COMPUTER-AIDED QUANTITATIVE EARLY DIAGNOSIS OF DIABETIC FOOT

Diabetes is an incurable metabolic disease characterized by high blood sugar levels. The feet of people with diabetes are at the risk of a variety of pathological consequences including peripheral vascular disease, deformity, ulceration, and ultimately amputation. The key to managing the diabetic foot is prevention and early detection. Unfortunately, current hospital centered reactive diabetes care and the availability of inadequate qualitative diagnostic screening procedures causes physicians to miss the diagnosis in 61% of the patients. We have developed a computer aided diagnostic system for early detection of diabetic foot. The key idea is that diabetic foot exhibits significant neuropathic and vascular damages. When a diabetic foot is placed under cold stress, the thermal recovery will be much slower. This thermal recovery speed can be a quantitative measure for the diagnosis of diabetic foot condition. In our research, thermal recovery of the feet following cold stress is captured using an infrared camera. The captured infrared video is then filtered, segmented, and registered. The temperature recovery at each point on the foot is extracted and analyzed using a thermal regulation model, and the problematic regions are identified. In this thesis, we present our research on the following aspects of the developed computer aided diagnostic systems: subject measurement protocols, a trustful numerical model of the camera noise and noise parameter estimations, infrared video segmentation, new models of thermal regulations, thermal patterns classifications, and our preliminary findings based on small scale clinical study of about 40 subjects, which demonstrated the potential the new diagnostic system

Understanding Hereditary Sensory and Autonomic Neuropathy type IV through a novel knock-in mouse model

in pain sensation. Indeed, a functional NGF-TrkA system is an essential requisite for the generation and maintenance of long-lasting thermal and mechanical hyperalgesia in adult mammals. Mutations in the gene encoding for TrkA are responsible for a rare condition, named Hereditary Sensory and Autonomic Neuropathy type IV (HSAN IV), characterized by the loss of response to noxious stimuli, sweating defects and cognitive impairment. However, to date, there is no available mouse model to properly understand how the NGF-TrkA system can lead to pathological phenotypes that are distinctive of HSAN IV. Since the diversity of HSAN IV TrkA-related mutations determines variable degrees of clinical phenotype and intellectual disabilities in affected individuals, we have decided to deeply investigate the missense Arg649Trp (R649W) mutation, located in the intracellular tyrosine kinase domain of TrkA receptor and known to induce a diminished kinase activity and reduced phosphorylation after NGF stimulation in transfected cells. First, by in vitro biochemical and biophysical analyses, I showed that the pathological R649W mutation leads to kinase-inactive TrkA, reducing the constitutive ubiquitination and also affecting the membrane dynamics and trafficking. Then, after the generation of the knock-in mouse line carrying the HSAN IV TrkAR649W mutation, I demonstrated that TrkAR649W/m mice displayed a lower response to thermal and chemical noxious stimuli, correlating with reduced skin innervation and altered expression of nociceptive markers in Dorsal Root Ganglia (DRGs). By performing a sweat assay, I also found that the pathological TrkAR649W mutation causes sweating deficits in HSAN IV TrkAR649W/m mice compared to TrkAh/m controls. Moreover, the R649W mutation decreased anxiety-like behavior and compromised cognitive abilities, by impairing spatial-working and social memory. In addition, the results obtained in this thesis uncovered unexplored roles of TrkA in thermoregulation and sociability. By exploiting suitable control animal models such as HSAN V NGFR100W/m and TrkA+/- mice, I demonstrated that HSAN IV TrkAR649W/m mice mimic the clinical phenotype of HSAN IV patients and they can be considered a suitable experimental platform to explain the clinical aspect of HSAN IV disease, also offering promising new routes for testing future therapies

Implementation of Thermal and Spectral Image Analysis for Neuropathic Foot

Diabetes is a grave metabolic disease described by high glucose levels. The feet of pa-tients with diabetes are at the danger of a variety of neurotic results including peripheral vascular infection, disfigurement, ulceration, and necrosis (infection caused by localized death of living cells or tissue) leading to amputation. The way to deal with the diabetic foot is anticipation and early location. Sadly, currently health provider’s focus on re-sponsive diabetes mind and the accessibility of lacking subjective demonstrative screen-ing methodology makes doctors miss the finding of a few patients. The main objective is that diabetic foot demonstrates basic neuropathic and vascular symptoms. When a foot patient is inactive, the thermal recuperation will be much slow-er. This thermal response speed can be used as a quantitative measure for the study of diabetic foot condition. In our study, thermal recovery of the foot following cold pressure is discovered using a thermal camera. The captured thermal image is then analysed, and the temperature re-covery at each point on the foot is extracted and calibrated using a thermal control ap-pears, and the precarious regions are recognized. In addition, LED-based spectral imag-ing is tested to estimate oxygen saturation in the foot. In this subject, we show our examinations on the following parts of the implementation of medical application analytic system based on: measurement protocols, thermal image segmentation, new techniques to perform model analysis of gathered images, and our preliminary discoveries focused on small scale clinical investigation of some patients, which demonstrate the potential of the diagnostic system.fi=Opinnäytetyö kokotekstinä PDF-muodossa.|en=Thesis fulltext in PDF format.|sv=Lärdomsprov tillgängligt som fulltext i PDF-format

NONINVASIVE ASSESSMENT AND MODELING OF DIABETIC CARDIOVASCULAR AUTONOMIC NEUROPATHY

Noninvasive assessment of diabetic cardiovascular autonomic neuropathy (AN): Cardiac and vascular dysfunctions resulting from AN are complications of diabetes, often undiagnosed. Our objectives were to: 1) determine sympathetic and parasympathetic components of compromised blood pressure regulation in patients with polyneuropathy, and 2) rank noninvasive indexes for their sensitivity in diagnosing AN. Continuous 12-lead electrocardiography (ECG), blood pressure (BP), respiration, regional blood flow and bio-impedance were recorded from 12 able-bodied subjects (AB), 7 diabetics without (D0), 7 with possible (D1) and 8 with definite polyneuropathy (D2), during 10 minutes supine control, 30 minutes 70-degree head-up tilt and 5 minutes supine recovery. During the first 3 minutes of tilt, systolic BP decreased in D2 while increased in AB. Parasympathetic control of heart rate, baroreflex sensitivity, and baroreflex effectiveness and sympathetic control of heart rate and vasomotion were reduced in D2, compared with AB. Baroreflex effectiveness index was identified as the most sensitive index to discriminate diabetic AN. Four-dimensional multiscale modeling of ECG indexes of diabetic autonomic neuropathy: QT interval prolongation which predicts long-term mortality in diabetics with AN, is well known. The mechanism of QT interval prolongation is still unknown, but correlation of regional sympathetic denervation of the heart (revealed by cardiac imaging) with QT interval in 12-lead ECG has been proposed. The goal of this study is to 1) reproduce QT interval prolongation seen in diabetics, and 2) develop a computer model to link QT interval prolongation to regional cardiac sympathetic denervation at the cellular level. From the 12-lead ECG acquired in the study above, heart rate-corrected QT interval (QTc) was computed and a reduced ionic whole heart mathematical model was constructed. Twelve-lead ECG was produced as a forward solution from an equivalent cardiac source. Different patterns of regional denervation in cardiac images of diabetic patients guided the simulation of pathological changes. Minimum QTc interval of lateral leads tended to be longer in D2 than in AB. Prolonging action potential duration in the basal septal region in the model produced ECG and QT interval similar to that of D2 subjects, suggesting sympathetic denervation in this region in patients with definite neuropathy

Thermographic patterns of the upper and lower limbs : baseline data

This study was supported by an internal University of Malta Research Grant PODRP01-1. The study sponsor had no involvement in the execution and analysis of this study.To collect normative baseline data and identify any significant differences between hand and foot thermographic distribution patterns in a healthy adult population. Design. A single-centre, randomized, prospective study. Methods. Thermographic data was acquired using a FLIR camera for the data acquisition of both plantar and dorsal aspects of the feet, volar aspects of the hands, and anterior aspects of the lower limbs under controlled climate conditions. Results. There is general symmetry in skin temperature between the same regions in contralateral limbs, in terms of both magnitude and pattern. There was also minimal intersubject temperature variation with a consistent temperature pattern in toes and fingers. The thumb is the warmest digit with the temperature falling gradually between the 2nd and the 5th fingers. The big toe and the 5th toe are the warmest digits with the 2nd to the 4th toes being cooler. Conclusion. Measurement of skin temperature of the limbs using a thermal camera is feasible and reproducible. Temperature patterns in fingers and toes are consistent with similar temperatures in contralateral limbs in healthy subjects. This study provides the basis for further research to assess the clinical usefulness of thermography in the diagnosis of vascular insufficiency.peer-reviewe