A personalized clinical assessment: multi-sensor approach for understanding musculoskeletal health in the frail population.

BACKGROUND: Sarcopenia is a muscle disorder causing a progressive reduction of muscle mass and strength, but the mechanism of its manifestation is still partially unknown. The three main parameters to assess are: muscle strength, muscle volume or quality and low physical performance. There is not a definitive approach to assess the musculoskeletal condition of frail population and often the available tests to be performed in those clinical bedridden patients is reduced because of physical impairments. In this paper, we propose a novel instrumental multi-domain and non-invasive approach during a well-defined protocol of measurements for overcoming these limitations. A group of 28 bedridden elder people, subjected to surgery after hip fracture, was asked to perform voluntary isometric contractions at the 80% of their maximum voluntary contraction with the non-injured leg. The sensor employed before and/or during the exercise were: ultrasound to determine the muscle architecture (vastus lateralis); force acquisition with a load cell placed on the chair, giving an indication of the muscle strength; surface electromyography (EMG) for monitoring muscular electrical activity; time-domain (TD) near-infrared spectroscopy (NIRS) for evaluating muscle oxidative metabolism. RESULTS: A personalized "report card" for each subject was created. It includes: the force diagram (both instantaneous and cumulative, expected and measured); the EMG-force diagram for a comparison between EMG derived median frequency and measured force; two graphs related to the hemodynamic parameters for muscle oxidative metabolism evaluation, i.e., oxy-, deoxy-, total-hemoglobin and tissue oxygen saturation for the whole exercise period. A table with the absolute values of the previous hemodynamic parameters during the rest and the ultrasound related parameters are also included. CONCLUSIONS: In this work, we present the union of protocols, multi-domain sensors and parameters for the evaluation of the musculoskeletal condition. The novelties are the use of sensors of different nature, i.e., force, electrical and optical, together with a new way to visualize and combine the results, by means of a concise, exhaustive and personalized medical report card for each patient. This assessment, totally non-invasive, is focused on a bedridden population, but can be extended to the monitoring of rehabilitation progresses or of the training of athletes.

No Difference in Muscle Basal Oxygenation in a Bedridden Population Pre and Post Rehabilitation.

Long periods of bed rest for elderly population, due to a femur fracture event, can cause a deterioration in the muscular capacity. Therefore, monitoring of the muscle oxidative capacity in this fragile population is necessary to define the muscular oxidative metabolism state before and after a rehabilitation period. The time-domain near-infrared spectroscopy (TD-NIRS) technique enables the absolute values to be calculated for hemodynamic parameters such as oxy- (O2Hb), deoxy- (HHb), total- (tHb) haemoglobin, and tissue oxygen saturation (SO2) of the muscular tissue. In this work, we have characterized vastus lateralis muscle hemodynamics during a baseline period at two different time points: after the surgery (PRE) and after 15 days of rehabilitation (POST). The mean values for the absolute values of the hemodynamic parameters were: O2Hb_PRE = 49.1 ± 14.1 µM; O2Hb_POST = 47.1 ± 13.4 µM; HHb_PRE = 28.3 ± 10.3 µM; HHb_POST = 26.7 ± 9.9 µM; tHb_PRE = 77.3 ± 23.6 µM; tHb_POST = 73.8 ± 21.4 µM; SO2_PRE = 63.9 ± 4.0% and SO2_POST = 64.9 ± 5.6%. The hemodynamic parameters did not show significant differences at both group and single subject level. These results suggest that for this kind of population, the baseline of the hemodynamic parameters is not the best one to consider to assess the rehabilitation progresses in terms of muscular oxidative metabolism.

Hemodynamic and EEG Time-Courses During Unilateral Hand Movement in Patients with Cortical Myoclonus. An EEG-fMRI and EEG-TD-fNIRS Study.

Multimodal human brain mapping has been proposed as an integrated approach capable of improving the recognition of the cortical correlates of specific neurological functions. We used simultaneous EEG-fMRI (functional magnetic resonance imaging) and EEG-TD-fNIRS (time domain functional near-infrared spectroscopy) recordings to compare different hemodynamic methods with changes in EEG in ten patients with progressive myoclonic epilepsy and 12 healthy controls. We evaluated O2Hb, HHb and Blood oxygen level-dependent (BOLD) changes and event-related desynchronization/synchronization (ERD/ERS) in the α and ß bands of all of the subjects while they performed a simple motor task. The general linear model was used to obtain comparable fMRI and TD-fNIRS activation maps. We also analyzed cortical thickness in order to evaluate any structural changes. In the patients, the TD-NIRS and fMRI data significantly correlated and showed a significant lessening of the increase in O2Hb and the decrease in BOLD. The post-movement ß rebound was minimal or absent in patients. Cortical thickness was moderately reduced in the motor area of the patients and correlated with the reduction in the hemodynamic signals. The fMRI and TD-NIRS results were consistent, significantly correlated and showed smaller hemodynamic changes in the patients. This finding may be partially attributable to mild cortical thickening. However, cortical hyperexcitability, which is known to generate myoclonic jerks and probably accounts for the lack of EEG ß-ERS, did not reflect any increased energy requirement. We hypothesize that this is due to a loss of inhibitory neuronal components that typically fire at high frequencies.

Non-contact time-resolved diffuse reflectance imaging at null source-detector separation.

We report results of the proof-of-principle tests of a novel non-contact tissue imaging system. The system utilizes a quasi-null source-detector separation approach for time-domain near-infrared spectroscopy, taking advantage of an innovative state-of-the-art fast-gated single photon counting detector. Measurements on phantoms demonstrate the feasibility of the non-contact approach for the detection of optically absorbing perturbations buried up to a few centimeters beneath the surface of a tissue-like turbid medium. The measured depth sensitivity and spatial resolution of the new system are close to the values predicted by Monte Carlo simulations for the inhomogeneous medium and an ideal fast-gated detector, thus proving the feasibility of the non-contact approach for high density diffuse reflectance measurements on tissue. Potential applications of the system are also discussed.

Monitoring the haemodynamic response to visual stimulation in glaucoma patients.

In this paper, we used time-domain functional near infrared spectroscopy (TD-fNIRS) to evaluate the haemodynamic response function (HRF) in the occipital cortex following visual stimulation in glaucomatous eyes as compared to healthy eyes. A total of 98 subjects were enrolled in the study and clinically classified as healthy subjects, glaucoma patients (primary open-angle glaucoma) and mixed subjects (i.e. with a different classification for the two eyes). After quality check data were used from HRF of 73 healthy and 62 glaucomatous eyes. The amplitudes of the oxygenated and deoxygenated haemoglobin concentrations, together with their latencies with respect to the stimulus onset, were estimated by fitting their time course with a canonical HRF. Statistical analysis showed that the amplitudes of both haemodynamic parameters show a significant association with the pathology and a significant discriminating ability, while no significant result was found for latencies. Overall, our findings together with the ease of use and noninvasiveness of TD-NIRS, make this technique a promising candidate as a supporting tool for a better evaluation of the glaucoma pathology.

Coronary artery perforations in the contemporary interventional era.

BACKGROUND: Coronary perforations represent a serious complication of percutaneous coronary intervention (PCI). METHODS: We performed a retrospective analysis of documented coronary perforations at Massachusetts General Hospital from 2000 to 2008. Medical records review and detailed angiographic analysis were performed in all patients. RESULTS: Sixty-eight cases of coronary perforation were identified from a total of 14,281 PCIs from March 2000 to March 2008 representing an overall incidence of 0.48%. The study cohort was predominantly male (61.8%), mean age 71+/-11 years with 78% representing acute cases (unstable angina: 36.8%, NSTEMI: 30.9%, STEMI: 10.3%). Coronary artery perforation occurred as a complication of wire manipulation in 45 patients (66.2%) with 88.9% of this group being hydrophilic wires, of coronary stenting in 11 (16.2%), of angioplasty alone in 6 (8.8%), and of rotational atherectomy in 8 (11.8%). The perforation was sealed with an angioplasty balloon alone in 16 patients (23.5%), and with stents in 14 patients (20.6%) (covered stents: 11.8% and noncovered stents: 8.8%). Emergency CABG was performed in 2 patients (2.9%). Five patients (7.4%) developed periprocedural MI. The in-hospital mortality rate was 5.9% in the study cohort. CONCLUSION: Coronary artery perforation as a complication of PCI is still rare as demonstrated in our series with an incidence of 0.48%. The predominant cause of coronary perforations in the current era of PCI is wire injury.

Bandpass effects in time-resolved diffuse spectroscopy.

This paper discusses the spectral distortions occurring when time-resolved spectroscopy of diffusive media is performed illuminating with a wide bandpass. It is shown that the spectral region within the bandpass that exhibits the lowest absorption will dominate the resulting time-resolved curve, leading to significant underestimations of absorption as well as distortions in the spectral shape (including shifts in peak positions). Due to the nonlinear behavior of absorption, this effect becomes even more pronounced when including longer and longer photon path lengths. First, a theoretical treatment of the problem is given, and then the distortion is described by time-resolved reflectance simulations and experimental measurements of lipid and water samples. A spectrally constrained data analysis is proposed that takes into account the spectrum of the light injected into the sample, used to overcome the distortion and improve the accuracy of the estimation of chromophore concentrations from absorption spectra. Measurements on a lipid sample show a reduction of the error from 30% to 6%.

Time-resolved optical spectroscopy of wood.

We have proposed and experimentally demonstrated that picosecond time-resolved optical spectroscopy in the visible/near-infrared (NIR) region (700-1040 nm) is a useful technique for noninvasive characterization of wood. This technique has been demonstrated on both softwood and hardwood samples treated in different ways simulating the aging process suffered by waterlogged woods. In all the cases, alterations of absorption and scattering spectra were observed, revealing changes of chemical and structural composition.

Time-resolved spectrally constrained method for the quantification of chromophore concentrations and scattering parameters in diffusing media.

We have devised and experimentally validated, on tissue-simulating phantoms and in vivo, a time-resolved spectral fitting analysis for direct assessment of chromophore concentrations and scattering parameters. Experimental data have been acquired with a time-resolved broadband system based on supercontinuum light generated in a photonic crystal fiber and a 32 channel Time Correlated Single Photon Counting system. The novel method is more robust than conventional techniques, especially at low signal-to-noise ratio.

Effects of laser irradiation on hematoporphyrin-treated normal and transformed thyroid cells in culture.

Laser irradiation of tissues treated in vivo with the hematoporphyrin derivative (HPD) is known to result in a cytocidal effect, reportedly more pronounced in the tumor than in the surrounding normal tissues. In order to ascertain if this phenomenon had a clear cellular basis, it has been now reproduced in vitro in a model system consisting of normal and transformed cell lines. Epithelial rat thyroid cells were infected and transformed with a RNA oncogenic virus. Both the original (normal) and the viral-transformed (tumorigenic) cells were incubated with HPD and exposed to two types of laser irradiation: 631 nm, continuous wave; and 337.1 nm, pulsed. Under the conditions tested, the percentage survival of the transformed cells was found to be lower (up to approximately 3 times) than that of the normal cells. The cytocidal effect was greater using the pulsed than using the continuous-wave irradiation. The difference between normal and tumor cells was more evident at 30 micrograms than at 50 micrograms of HPD per ml. The HPD not followed by laser irradiation had no effect on the cell growth rate. The findings of a significant difference in the sensitivity to photoactivated HPD between normal and tumor cells under strictly controlled and highly comparable conditions opens new possibilities to the study of the cellular and molecular mechanisms involved in the phototherapy of tumors. Furthermore, studies in vitro on the active components of the photosensitizer and on their selectivity towards the tumor cells, explained at a cellular level, will lead to better approaches to photochemotherapy in vivo.

Analyzing integrated circuits at work with a picosecond time-gated imager.

A system based on a picosecond time-gated image intensifier is proposed for non-contact testing of CMOS circuits. The apparatus allows one to record the temporal evolution of the luminescence emitted during transistor switching as a function of the position inside the chip. The system is characterized by an intrinsic parallelism in the spatial dimensions. This feature is noticeable for studying wide sections of complex circuits, like microprocessors and random access memories, where multiple electrical events occur simultaneously. Experiments on a CMOS inverter chain and on a static memory have been carried out, in order to demonstrate the applicability of a picosecond time-gated imager to circuit analysis.

Determination of visible near-IR absorption coefficients of mammalian fat using time- and spatially resolved diffuse reflectance and transmission spectroscopy.

In-vivo optical spectroscopy and the determination of tissue absorption and scattering properties have a central role in the development of novel optical diagnostic and therapeutic modalities in medicine. A number of techniques are available for the optical characterization of tissue in the visible near-IR region of the spectrum. An important consideration for many of these techniques is the reliability of the absorption spectrum of the various constituents of tissue. The availability of accurate absorption spectra in the range 600 to 1100 nm may allow for the determination of the concentration of key tissue constituents such as oxy- and deoxy-hemoglobin, water, and lipids. The objective of the current study is the determination of a reliable absorption spectrum of lipid(s) that can be used for component analysis of in-vivo spectra. We report the absorption spectrum of a clear purified oil obtained from pig lard. In the liquid phase above 36 degrees C, the oil is transparent and thus suitable for collimated transmission measurements. At room temperature, the oil is a solid grease that is highly scattering. The absorption and scattering properties in this solid phase are measured using time- and spatially resolved diffuse reflectance spectroscopy. Using these three independent measurement techniques, we have determined an accurate estimate for the absorption spectrum of mammalian fat.

Multi-wavelength time domain optical mammography.

A time-resolved optical mammograph operating at 7 wavelengths (637, 683, 785, 832, 905, 916, and 975 nm) in compressed breast geometry was developed. Its clinical application was started on patients bearing malignant and benign lesions. Late gated intensity images are used to obtain information on the spatial distribution of the absorption properties of breast. Scattering images derived from the diffusion theory are also applied for lesion detection and characterization. Cancers are identified in intensity images at short wavelengths, due to the high blood content, while cysts are typically characterized by low scattering at all wavelengths. The increase (from 4 to 7) in the number of wavelengths as compared to the previous versions of the instrument aims at improving the robustness of the fitting procedures for a better estimate of tissue composition and structure and of physiological parameters. Moreover, the new wavelengths contribute to the qualitatively identify tissue composition from intensity images, and could assist lesion detection.

Photodynamic therapy of spontaneous animal tumors using the active component of hematoporphyrin derivative (DHE) as photosensitizing drug: clinical results.

Photodynamic therapy was performed on 25 primary spontaneous tumors in dogs and cats. The animals were injected with 2.5 mg/kg body wt. of tumor localizing fraction of hematoporphyrin derivative and treated 48 h later with laser light at 631 nm. In 5 cases the treatment was performed on the tumor bed after surgical excision of the tumor mass. An evaluation of clinical results is presented and discussed. Complete remission was obtained in 19 cases and partial remission in 6 cases.

Hematoporphyrin derivative photochemotherapy of spontaneous animal tumors: clinical results with optimized drug dose.

Hematoporphyrin derivative (HpD) photochemotherapy was performed on 13 primary spontaneous tumors in dog and cat. The animals received an optimized drug dose of 5 mg/kg body wt i.v. 48 h before the first treatment with laser light at 631 nm. An evaluation of the clinical results is presented and discussed. Complete disappearance of the primary tumors was obtained in all cases with one or more light irradiations. Five cases presented recurrences that were cured with a further treatment. In 4 cases treated after surgical exeresis of the primary tumors, this therapy resulted in complete cure.

Comparative study of the therapeutic effect of photoactivated hematoporphyrin derivative and aluminum disulfonated phthalocyanines on tumor bearing mice.

Although the hematoporphyrin derivative (Hpd) is one of the most studied photosensitisers for photodynamic therapy (PDT), it is far from ideal. Therefore, many laboratories have been investigating a new group of sensitisers, the phthalocyanines. Particularly, in our laboratory we decided to study the aluminum disulfonated phthalocyanines (AlS2PC). They are chemically stable, readily soluble in water and have a strong absorption in the red part of the spectrum at 675 nm. Mice bearing the MS-2 fibrosarcoma treated with 5 mg/kg of AlS2PC survived indefinitely also using a low laser power of 100 mW/cm2 X 10' of exposure time, in contrast to experiments carried out with Hpd where the optical therapeutic laser power was 400 mW/cm2 X 10' and the dose of Hpd was 25 mg/kg. Furthermore, treatment of mice bearing the highly metastatic tumor, B16 melanoma, with 5 mg/kg of AlS2PC and laser light (100 mW/cm2 X 10'), significantly prolonged the survival time in respect to mice treated with 25 mg/kg of Hpd and laser light (400 mW/cm2 X 10').

Hematoporphyrin derivative photoradiation therapy in murine solid tumors.

The cytocidal activity of light-activated hematoporphyrin derivative (Hpd) in experimental and human tumors is under investigation in many laboratories. This activity is based upon preferential incorporation of Hpd in malignant tissues and its photosensibilization by red light. Treatment of mice bearing MS-2 fibrosarcoma and B16 melanoma, a metastastic tumor, with Hpd and laser light, externally or delivered through a quartz fiber optic imbedded directly into the tumor, significantly prolonged the median survival time. This therapy was compared with surgical excision of primary tumors, and preliminary results on metastatic neoplasm suggest that the photoradiation therapy is more effective than surgery.

Antitumor efficacy of the combination of photodynamic therapy and chemotherapy in murine tumors.

Photodynamic therapy (PDT) is based on the administration of tumor-localizing photosensitizers followed by light exposure of the tumor mass. The photocytotoxic effects are mainly caused by the generation of singlet oxygen. Recently, PDT has been proposed for use in combination with anticancer chemotherapy with a view to exploiting any additive antitumor effect. We investigated the effect of PDT with photoactivated aluminum disulfonated phthalocyanine (AlS2Pc) combined with the antiblastic drugs Adriamycin (ADR) and cisplatinum (CDDP) on murine tumors. Mice bearing L1210 leukemia and P388 lymphoma were treated with ADR or CDDP and subsequently treated with PDT. Low chemotherapy doses were ineffective, but the combination of antiblastic drugs + PDT had a significantly additive antitumor effect. In conclusion, with this combined therapy we were able to greatly reduce the effective doses of antiblastic drugs, thus lowering their toxic effects on normal host tissues.

Efficacy of photodynamic therapy against doxorubicin-resistant murine tumors.

Photodynamic therapy (PDT) is a relatively new cancer treatment modality that employs light excitation of a photosensitizer to yield cytotoxic oxygen-related species. In the present study we explored whether PDT would have therapeutic effect against doxorubicin-resistant murine tumors. We compared the efficacy of PDT with aluminium disulphonated phthalocyanine (A1S2Pc) and laser light on the doxorubicin-sensitive murine tumors, B16 melanoma (B16), L1210 leukemia (L1210), P388 lymphoma (P388) and the corresponding doxorubicin-resistant lines (B16/Dx, L1210/Dx and P388/Dx). Mice bearing L1210-L1210/Dx, P388-P388/Dx and B16-B16/Dx, were treated with 5 mg/kg of A1S2Pc and laser light (100 mW/cm2 x 10 min of exposure) or with doxorubicin (10 or 12 mg/kg i.v.). The results show that PDT is active versus all tumors while doxorubicin is effective only against the three sensitive tumor lines (L1210, P388 and B16). These observations suggest that PDT might be a beneficial alternative treatment for drug-resistant tumors.

Liquid phantom for investigating light propagation through layered diffusive media.

A liquid phantom for investigating light propagation through layered diffusive media is described. The diffusive medium is an aqueous suspension of calibrated scatterers and absorbers. A thin membrane separates layers with different optical properties. Experiments showed that a material with scattering properties should be used for the membrane to avoid the perturbation due to the guided propagation that occurs through a transparent layer. Examples of measurements on a three-layered medium are reported both in the cw and in the time domain.