessions between January 2007 and August 2015. No significant differences were noted in age (P = 0.27), gender (P = 0.85), treated gross tumor volume (P = 0.26), or the diagnosis-specific graded prognostic assessment (P = 0.51) between the treatment cohorts. Twelve-month Kaplan-Meier (KM) distant MBM control rates were 38%, 21%, 20%, 8%, and 5% (P = 0.008) for SRS with anti-PD-1 therapies, anti-CTLA-4 therapy, BRAF/MEKi, BRAFi, and conventional chemotherapy, respectively. No significant differences were noted in the KM local MBM control rates among treatment groups (P = 0.25). Treatment with anti-PD-1 therapy, anti-CTLA-4 therapy, or BRAF/MEKi significantly improved OS on both univariate and multivariate analyses when compared with conventional chemotherapy. CONCLUSION: In our institutional analysis of patients treated with SRS and various systemic immunologic and targeted melanoma agents, significant differences in distant MBM control and OS are noted. Prospective evaluation of the potential synergistic effect between these agents and SRS is warranted.

GM3 ganglioside and phosphatidylethanolamine-containing lipids are adipose tissue markers of insulin resistance in obese women.

AIMS: The association between central obesity and insulin resistance reflects the properties of visceral adipose tissue. Our aim was to gain further insight into this association by analysing the lipid composition of subcutaneous and omental adipose tissue in obese women with and without insulin resistance. METHODS: Subcutaneous and omental adipose tissue and serum were obtained from 29 obese non-diabetic women, 13 of whom were hyperinsulinemic. Histology, lipid and gene profiling were performed. RESULTS: In omental adipose tissue of obese, insulin-resistant women, adipocyte hypertrophy and macrophage infiltration were accompanied by an increase in GM3 ganglioside and its synthesis enzyme ST3GAL5; in addition, phosphatidylethanolamine (PE) lipids were increased and their degradation enzyme, phosphatidylethanolamine methyl transferase (PEMT), decreased. ST3GAL5 was expressed predominantly in adipose stromovascular cells and PEMT in adipocytes. Insulin resistance was also associated with an increase in PE lipids in serum. INTERPRETATION: The relevance of these findings to insulin resistance in humans is supported by published mouse studies, in which adipocyte GM3 ganglioside, increased by the inflammatory cytokine tumour necrosis factor-α, impaired insulin action and PEMT was required for adipocyte lipid storage. Thus in visceral adipose tissue of obese humans, an increase in GM3 ganglioside secondary to inflammation may contribute to insulin resistance and a decrease in PEMT may be a compensatory response to adipocyte hypertrophy.

Diabetic hepatosclerosis: another diabetes microvascular complication?

BACKGROUND: Liver disease in diabetes is common and is frequently the result of hepatic steatosis. Diabetic hepatosclerosis is a relatively recent description of sinusoidal fibrosis, without steatosis, observed in liver biopsies of people with diabetes presenting with cholestasis. Its association with other microvascular complications suggests it is a form of hepatic diabetic microangiopathy. CASE REPORT: We report the case of a 50-year-old woman with longstanding Type 1 diabetes, complicated by nephropathy resulting in cadaveric renal transplant, retinopathy, gastroparesis and neuropathy with slowly healing ulceration to her right foot. She was noted to have deranged liver function tests: alanine aminotransferase, 162 IU/l; bilirubin, 44 IU/l; alkaline phosphatase, 5279 IU/l (isoenzymes; bone 1029 IU/l, liver 4250 IU/l); γ-glutamyl transferase, 662 IU/l. A non-invasive liver screen did not reveal the cause of the cholestasis. A liver biopsy demonstrated sinusoidal fibrosis without evidence of steatosis and thus a diagnosis of diabetic hepatosclerosis was made. Comparison with a biopsy performed 11 years previously at a different trust due to elevated alkaline phosphatase levels revealed slow progression of the sinusoidal fibrosis. DISCUSSION: This case describes the longest reported clinical course of diabetic hepatosclerosis, spanning 11 years, in which time the patient did not develop evidence of cirrhosis or portal hypertension. It is difficult to estimate the clinical relevance of this condition because little is known regarding its clinical course and effect on morbidity and mortality. Identified patients should undergo low-intensity, long-term follow-up to improve understanding of its clinical sequelae and relevance.