The automated Greulich and Pyle: a coming-of-age for segmental methods?

The well-known Greulich and Pyle (GP) method of bone age assessment (BAA) relies on comparing a hand X-ray against templates of discrete maturity classes collected in an atlas. Automated methods have recently shown great success with BAA, especially using deep learning. In this perspective, we first review the success and limitations of various automated BAA methods. We then offer a novel hypothesis: When networks predict bone age that is not aligned with a GP reference class, it is not simply statistical error (although there is that as well); they are picking up nuances in the hand X-ray that lie "outside that class." In other words, trained networks predict distributions around classes. This raises a natural question: How can we further understand the reasons for a prediction to deviate from the nominal class age? We claim that segmental aging, that is, ratings based on characteristic bone groups can be used to qualify predictions. This so-called segmental GP method has excellent properties: It can not only help identify differential maturity in the hand but also provide a systematic way to extend the use of the current GP atlas to various other populations.

Characterization of palmitic acid toxicity induced insulin resistance in HepG2 cells.

BACKGROUND: An etiology of palmitic acid (PA) induced insulin resistance (IR) is complex for which two mechanisms are proposed namely ROS induced JNK activation and lipid induced protein kinase-C (PKCε) activation. However, whether these mechanisms act alone or in consortium is not clear. METHODS AND RESULTS: In this study, we have characterized PA induced IR in liver cells. These cells were treated with different concentrations of PA for either 8 or 16 h. Insulin responsiveness of cells treated with PA for 8 h was found to be same as that of control. However, cells treated with PA for 16 h, showed increased glucose output both in the presence and in absence of insulin only at higher concentrations, indicating development of IR. In these, both JNK and PKCε were activated in response to increased ROS and lipid accumulation, respectively. Activated JNK and PKCε phosphorylated IRS1 at Ser-307 resulting in inhibition of AKT which in turn inactivated GSK3ß, leading to reduced glycogen synthase activity. Inhibition of AKT also reduced insulin suppression of hepatic gluconeogenesis by activating Forkhead box protein O1 (FOXO1) and increased expression of the gluconeogenic enzymes and their transcription factors. CONCLUSION: Thus, our data clearly demonstrate that both these mechanisms work simultaneously and more importantly, identified a threshold of HepG2 cells, which when crossed led to the pathological state of IR in response to PA.

BoneXpert-derived bone health index reference curves constructed on healthy Indian children and adolescents.

BACKGROUND: Artificial intelligence (AI)-based applications for the assessment of the paediatric musculoskeletal system like BoneXpert are not only useful to assess bone age (BA) but also to provide a bone health index (BHI) and a standard deviation score (SDS) for both. This allows comparison of the BHI with age- and sex-matched healthy Caucasian children. OBJECTIVE: We conducted this study with the objective of generating BHI curves using BoneXpert in healthy Indian children with BA between 2 and 17 years. METHOD: We retrospectively reviewed anthropometric parameters, BHI, and BHI SDS data of digitalized left-hand radiographs (joint photographic experts group [jpg] format) of a cohort of 788 paediatric patients from a previous study to which they were recruited to compare various methods of BA assessment. The recruited children represented all age groups for both sexes. The corrected BHI for jpg images was calculated using the formula corrected BHI=BHI*(stature/(avL*50))^0.33333 where stature is height of subject and avL is average length of metacarpal bones. The reference Indian BHI curves and centiles were generated using the Lambda-Mu-Sigma method. RESULT: The mean BHI and BHI SDS of the study group were 4.02±0.57 and -1.73±1.09, respectively. The average increase in median BHI from each age group was between 2.5% and 3% in both sexes up to age of 14 years after which it increased to 4.5% to 5%. The mean BHI of Indian children was lower than that of Caucasian children with maximum differences noted in boys at 16 years (21.7%) and girls at 14 years (16%). We report 8.4% SD of BHI for our study sample. Reference percentile curves for BHI according to BA were derived separately for boys and girls. CONCLUSION: Reference data has been provided for the screening of bone health status of Indian children and adolescents.

Adaptation and validation of an artificial intelligence based digital radiogrammetry tool for assessing bone health of indian children and youth with type-1 diabetes.

BACKGROUND AND OBJECTIVES: BoneXpert (BX) is an artificial intelligence software used primarily for bone age assessment. Besides, it can also be used to screen for bone health using the digital radiogrammetry tool called bone health index (BHI) for which normative reference values available are calculated from healthy European children. Due to ethnic difference in bone geometry, in a previous study, we generated reference curves based on healthy Indian children. The objectives of this study were: 1) To assess and compare bone health of Indian children with Type 1 diabetes (T1D) using both European and Indian BHI SDS reference data and 2) To identify determinants of poor bone health in Indian children and youth with T1D by using BHI tool (based on BHI-SDS Indian reference data) of BX. METHOD: The BHI was assessed retrospectively in 1159 subjects with T1D using digitalised left-hand x-rays and SDS were computed using European and Indian data. The demographic, anthropometric, clinical, biochemistry, dual x-ray absorptiometry (DXA) data and peripheral quantitative computed tomography (pQCT) data collection were performed using standard protocols and were extracted from hospital records. RESULTS: The BHI correlated well with DXA and pQCT parameters in subjects with T1D. BHI-SDS calculated using Indian reference data had better correlation with height and DXA parameters. 8.6% study participants had low (less than -2) BHI-SDS (Indian), with height SDS having significant effect. Subjects with low BHI-SDS were older, shorter and had higher duration of diabetes. They also had lower IGF1 and vitamin D concentrations, bone mineral density, and trabecular density. Female gender, increased duration of illness, poor glycaemic control, and vitamin D deficiency/insufficiency were significant predictors of poor BHI-SDS. CONCLUSION: Our study highlights the utility of digital radiogrammetry AI tool to screen for bone health of children with T1D and demonstrates and highlights the necessity of interpretation using ethnicity specific normative data.

Evaluation of HbA1c from CGM traces in an Indian population.

Introduction: The development of continuous glucose monitoring (CGM) over the last decade has provided access to many consecutive glucose concentration measurements from patients. A standard method for estimating glycated hemoglobin (HbA1c), already established in the literature, is based on its relationship with the average blood glucose concentration (aBG). We showed that the estimates obtained using the standard method were not sufficiently reliable for an Indian population and suggested two new methods for estimating HbA1c. Methods: Two datasets providing a total of 128 CGM and their corresponding HbA1c levels were received from two centers: Health Centre, Savitribai Phule Pune University, Pune and Joshi Hospital, Pune, from patients already diagnosed with diabetes, non-diabetes, and pre-diabetes. We filtered 112 data-sufficient CGM traces, of which 80 traces were used to construct two models using linear regression. The first model estimates HbA1c directly from the average interstitial fluid glucose concentration (aISF) of the CGM trace and the second model proceeds in two steps: first, aISF is scaled to aBG, and then aBG is converted to HbA1c via the Nathan model. Our models were tested on the remaining 32 data- sufficient traces. We also provided 95% confidence and prediction intervals for HbA1c estimates. Results: The direct model (first model) for estimating HbA1c was HbA1cmmol/mol = 0.319 × aISFmg/dL + 16.73 and the adapted Nathan model (second model) for estimating HbA1c is HbA1cmmol/dL = 0.38 × (1.17 × ISFmg/dL) - 5.60. Discussion: Our results show that the new equations are likely to provide better estimates of HbA1c levels than the standard model at the population level, which is especially suited for clinical epidemiology in Indian populations.

Corrigendum: Quantification of joint mobility limitation in adult type 1 diabetes.

[This corrects the article DOI: 10.3389/fendo.2023.1238825.].

Quantification of joint mobility limitation in adult type 1 diabetes.

Aims: Diabetic cheiroarthropathies limit hand mobility due to fibrosis and could be markers of a global profibrotic trajectory. Heterogeneity in definitions and lack of a method to measure it complicate studying associations with organ involvement and treatment outcomes. We measured metacarpophalangeal (MCP) joint extension as a metric and describe magnetic resonance (MR) imaging determinants of MCP restriction. Methods: Adults with type 1 diabetes were screened for hand manifestations using a symptom questionnaire, clinical examination, and function [Duruoz hand index (DHI) and grip strength]. Patients were segregated by mean MCP extension (<20°, 20°-40°, 40°-60°, and >60°) for MR imaging (MRI) scanning. Patients in the four groups were compared using ANOVA for clinical features and MRI tissue measurements (tenosynovial, skin, and fascia thickness). We performed multiple linear regression for determinants of MCP extension. Results: Of the 237 patients (90 men), 79 (33.8%) with cheiroarthropathy had MCP extension limitation (39° versus 61°, p < 0.01). Groups with limited MCP extension had higher DHI (1.9 vs. 0.2) but few (7%) had pain. Height, systolic blood pressure, and nephropathy were associated with mean MCP extension. Hand MRI (n = 61) showed flexor tenosynovitis in four patients and median neuritis in one patient. Groups with MCP mobility restriction had the thickest palmar skin; tendon thickness or median nerve area did not differ. Only mean palmar skin thickness was associated with MCP extension angle on multiple linear regression. Conclusion: Joint mobility limitation was quantified by restricted mean MCP extension and had structural correlates on MRI. These can serve as quantitative measures for future associative and interventional studies.

Computer vision detects inflammatory arthritis in standardized smartphone photographs in an Indian patient cohort.

Introduction: Computer vision extracts meaning from pixelated images and holds promise in automating various clinical tasks. Convolutional neural networks (CNNs), a deep learning network used therein, have shown promise in analyzing X-ray images and joint photographs. We studied the performance of a CNN on standardized smartphone photographs in detecting inflammation in three hand joints and compared it to a rheumatologist's diagnosis. Methods: We enrolled 100 consecutive patients with inflammatory arthritis with an onset period of less than 2 years, excluding those with deformities. Each patient was examined by a rheumatologist, and the presence of synovitis in each joint was recorded. Hand photographs were taken in a standardized manner, anonymized, and cropped to include joints of interest. A ResNet-101 backbone modified for two class outputs (inflamed or not) was used for training. We also tested a hue-augmented dataset. We reported accuracy, sensitivity, and specificity for three joints: wrist, index finger proximal interphalangeal (IFPIP), and middle finger proximal interphalangeal (MFPIP), taking the rheumatologist's opinion as the gold standard. Results: The cohort consisted of 100 individuals, of which 22 of them were men, with a mean age of 49.7 (SD 12.9) years. The majority of the cohort (n = 68, 68%) had rheumatoid arthritis. The wrist (125/200, 62.5%), MFPIP (94/200, 47%), and IFPIP (83/200, 41.5%) were the three most commonly inflamed joints. The CNN achieved the highest accuracy, sensitivity, and specificity in detecting synovitis in the MFPIP (83, 77, and 88%, respectively), followed by the IFPIP (74, 74, and 75%, respectively) and the wrist (62, 90, and 21%, respectively). Discussion: We have demonstrated that computer vision was able to detect inflammation in three joints of the hand with reasonable accuracy on standardized photographs despite a small dataset. Feature engineering was not required, and the CNN worked despite a diversity in clinical diagnosis. Larger datasets are likely to improve accuracy and help explain the basis of classification. These data suggest a potential use of computer vision in screening and follow-up of inflammatory arthritis.

Effect of long-term oral glutathione supplementation on gut microbiome of type 2 diabetic individuals.

The aim of this study was to check the effect of long-term oral glutathione (GSH) supplementation on alteration in gut microbiome of Indian diabetic individuals. Early morning fresh stool sample of diabetic individuals recruited in a randomized clinical trial wherein they were given 500 mg GSH supplementation orally once a day for a period of 6 months was collected and gut microbiome was analysed using high throughput 16S rRNA metagenomic sequencing. Long-term GSH supplementation as reported in our earlier work showed significant increase in body stores of GSH and stabilized decreased glycated haemoglobin (HbA1c). Analysis of gut microbiome revealed that abundance of phylum Proteobacteria significantly decreased (P < 0.05) in individuals with GSH supplementation after 6 months compared to those without it. Beneficial dominant genera such as Megasphaera, Bacteroides, and Megamonas were found to be significantly enriched (P < 0.05), while pathogenic Escherichia/Shigella was found to be depleted (P < 0.05) after supplementation. Data clearly demonstrate that GSH supplementation along with antidiabetic treatment helps restore the gut microbiome by enriching beneficial bacteria of healthy gut and reducing significantly the load of pathogenic bacteria of diabetic gut.

Does hand stiffness reflect internal organ fibrosis in diabetes mellitus?

Fibrosis leads to irreversible stiffening of tissue and loss of function, and is a common pathway leading to morbidity and mortality in chronic disease. Diabetes mellitus (both type 1 and type 2 diabetes) are associated with significant fibrosis in internal organs, chiefly the kidney and heart, but also lung, liver and adipose tissue. Diabetes is also associated with the diabetic cheirarthropathies, a collection of clinical manifestations affecting the hand that include limited joint mobility (LJM), flexor tenosynovitis, Duypuytren disease and carpal tunnel syndrome. Histo-morphologically these are profibrotic conditions affecting various soft tissue components in the hand. We hypothesize that these hand manifestations reflect a systemic profibrotic state, and are potential clinical biomarkers of current or future internal organ fibrosis. Epidemiologically, there is evidence that fibrosis in one organ associates with fibrosis with another; the putative exposures that lead to fibrosis in diabetes (advanced glycation end product deposition, microvascular disease and hypoxia, persistent innate inflammation) are 'systemic'; a common genetic susceptibility to fibrosis has also been hinted at. These data suggest that a subset of the diabetic population is susceptible to multi-organ fibrosis. The hand is an attractive biomarker to clinically detect this susceptibility, owing to its accessibility to physical examination and exposure to repeated mechanical stresses. Testing the hypothesis has a few pre-requisites: being able to measure hand fibrosis in the hand, using clinical scores or imaging based scores, which will facilitate looking for associations with internal organ fibrosis using validated methodologies for each. Longitudinal studies would be essential in delineating fibrosis trajectories in those with hand manifestations. Since therapies reversing fibrosis are few, the onus lies on identification of a susceptible subset for preventative measures. If systematically validated, clinical hand examination could provide a low-cost, universally accessible and easily reproducible screening step in selecting patients for clinical trials for fibrosis in diabetes.

Pune GSH supplementation study: Analyzing longitudinal changes in type 2 diabetic patients using linear mixed-effects models.

Oral GSH supplementation along with antidiabetic treatment was shown to restore the body stores of GSH significantly and reduce oxidative DNA damage (8-OHdG) in Indian Type 2 diabetic (T2D) patients over 6 months in our recent clinical study. Post hoc analysis of the data also suggested that elder patients benefit from improved HbA1c and fasting insulin. We modeled longitudinal changes in diabetic individuals using a linear mixed-effects (LME) framework and obtained i) the distribution of individual trajectories with and without GSH supplementation and ii) the overall rates of changes in the different study arms. Serial changes in elder and younger diabetic individuals were also modeled independently to examine differences in their progression. The average linear trajectories obtained from the model explain how biochemical parameters in T2D patients progress over 6 months on GSH supplementation. Model estimates show improvements in erythrocytic GSH of 108 µM per month and a reduction in 8-OHdG at a rate of 18.5 ng/µg DNA per month in T2D patients. GSH replenishes faster in younger people than in the elder. 8-OHdG reduced more rapidly in the elder (24 ng/µg DNA per month) than in younger (12 ng/µg DNA per month) individuals. Interestingly, elder individuals show a substantial reduction in HbA1c (0.1% per month) and increased fasting insulin (0.6 µU/mL per month). Changes in GSH correlate strongly with changes in HbA1c, 8-OHdG, and fasting insulin in the elder cohort. The model estimates strongly suggest it improves the rate of replenishment in erythrocytic GSH stores and reduces oxidative DNA damage. Elder and younger T2D patients respond differently to GSH supplementation: It improves the rate of reduction in HbA1c and increases fasting insulin in elder patients. These model forecasts have clinical implications that aid in personalizing treatment targets for using oral GSH as adjuvant therapy in diabetes.

Assessment of height growth in Indian children using growth centiles and growth curves.

BACKGROUND: Growth centiles and growth curves are two ways to present child anthropometry; however, they differ in the type of data used, the method of analysis, the biological parameters fitted and the form of interpretation. AIM: To fit and compare height growth centiles and curves in Indian children. SUBJECTS AND METHODS: 1468 children (796 boys) from Pune India aged 6-18 years with longitudinal data on age and height (n = 7781) were analysed using GAMLSS (Generalised Additive Models for Location Scale and Shape) for growth centiles, and SITAR (SuperImposition by Rotation and Translation) for growth curves. RESULTS: SITAR explained 98.7% and 98.8% of the height variance in boys and girls, with mean age at peak height velocity 13.1 and 11.0 years, and mean peak velocity 9.0 and 8.0 cm/year, respectively. GAMLSS (Box-Cox Cole Green model) also captured the pubertal growth spurt but the centiles were shallower than the SITAR mean curve. Boys showed a mid-growth spurt at age 8 years. CONCLUSION: GAMLSS displays the distribution of height in the population by age and sex, while SITAR effectively and parsimoniously summarises the pattern of height growth in individual children. The two approaches provide distinct, useful information about child growth.

A comparison of bone age assessments using automated and manual methods in children of Indian ethnicity.

BACKGROUND: Bone age is useful for pediatric endocrinologists in evaluating various disorders related to growth and puberty. Traditional methods of bone age assessment, namely Greulich and Pyle (GP) and Tanner-Whitehouse (TW), have intra- and interobserver variations. Use of computer-automated methods like BoneXpert might overcome these subjective variations. OBJECTIVE: The aim of our study was to assess the validity of BoneXpert in comparison to manual GP and TW methods for assessing bone age in children of Asian Indian ethnicity. MATERIALS AND METHODS: We extracted from a previous study the deidentified left hand radiographs of 920 healthy children aged 2-19 years. We compared bone age as determined by four well-trained manual raters using GP and TW methods with the BoneXpert ratings. We computed accuracy using root mean square error (RMSE) to assess how close the bone age estimated by BoneXpert was to the reference rating. RESULTS: The standard deviations (SDs) of rating among the four manual raters were 0.52 years, 0.52 years and 0.47 years for GP, TW2 and TW3 methods, respectively. The RMSEs between the automated bone age estimates and the true ratings were 0.39 years, 0.41 years and 0.36 years, respectively, for the same methods. The RMSE values were significantly lower in girls than in boys (0.53, 0.5 and 0.47 vs. 0.39, 0.47 and 0.4) by all the methods; however, no such difference was noted in classification by body mass index. The best agreement between BoneXpert and manual rating was obtained by using 50% weight on carpals (GP50). The carpal bone age was retarded in Indian children, more so in boys. CONCLUSION: BoneXpert was accurate and performed well in estimating bone age by both GP and TW methods in healthy Asian Indian children; the error was larger in boys. The GP50 establishes "backward compatibility" with manual rating.

Randomized Clinical Trial of How Long-Term Glutathione Supplementation Offers Protection from Oxidative Damage and Improves HbA1c in Elderly Type 2 Diabetic Patients.

Complications in type 2 diabetes (T2D) arise from hyperglycemia-induced oxidative stress. Here, we examined the effectiveness of supplementation with the endogenous antioxidant glutathione (GSH) during anti-diabetic treatment. A total of 104 non-diabetic and 250 diabetic individuals on anti-diabetic therapy, of either sex and aged between 30 and 78 years, were recruited. A total of 125 diabetic patients were additionally given 500 mg oral GSH supplementation daily for a period of six months. Fasting and PP glucose, insulin, HbA1c, GSH, oxidized glutathione (GSSG), and 8-hydroxy-2-deoxy guanosine (8-OHdG) were measured upon recruitment and after three and six months of supplementation. Statistical significance and effect size were assessed longitudinally across all arms. Blood GSH increased (Cohen's d = 1.01) and 8-OHdG decreased (Cohen's d = −1.07) significantly within three months (p < 0.001) in diabetic individuals. A post hoc sub-group analysis showed that HbA1c (Cohen's d = −0.41; p < 0.05) and fasting insulin levels (Cohen's d = 0.56; p < 0.05) changed significantly in diabetic individuals above 55 years. GSH supplementation caused a significant increase in blood GSH and helped maintain the baseline HbA1c overall. These results suggest GSH supplementation is of considerable benefit to patients above 55 years, not only supporting decreased glycated hemoglobin (HbA1c) and 8-OHdG but also increasing fasting insulin. The clinical implication of our study is that the oral administration of GSH potentially complements anti-diabetic therapy in achieving better glycemic targets, especially in the elderly population.

Gabrb3 endothelial cell-specific knockout mice display abnormal blood flow, hypertension, and behavioral dysfunction.

Our recent studies uncovered a novel GABA signaling pathway in embryonic forebrain endothelial cells that works independently from neuronal GABA signaling and revealed that disruptions in endothelial GABAA receptor-GABA signaling from early embryonic stages can directly contribute to the origin of psychiatric disorders. In the GABAA receptor ß3 subunit endothelial cell conditional knockout (Gabrb3ECKO) mice, the ß3 subunit is deleted selectively from endothelial cells, therefore endothelial GABAA receptors become inactivated and dysfunctional. There is a reduction in vessel densities and increased vessel morphology in the Gabrb3ECKO telencephalon that persists in the adult neocortex. Gabrb3ECKO mice show behavioral deficits such as impaired reciprocal social interactions, communication deficits, heightened anxiety, and depression. Here, we characterize the functional changes in Gabrb3ECKO mice by evaluating cortical blood flow, examine the consequences of loss of endothelial Gabrb3 on cardiac tissue, and define more in-depth altered behaviors. Red blood cell velocity and blood flow were increased in the cortical microcirculation of the Gabrb3ECKO mice. The Gabrb3ECKO mice had a reduction in vessel densities in the heart, similar to the brain; exhibited wavy, myocardial fibers, with elongated 'worm-like' nuclei in their cardiac histology, and developed hypertension. Additional alterations in behavioral function were observed in the Gabrb3ECKO mice such as increased spontaneous exploratory activity and rearing in an open field, reduced short term memory, decreased ambulatory activity in CLAMS testing, and altered prepulse inhibition to startle, an important biomarker of psychiatric diseases such as schizophrenia. Our results imply that vascular Gabrb3 is a key player in the brain as well as the heart, and its loss in both organs can lead to concurrent development of psychiatric and cardiac dysfunction.

A Minimal Model Approach for Analyzing Continuous Glucose Monitoring in Type 2 Diabetes.

Continuous glucose monitoring (CGM), a technique that records blood glucose at a regular intervals. While CGM is more commonly used in type 1 diabetes, it is increasingly becoming attractive for treating type 2 diabetic patients. The time series obtained from a CGM provides a rich picture of the glycemic state of the subjects and may help have tighter control on blood sugar by revealing patterns in their physiological responses to food. However, despite its importance, the biophysical understanding of CGM is far from complete. CGM data series is complex not only because it depends on the composition of the food but also varies with individual physiology. All of these make a full modeling of CGM data a difficult task. Here we propose a simple model to explain CGM data in type 2 diabetes. The model combines a relatively simple glucose-insulin dynamics with a two-compartment food model. Using CGM data of a healthy and a diabetic individual we show that this model can capture liquid meals well. The model also allows us to estimate the parameters in a relatively straightforward manner. This opens up the possibility of personalizing the CGM data. The model also predicts insulin time series from the model, and the rate of appearance of glucose due to food. Our methodology thus paves the way for novel analyses of CGM which have not been possible before.

Deletion of Nedd4-2 results in progressive kidney disease in mice.

NEDD4-2 (NEDD4L), a ubiquitin protein ligase of the Nedd4 family, is a key regulator of cell surface expression and activity of the amiloride-sensitive epithelial Na+ channel (ENaC). While hypomorphic alleles of Nedd4-2 in mice show salt-sensitive hypertension, complete knockout results in pulmonary distress and perinatal lethality due to increased cell surface levels of ENaC. We now show that Nedd4-2 deficiency in mice also results in an unexpected progressive kidney injury phenotype associated with elevated ENaC and Na+Cl- cotransporter expression, increased Na+ reabsorption, hypertension and markedly reduced levels of aldosterone. The observed nephropathy is characterized by fibrosis, tubule epithelial cell apoptosis, dilated/cystic tubules, elevated expression of kidney injury markers and immune cell infiltration, characteristics reminiscent of human chronic kidney disease. Importantly, we demonstrate that the extent of kidney injury can be partially therapeutically ameliorated in mice with nephron-specific deletions of Nedd4-2 by blocking ENaC with amiloride. These results suggest that increased Na+ reabsorption via ENaC causes kidney injury and establish a novel role of NEDD4-2 in preventing Na+-induced nephropathy. Contrary to some recent reports, our data also indicate that ENaC is the primary in vivo target of NEDD4-2 and that Nedd4-2 deletion is associated with hypertension on a normal Na+ diet. These findings provide further insight into the critical function of NEDD4-2 in renal pathophysiology.

A Decision Tree Analysis of Diabetic Foot Amputation Risk in Indian Patients.

AIM: The aim of this study is to create an evidence-based tool that guides the risk of amputation in diabetic foot patients. MATERIALS AND METHODS: Hospital records of 301 diabetic foot patients were examined retrospectively for explanatory variables of foot amputation decisions. The study included all patients with a lower limb ulcer with a known history of diabetes mellitus or those diagnosed post-admission. The dataset was analyzed, and a risk scoring system was constructed using the decision tree algorithm, C5.0. Two classifiers, one simple and another complex, were constructed for predicting amputation outcome. RESULTS AND DISCUSSION: Based on our evaluation, the most influential predictors for a decision to amputate are Doppler flow measurements and the Wagner grading of the ulceration. The simple classifier uses just these two parameters in determining risk. The results obtained show an accuracy of 96.4% in the primary group and an accuracy of 94% in the test group. The second classifier is a more complex computer-derived construct that showed 100% accuracy in the principle group and an accuracy of 96% during testing. CONCLUSION: In the present era of precision medicine, these two classifiers act as an accurate guide to the prognosis of the limb in patients with diabetic foot and can predict the risk of future amputation.

Mathematical Modeling of Glutathione Status in Type 2 Diabetics with Vitamin B12 Deficiency.

Deficiencies in vitamin B12 and glutathione (GSH) are associated with a number of diseases including type 2 diabetes mellitus. We tested newly diagnosed Indian diabetic patients for correlation between their vitamin B12 and GSH, and found it to be weak. Here we seek to examine the theoretical dependence of GSH on vitamin B12 with a mathematical model of 1-carbon metabolism due to Reed and co-workers. We study the methionine cycle of the Reed-Nijhout model by developing a simple "stylized model" that captures its essential topology and whose kinetics are analytically tractable. The analysis shows-somewhat counter-intuitively-that the flux responsible for the homeostasis of homocysteine is, in fact, peripheral to the methionine cycle. Elevation of homocysteine arises from reduced activity of methionine synthase, a vitamin B12-dependent enzyme, however, this does not increase GSH biosynthesis. The model suggests that the lack of vitamin B12-GSH correlation is explained by suppression of activity in the trans-sulfuration pathway that limits the synthesis of cysteine and GSH from homocysteine. We hypothesize this "cysteine-block" is an essential consequence of vitamin B12 deficiency. It can be clinically relevant to appreciate that these secondary effects of vitamin B12 deficiency could be central to its pathophysiology.

Insulin resistance or hypersecretion? The ßIG picture revisited.

Mathematical models of glucose, insulin and pancreatic beta-cell mass dynamics are essential to our understanding of the physiological basis of the development of type 2 diabetes. The classical view of diabetes is that the disease develops due to insulin insufficiency. An alternate viewpoint that has recently staged a revival is that diabetogenesis is a hypersecretion disorder. A prominent model of diabetes progression is the ßIG model due to Topp and coworkers. Here we study two new variants of the Topp model, which we name "Topp-IR" and "Topp-HS". Topp-IR is a model in which increasing insulin resistance is sufficient to drive a system away from health towards hyperglycemia. Topp-HS describes the hypersecretion model in mathematical terms. We thus show that the hypersecretion hypothesis is theoretically sound, and is therefore a potential route to diabetes. On the basis of insights derived from modeling, we clarify several subtleties of that argument, including postulating a central role for transient insulin peaks in driving insulin resistance.