Assessment of Spinal Cord Ischemia With Near-Infrared Spectroscopy: Myth or Reality?

Non-invasive near-infrared spectroscopy is gaining popularity in the detection of spinal cord ischemia following aortic aneurysm repair. However, practical recommendations are lacking. This review focuses on the physiological and anatomical background, as well as on the clinical implementations of near-infrared spectroscopy as a tool for monitoring ischemia of the spinal cord. Clinical recommendations based on the currently available evidence are rendered.

Phenotypic spectrum of Charcot-Marie-Tooth disease due to LITAF/SIMPLE mutations: a study of 18 patients.

BACKGROUND AND PURPOSE: Charcot-Marie-Tooth (CMT) 1C due to mutations in LITAF/SIMPLE is a rare subtype amongst the autosomal dominant demyelinating forms of CMT. Our objective was to report the clinical and electrophysiological characteristics of 18 CMT1C patients and compare them to 20 patients with PMP22 mutations: 10 CMT1A patients and 10 patients with hereditary neuropathy with liability to pressure palsies (HNPP). METHODS: Charcot-Marie-Tooth 1C patients were followed-up in referral centres for neuromuscular diseases or were identified by familial survey. All CMT1A and HNPP patients were recruited at the referral centre for neuromuscular diseases of Pitié-Salpêtrière Hospital. RESULTS: Two phenotypes were identified amongst 18 CMT1C patients: the classical CMT form ('CMT-like', 11 cases) and a predominantly sensory form ('sensory form', seven cases). The mean CMT neuropathy score was 4.45 in CMT1C patients. Motor nerve conduction velocities in the upper limbs were significantly more reduced in CMT1A than in CMT1C patients. On the other hand, the motor nerve conduction velocity of the median nerve was significantly lower in CMT1C compared to the HNPP group. Distal motor latency was significantly more prolonged in CMT1A patients compared to the CMT1C and HNPP groups, the latter two groups having similar distal motor latency values. Molecular analysis revealed five new LITAF/SIMPLE mutations (Ala111Thr, Gly112Ala, Trp116Arg, Pro135Leu, Arg160Cys). CONCLUSIONS: Our study delineates CMT1C as mostly a mild form of neuropathy, and gives clinical and electrophysiological clues differentiating CMT1C from CMT1A and HNPP. Delineating phenotypes in CMT subtypes is important to orient molecular diagnosis and to help to interpret complex molecular findings.

The effect of hydroxyethyl starch 6% 130/0.4 compared with gelatin on microvascular reactivity.

We compared the effects on microvascular reactivity of hydroxyethylstarch (Volulyte(®) ) and gelatin (Geloplasma(®) ) during acute haemodilution. The hypothesis was that Volulyte would provide better microvascular reactivity than Geloplasma. Forty patients undergoing elective cardiac surgery were randomly assigned to receive either Volulyte or Geloplasma as the exclusive priming solution of the cardiopulmonary bypass. To evaluate microvascular reactivity, postocclusive reactive hyperaemia was examined before and after cardiopulmonary bypass. Microvascular reactivity assessments included the rate of the occlusion and reperfusion slopes and reperfusion times. After cardiopulmonary bypass, increases in reperfusion time were significantly smaller in the Volulyte group (3 (-27 to 9 [-35 to 33]%) vs 29 (-17 to 76 [-34 to 137]%) in the Geloplasma group, p = 0.02 between groups). Rate of reperfusion increased in the Volulyte group (26 (-17 to 43 [-59 to 357])%), whereas it decreased in the Geloplasma group (-22 (-47 to 16 [-84 to 113])%), p = 0.02 between groups. The shorter reperfusion times and increased reperfusion rate suggest that Volulyte maintains better microvascular reactivity than Geloplasma.

Relation between mixed venous oxygen saturation and cerebral oxygen saturation measured by absolute and relative near-infrared spectroscopy during off-pump coronary artery bypass grafting.

BACKGROUND: We hypothesized that previously reported contradictory results regarding the equivalence of mixed venous (Smv(O(2))) and cerebral (rS(c)O(2)) oxygen saturation might be related to time delay issues and to measurement technology. In order to explore these two factors, we designed a prospective clinical study comparing with relative (INVOS(®)) and absolute (Foresight(®)) rS(c)O(2) measurements. METHODS: Forty-two consenting patients undergoing elective off-pump coronary artery bypass grafting were included. Two INVOS and two Foresight sensors continuously registered rS(c)O(2). Smv(O(2)) was measured continuously via a pulmonary artery catheter. Data were assessed by within- and between-group comparisons and correlation analysis. RESULTS: A similar time delay of 19 (4) and 18 (4) s was found for compared with rS(c)O(2) measurements by Foresight and INVOS, respectively, during haemodynamic changes. After adjusting for this time delay, the correlation between Smv(O(2)) and rS(c)O(2) increased from r=0.25 to 0.75 (P<0.001) for Foresight, and from r=0.28 to 0.73 (P<0.001) for INVOS. Comparison of Foresight and INVOS revealed significant differences in absolute rS(c)O(2) values (range 58-89% for Foresight and 28-95% for INVOS). Changes in rS(c)O(2) in response to acute haemodynamic alterations were significantly more pronounced with INVOS compared with Foresight (P<0.001). CONCLUSIONS: Considering the important time delay with Smv(O(2)), rS(c)O(2) seems to reflect more appropriately acute haemodynamic alterations. This might suggest its use as a valid alternative to invasive monitoring of tissue oxygen saturation. Relative and absolute rS(c)O(2) measurements demonstrated significant differences in measured rS(c)O(2) values and in the magnitude of rS(c)O(2) changes during haemodynamic alterations.

Influence of variations in systemic blood flow and pressure on cerebral and systemic oxygen saturation in cardiopulmonary bypass patients.

BACKGROUND: Although both pressure and flow are considered important determinants of regional organ perfusion, the relative importance of each is less established. The aim of the present study was to evaluate the impact of variations in flow, pressure, or both on cerebral and whole-body oxygen saturation. METHODS: Thirty-four consenting patients undergoing elective cardiac surgery on cardiopulmonary bypass were included. Using a randomized cross-over design, four different haemodynamic states were simulated: (i) 20% flow decrease, (ii) 20% flow decrease with phenylephrine to restore baseline pressure, (iii) 20% pressure decrease with sodium nitroprusside (SNP) under baseline flow, and (iv) increased flow with baseline pressure. The effect of these changes was evaluated on cerebral (Sc(O2)) and systemic (Sv(O2)) oxygen saturation, and on systemic oxygen extraction ratio (OER). Data were assessed by within- and between-group comparisons. RESULTS: Decrease in flow was associated with a decrease in [from 63.5 (7.4) to 62.0 (8.5) %, P<0.001]. When arterial pressure was restored with phenylephrine during low flow, Sc(O2) further decreased from 61.0 (9.7) to 59.2 (10.2) %, P<0.001. Increase in flow was associated with an increase in Sc(O2) from 62.6 (7.7) to 63.6 (8.9) %, P=0.03, while decreases in pressure with the use of SNP did not affect Sc(O2). Sv(O2) was significantly lower (P<0.001) and OER was significantly higher (P<0.001) in the low flow arms. CONCLUSIONS: In the present elective cardiac surgery population, Sc(O2) and Sv(O2) were significantly lower with lower flow, regardless of systemic arterial pressure. Moreover, phenylephrine administration was associated with a reduced cerebral and systemic oxygen saturation.

The Correlation Between Wall Shear Stress and Plaque Composition in Advanced Human Carotid Atherosclerosis.

The role of wall shear stress (WSS) in atherosclerotic plaque development is evident, but the relation between WSS and plaque composition in advanced atherosclerosis, potentially resulting in plaque destabilization, is a topic of discussion. Using our previously developed image registration pipeline, we investigated the relation between two WSS metrics, time-averaged WSS (TAWSS) and the oscillatory shear index (OSI), and the local histologically determined plaque composition in a set of advanced human carotid plaques. Our dataset of 11 carotid endarterectomy samples yielded 87 histological cross-sections, which yielded 511 radial bins for analysis. Both TAWSS and OSI values were subdivided into patient-specific low, mid, and high tertiles. This cross-sectional study shows that necrotic core (NC) size and macrophage area are significantly larger in areas exposed to high TAWSS or low OSI. Local TAWSS and OSI tertile values were generally inversely related, as described in the literature, but other combinations were also found. Investigating the relation between plaque vulnerability features and different combinations of TAWSS and OSI tertile values revealed a significantly larger cap thickness in areas exposed to both low TAWSS and low OSI. In conclusion, our study confirmed previous findings, correlating high TAWSS to larger macrophage areas and necrotic core sizes. In addition, our study demonstrated new relations, correlating low OSI to larger macrophage areas, and a combination of low TAWSS and low OSI to larger cap thickness.

Near-infrared spectroscopy (NIRS) monitoring in contemporary anesthesia and critical care.

Near-infrared spectroscopy (NIRS) is a noninvasive technology that continuously monitors regional tissue oxygenation. Originally used for assessment of oxygen saturation of the brain, its use has now been expanded to evaluation of oxygenation of tissues other than the brain. There is also growing evidence for the larger applicability of NIRS as an estimate of systemic venous saturation in correspondence with the adequacy of the circulatory status. New and promising advances may further this technology to become part of our standard armamentarium, in order to optimize patient care in daily anesthesia practice. The present paper briefly reviews the basic principles of operation, the inherent limitations of the technology and the clinical data that have been acquired with NIRS monitoring in the broad field of acute clinical medicine.

An MRI-based method to register patient-specific wall shear stress data to histology.

Wall shear stress (WSS), the frictional force exerted on endothelial cells by blood flow, is hypothesised to influence atherosclerotic plaque growth and composition. We developed a methodology for image registration of MR and histology images of advanced human carotid plaques and corresponding WSS data, obtained by MRI and computational fluid dynamics. The image registration method requires four types of input images, in vivo MRI, ex vivo MRI, photographs of transversally sectioned plaque tissue and histology images. These images are transformed to a shared 3D image domain by applying a combination of rigid and non-rigid registration algorithms. Transformation matrices obtained from registration of these images are used to transform subject-specific WSS data to the shared 3D image domain as well. WSS values originating from the 3D WSS map are visualised in 2D on the corresponding lumen locations in the histological sections and divided into eight radial segments. In each radial segment, the correlation between WSS values and plaque composition based on histological parameters can be assessed. The registration method was successfully applied to two carotid endarterectomy specimens. The resulting matched contours from the imaging modalities had Hausdorff distances between 0.57 and 0.70 mm, which is in the order of magnitude of the in vivo MRI resolution. We simulated the effect of a mismatch in the rigid registration of imaging modalities on WSS results by relocating the WSS data with respect to the stack of histology images. A 0.6 mm relocation altered the mean WSS values projected on radial bins on average by 0.59 Pa, compared to the output of original registration. This mismatch of one image slice did not change the correlation between WSS and plaque thickness. In conclusion, we created a method to investigate correlations between WSS and plaque composition.

Temporal and spatial changes in wall shear stress during atherosclerotic plaque progression in mice.

Wall shear stress (WSS) is involved in atherosclerotic plaque initiation, yet its role in plaque progression remains unclear. We aimed to study (i) the temporal and spatial changes in WSS over a growing plaque and (ii) the correlation between WSS and plaque composition, using animal-specific data in an atherosclerotic mouse model. Tapered casts were placed around the right common carotid arteries (RCCA) of ApoE-/- mice. At 5, 7 and 9 weeks after cast placement, RCCA geometry was reconstructed using contrast-enhanced micro-CT. Lumen narrowing was observed in all mice, indicating the progression of a lumen intruding plaque. Next, we determined the flow rate in the RCCA of each mouse using Doppler Ultrasound and computed WSS at all time points. Over time, as the plaque developed and further intruded into the lumen, absolute WSS significantly decreased. Finally at week 9, plaque composition was histologically characterized. The proximal part of the plaque was small and eccentric, exposed to relatively lower WSS. Close to the cast a larger and concentric plaque was present, exposed to relatively higher WSS. Lower WSS was significantly correlated to the accumulation of macrophages in the eccentric plaque. When pooling data of all animals, correlation between WSS and plaque composition was weak and no longer statistically significant. In conclusion, our data showed that in our mouse model absolute WSS strikingly decreased during disease progression, which was significantly correlated to plaque area and macrophage content. Besides, our study demonstrates the necessity to analyse individual animals and plaques when studying correlations between WSS and plaque composition.

The effect of the heart rate lowering drug Ivabradine on hemodynamics in atherosclerotic mice.

The heart rate lowering drug Ivabradine was shown to improve cardiac outcome in patients with previous heart failure. However, in patients without heart failure, no beneficial effect of Ivabradine was observed. Animal studies suggested a preventive effect of Ivabradine on atherosclerosis which was due to an increase in wall shear stress (WSS), the blood flow-induced frictional force exerted on the endothelium, triggering anti-inflammatory responses. However, data on the effect of Ivabradine on WSS is sparse. We aim to study the effect of Ivabradine on (i) the 3D WSS distribution over a growing plaque and (ii) plaque composition. We induced atherosclerosis in ApoE-/- mice by placing a tapered cast around the right common carotid artery (RCCA). Five weeks after cast placement, Ivabradine was administered via drinking water (15 mg/kg/day) for 2 weeks, after which the RCCA was excised for histology analyses. Before and after Ivabradine treatment, animals were imaged with Doppler Ultrasound to measure blood velocity. Vessel geometry was obtained using contrast-enhanced micro-CT. Time-averaged WSS during systole, diastole and peak WSS was subsequently computed. Ivabradine significantly decreased heart rate (459 ± 28 bpm vs. 567 ± 32 bpm, p < 0.001). Normalized peak flow significantly increased in the Ivabradine group (124.2% ± 40.5% vs. 87.3% ± 25.4%, p < 0.05), reflected by an increased normalized WSS level during systole (110.7% ± 18.4% vs. 75.4% ± 24.6%, p < 0.05). However, plaque size or composition including plaque area, relative necrotic core area and macrophage content were not altered in mice treated with Ivabradine compared to controls. We conclude that increased WSS in response to Ivabradine treatment did not affect plaque progression in a murine model.

Cloning, structural analysis and expression of the gene encoding Hsp32 from Dictyostelium discoideum.

We have isolated and characterized genomic clones encoding a novel small heat shock (HS) protein (Hsp32) from Dictyostelium discoideum that is not homologous to the alpha-crystallin family Hsps. Besides its induction by HS, this gene is also regulated during the life cycle of the organism. At physiologic temperatures hsp32 is expressed at high levels in growing cells and at low levels in cells starved to initiate their developmental programme. However, in both cases the gene can be induced by HS. A DNA fragment containing the upstream region of hsp32 was shown to confer HS induction to a cat reporter gene, indicating a transcriptional regulation for this gene. A single transcription start site, located at position -152 relative to the initiator Met, 17 nucleotides downstream from a putative TATA box, was determined both in vegetative cells and cells starved for 6 h. This site was unchanged when either vegetative or starved cells were submitted to HS at 30 degrees C for 30 min. Despite HS induction, a perfect HSE element was not found in the 5' regulatory region of the gene. The hsp32 coding region is interrupted by a single intron located near its 5' end, which is properly spliced even under HS conditions.

Congenital myopathy with central cores and fingerprint bodies in association with malignant hyperthermia susceptibility.

A 26-year-old man had proximal weakness in the shoulder and the pelvic girdle since infancy. His sister, aged 16 years, presented a similar phenotype with more pronounced pelvic weakness. His muscle biopsy showed dense non-reducing inclusions which had a lamellar pattern at the ultrastructural level. These structures showed the typical features of fingerprint inclusions which were widely distributed in the fibers. Several central cores and other structural changes such as Z-line streaming were also observed. In view of the central cores, the male patient was investigated for malignant hyperthermia susceptibility. After exposure to halothane or caffeine, unusual intense contractures were observed on fiber preparations. The coexistence of central cores associated with fingerprint inclusions is suggestive of mixed congenital myopathy, which is in our case associated with malignant hyperthermia susceptibility.

Insulin-like growth factor binding protein-3 is overexpressed in senescent and quiescent human fibroblasts.

Cellular insulin-like growth factor binding protein-3 (IGFBP-3) mRNA and IGFBP-3 levels in conditioned medium were consistently higher in cultures of late passage normal (old) fibroblasts and prematurely senescent fibroblasts derived from Werner syndrome (WS) during quiescence induced by serum depletion and during the renewed growth ensuing after serum repletion, compared to cultures of early passage normal (young) fibroblasts. Molar ratios of IGFBP-3/IGF-II were always higher in senescent cultures and maintained a hierarchy of old > WS > young human diploid fibroblasts. Transfection into fibroblasts of the normal full-length IGFBP-3 cDNA in an expression vector resulted in a significant reduction in colony formation compared to cells transfected with an empty expression vector (no cDNA) or with IGFBP-3 cDNA altered by a 273 base pair (bp) deletion. Addition to old and young cultures of recombinant human IGFBP-3 and IGF-I at 1:1 or 5:1 molar ratios inhibited IGF-I-mediated DNA synthesis by approximately 70-80%. These data indicate that IGFBP-3 may play an important role in the quiescent and senescent growth arrest of HDF.

Radioulnar synostosis, radial ray abnormalities, and severe malformations in the male: a new X-linked dominant multiple congenital anomalies syndrome?

We describe a multiple congenital anomalies (MCA) syndrome dominantly transmitted through three generations. Radial ray abnormalities with wide variability of expression were observed in four female patients. Moreover, a 14-week-gestation male fetus had severe radial ray malformation, anencephaly, unilateral renal agenesis, and a common dorsal mesentery. Results of high-resolution karyotyping were normal in the malformed fetus and his affected mother. Furthermore, several spontaneous abortions of male fetuses had occurred in this pedigree. To our knowledge, a similar association has not been described previously. It could represent a new X-linked dominant MCA syndrome, or an autosomal dominant condition with severe expression limited to males.

The Richieri-Costa and Pereira form of acrofacial dysostosis: first case in a non-Brazilian infant.

We report on a French boy with cleft mandible, pre/postaxial hand anomalies, and clubfoot born to consanguineous parents. These findings are comparable to those of previous cases of the autosomal recessive Richieri-Costa and Pereira syndrome of short stature, Robin sequence, cleft mandible, pre/postaxial hand anomalies, and clubfoot. This is the first case in a non-Brazilian infant.

Characterization of a neuronal kappaB-binding factor distinct from NF-kappaB.

Transcription factors that bind kappaB enhancer elements have begun to garner wide attention in neurobiology. Data suggest that activation of kappaB-binding factors in neurons can be protective against various neurotoxins, but other data have connected NF-kappaB to cell death. In electrophoretic mobility shift assays of kappaB-binding activity, we have found that the predominant activity in rat brain tissue, in primary neurons, and in neuronal cell lines has a mobility inconsistent with that of bona fide NF-kappaB (RelA-p50 heterodimer). We have tentatively termed this activity neuronal kappaB-binding factor (NKBF). Competition assays with various DNA probes distinguished NKBF from NF-kappaB. Probes that efficiently bind the p50 homodimer were able to compete with a conventional NF-kappaB probe for NKBF binding, but NKBF did not react with antibodies to p50 (or any other known Rel family members). Furthermore, UV-crosslinking indicated that NKBF is composed of two polypeptides of 82 kDa and 27 kDa. Although NKBF activity can be elevated in a manner independent of new macromolecular synthesis, it does not appear to be modulated by IkappaB. Finally, no NF-kappaB was induced by glutamate in highly enriched neuronal cultures, although it was induced in neuron-glia cocultures. These data suggest that the primary kappaB-binding transcription factor in neurons is a novel protein complex distinct from NF-kappaB.

Heat shock alters poly(A) tail length of Dictyostelium discoideum hsp32 RNA.

Hsp32 is a heat shock gene in D. discoideum. We have previously observed that heat stress-induced change produces a broad band on Northern blots, suggesting that more than one population of mRNA is present under those conditions. This was not the result of a defect in the splicing of the hsp32 mRNA, nor did it result from the use of a different transcription start site under heat shock conditions. Here, we show that the broad banding pattern reflects the appearance of a transcript with a poly(A) tail that is approximately 100 nt longer than that seen in unstressed cells. Experiments indicated that this tail was not a property of newly synthesized mRNA but rather a response to heat stress. This response appeared to be specific to the hsp32 transcript and did not result in the retention of the RNA in the nucleus. These results document a relatively unusual heat shock response and also indicate that the nature of the response differs among RNAs and has selective consequences.

Relevance of epidurography and epidural adhesiolysis in chronic failed back surgery patients.

OBJECTIVE: Pain treatment in the chronic failed back surgery patient remains problematic. Defining the pathogenesis of the pain could be helpful in treatment. The assumption that epidural fibrosis and adhesions might play an important role in the origin of the pain is verified. DESIGN: We investigated 34 patients in whom peridural fibrosis was suspected. An epidural catheter was inserted via the sacral hiatus. Injections of contrast dye, local anesthetic, corticosteroid, and hypertonic NaCl 10% were carried out daily for 3 days. Spread of the contrast dye in the epidural space was evaluated after 10 and 20 ml injection volume. SETTING: Subjects were patients in a pain clinic of a university hospital in Belgium. PATIENTS: Chronic pain patients with failed back surgery syndrome were examined. Nerve pathology was demonstrated and epidural fibrosis suspected or proved with magnetic resonance imaging (MRI) examination. OUTCOME MEASURES: Improvement in the contrast filling defects of the epidural space were noticed during treatment and correlated with pain improvement. RESULTS: Filling defects were noted in 30 of the 34 patients investigated. After the third day an objective improvement of contrast spread was documented in 14 patients. In seven patients improvement in pain occurred for only a very limited period (1 month). Statistical analysis (chi square analysis) could not demonstrate that improvement of contrast spread was correlated with better pain behavior. In 16 patients no improvement in contrast spread could be visualized. Pain improvement occurred in only four patients and for a limited period of 1 month. Long-term results are even worse. CONCLUSION: Epidurography might confirm epidural filling defects for contrast dye in the patients with epidural fibrosis. A better contrast dye spread, assuming scar lysis, does not guarantee a sustained pain relief. A more direct visualization of the resulting functional changes after adhesiolysis as with epiduroscopy might be useful.