Endogenous Fructose Production and Fructokinase Activation Mediate Renal Injury in Diabetic Nephropathy

Diabetes is associated with activation of the polyol pathway, in which glucose is converted to sorbitol by aldose reductase. Previous studies focused on the role of sorbitol in mediating diabetic complications. However, in the proximal tubule, sorbitol can be converted to fructose, which is then metabolized largely by fructokinase, also known as ketohexokinase, leading to ATP depletion, proinflammatory cytokine expression, and oxidative stress. We and others recently identified a potential deleterious role of dietary fructose in the generation of tubulointerstitial injury and the acceleration of CKD. In this study, we investigated the potential role of endogenous fructose production, as opposed to dietary fructose, and its metabolism through fructokinase in the development of diabetic nephropathy. Wild-type mice with streptozotocin-induced diabetes developed proteinuria, reduced GFR, and renal glomerular and proximal tubular injury. Increased renal expression of aldose reductase; elevated levels of renal sorbitol, fructose, and uric acid; and low levels of ATP confirmed activation of the fructokinase pathway. Furthermore, renal expression of inflammatory cytokines with macrophage infiltration was prominent. In contrast, diabetic fructokinase–deficient mice demonstrated significantly less proteinuria, renal dysfunction, renal injury, and inflammation. These studies identify fructokinase as a novel mediator of diabetic nephropathy and document a novel role for endogenous fructose production, or fructoneogenesis, in driving renal disease.Diabetic nephropathy is the most common kidney disease causing ESRD worldwide and also one of the most difficult diseases to treat. To date, treatment includes tight blood glucose and BP control and inhibition of the renin-angiotensin-aldosterone system. These efforts typically slow but do not arrest the progression of kidney disease.¹ It is therefore imperative to better understand the mechanisms responsible for renal injury and to develop additional therapies.Recently, fructose has emerged as a potential nephrotoxin. Fructose-fed rats develop modest tubulointerstitial injury,² and fructose supplementation accelerates renal disease in the remnant kidney model.³ While all studies to date have focused on dietary fructose as the source of fructose, fructose can also be generated from glucose in diabetes because of the activation of the polyol pathway in the proximal tubule. To date, no studies have examined the role of this endogenous fructose production or fructoneogenesis in driving diabetic nephropathy. Therefore, we tested the hypothesis that mice lacking fructokinase-ketohexokinase (khk−/−) show protection from diabetic nephropathy, even in the absence of dietary fructose, as a result of their inability to metabolize endogenously produced fructose.     

Arthroscopic dorsal wrist ganglion excision with color-aided visualization of the stalk: minimum 1-year follow-up

Background

Dorsal wrist ganglia (DWG) are a common, benign soft-tissue mass of the wrist. Excision of DWG is a common procedure performed by hand surgeons and may be performed using either open or arthroscopic techniques. This study aims to evaluate the frequency of stalk visualization with intralesional injection of inert dye in the course of arthroscopic excision along with incidence of recurrence with a minimum of 1-year follow-up.

Methods

Upon IRB approval, a retrospective chart review was performed identifying 27 patients who had consecutively undergone arthroscopic excision of a DWG with the color-aided technique at our institution with a minimum follow-up duration of 12 months. Intraoperative findings were reviewed. Patients were contacted to investigate for incidence of recurrence.

Results

Of the 27-patient cohort, the ganglion stalk was identified in 100 % of the color-aided arthroscopic DWG excisions. Ganglion recurrence was identified in one patient, an incidence of 3.7 %.

Conclusions

The color-aided technique for arthroscopic DWG visualization was found to be a safe and valuable tool for surgeons performing arthroscopic DWG resection. The intraarticular ganglion stalk was identified in 100 % of cases and patients responded well with a low incidence of recurrence.     

Adsorption of methylene blue and tetracycline onto biomass-based material prepared by sulfuric acid reflux

The adsorptive removal of environmental pollutants is an effective method for the treatment of contaminated water. Thus, the preparation of adsorbents from low-cost, readily available, and renewable resources has garnered immense attention in recent years. In this study, a facile one-step method for the preparation of a high-capacity adsorbent is demonstrated by refluxing pine cones in concentrated sulfuric acid. With sulfuric acid reflux, the pine cones undergone carbonization as well as functionalization with sulfonic acid groups. The adsorbent demonstrated high adsorption capacity for two emerging organic pollutants, methylene blue (MB) and tetracycline (TC). Different variables such as pH, temperature, contact time, and initial concentration of the pollutants were analyzed and showed that the adsorption capacity for MB increased in a basic pH and vice versa for TC. Also, the elevated temperature favored the adsorption for both MB and TC. The maximum adsorption capacity was found to be 1666.66, and 357.14 mg g⁻¹ for MB and TC, respectively. In comparison to the pristine pine cone, the sulfuric acid treated pine cone demonstrated an extraordinary improvement in the adsorption capacity. The adsorption of MB and TC was performed from the tap water matrix and similar adsorption capacities were found. A packed glass column was also prepared to demonstrate the adsorption of MB from tap water under flow conditions.

Facile conversion of pine cones into a high-capacity adsorbent for the removal of methylene blue and tetracycline from water.     

Effect of catheter diameter on resting pressures in anal fissure patients

PURPOSE: Controversy exists as to whether fissure patients have elevated resting pressures when compared with control patients. The diameter of manometry catheters used in past studies varies widely (1.5–25 mm) and may have contributed to differences observed in resting pressures. A prospective study was undertaken to determine the influence of manometry catheter diameter on maximum resting pressure in patients with idiopathic chronic anal fissures. METHODS: A total of 28 fissure patients and 28 control patients had manometry performed with both a 1.8-mm and a 4.8-mm (external diameter) water-perfused catheter. RESULTS: Mean maximum resting pressure (RP) for fissure patients as measured with the 1.8-mm catheter was 86 (range, 65–115) mmHg and 83 (range, 47–117) mmHg with the 4.8-mm catheter (P=0.65). Mean maximum RP for control patients with the 1.8-mm catheter was 70 (range, 30–108) mmHg and 72 (range, 35–109) mmHg with the 4.8-mm catheter (P=0.07). When fissure and control patients were compared, a significantly higher mean RP was observed in the fissure group for both the 1.8-mm catheter (86 vs.70 mmHg, respectively;P=0.01) and the 4.8-mm catheter (83 vs.72 mmHg, respectively;P=0.03). There was no significant difference in length of the high-pressure zone within each group or when the fissure group and controls were compared, regardless of catheter used. For both groups of patients, there was a significantly higher incidence of ultraslow waves (USWs) observed with the 4.8-mm catheter when compared with the 1.8-mm catheter. The USW frequency was not significantly different when fissure and control groups were compared with either catheter type. CONCLUSIONS: Catheter size did not influence measured maximum RP in fissure patients. The maximum RP was significantly greater for fissure patients overall when compared with the control group, regardless of catheter used. There was an increased frequency of USWs noted with the larger catheter size in all patients; however, these USWs only became apparent when catheter was left at each station until a true baseline RP was obtained.Supported in part by a Columbia-Presbyterian Department of Surgery Research Grant.Poster presentation at the meeting of The American Society of Colon and Rectal Surgeons, Orlando, Florida, May 8 to 13, 1994.     

A community-based study of early childhood sensory stimulation in home environment associated with growth and psychomotor development in Pakistan

Objectives

Sensory stimulation (SS) is a non-nutritional modifiable risk factor for early childhood development. We assessed SS in home environment and examined its influence on physical growth and psychomotor development (PD).

Methods

A cross-sectional study was conducted in 26 communities in Pakistan among children aged <3 (n = 1,219). They were assessed at home visits using (1) Bayley’s Infant Developmental Scale for PD, (2) home observation for measurement of the environment inventory for SS, (3) anthropometry and (4) socio-economic questionnaire.

Results

In rural homes, SS provided was lower as compared to urban counterparts (Adj mean diff: 4.47, 95 % CI 3.78, 5.16) and showed an association with stunting (Adj mean diff: ?1.30, 95 % CI ?1.93, ?0.66), and underweight (Adj mean diff: ?1.04, 95 % CI ?1.71, ?0.38) not explained by type of neighbourhood or socio-economic status. SS was associated with PD more than combined contribution of socio-economic status and rural–urban factors (Adj mean diff: 0.47, 95 % CI 0.30, 0.63).

Conclusions

SS in rural homes may be a significant factor influencing the child development. There is a need to corroborate these results by additional research for integration in health policy initiatives.     

Role of peroxynitrite-modified biomolecules in the etiopathogenesis of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease characterized by autoantibodies directed against various biomolecules. The initial immunogens that drive the development of SLE are unknown, but characteristics of the immune response in SLE suggest that it is an antigen-driven response, and a chromatin antigen could be one of the immunogens for the production of antinuclear antibodies (ANA) in SLE. Other factors implicated in the pathogenesis of SLE include nitrogen-free radicals such as nitric oxide and peroxynitrite. The free radical-mediated damage to proteins results in the modification of amino acid residues, cross-linking of side chains and fragmentation. The tyrosine residues in proteins are susceptible to attack by various reactive nitrogen intermediates, including peroxynitrite to form 3-nitrotyrosine (3-NT). The presence of nitrated proteins in vivo indicates that peptides derived from the proteolytic degradation of modified proteins could serve as neoantigens. Histones are highly conserved proteins that are rich in basic amino acids lysine and arginine. Autoantibodies against histones and anti-DNA antibodies are present in SLE. The anti-DNA autoantibodies coexist with anti-histone autoantibodies and may react with chromatin-associated histones and histone complexes. Elevated levels of reactive nitrogen species (RNS) in SLE patients suggest a possible role in the pathogenesis of the disease. The alteration of proteins resulting from photomodification or peroxynitrite could lead to the development of antibodies. Therefore, the modified proteins or photoadducts could have important implications in autoimmunity, and understanding the pathophysiology of peroxynitrite-modified biomolecules could lead to a better understanding of autoimmune phenomenon in SLE.     

Kidney protective potential of lactoferrin: pharmacological insights and therapeutic advances

Kidney disease is becoming a global public health issue. Acute kidney injury (AKI) and chronic kidney disease (CKD) have serious adverse health outcomes. However, there is no effective therapy to treat these diseases. Lactoferrin (LF), a multi-functional glycoprotein, is protective against various pathophysiological conditions in various disease models. LF shows protective effects against AKI and CKD. LF reduces markers related to inflammation, oxidative stress, apoptosis, and kidney fibrosis, and induces autophagy and mitochondrial biogenesis in the kidney. Although there are no clinical trials of LF to treat kidney disease, several clinical trials and studies on LF-based drug development are ongoing. In this review, we discussed the possible kidney protective mechanisms of LF, as well as the pharmacological and therapeutic advances. The evidence suggests that LF may become a potent pharmacological agent to treat kidney diseases.