The Restless Spinal Cord in Degenerative Cervical Myelopathy.

BACKGROUND AND PURPOSE: The spinal cord is subject to a periodic, cardiac-related movement, which is increased at the level of a cervical stenosis. Increased oscillations may exert mechanical stress on spinal cord tissue causing intramedullary damage. Motion analysis thus holds promise as a biomarker related to disease progression in degenerative cervical myelopathy. Our aim was characterization of the cervical spinal cord motion in patients with degenerative cervical myelopathy. MATERIALS AND METHODS: Phase-contrast MR imaging data were analyzed in 55 patients (37 men; mean age, 56.2 [SD,12.0] years; 36 multisegmental stenoses) and 18 controls (9 men, P = .368; mean age, 62.2 [SD, 6.5] years; P = .024). Parameters of interest included the displacement and motion pattern. Motion data were pooled on the segmental level for comparison between groups. RESULTS: In patients, mean craniocaudal oscillations were increased manifold at any level of a cervical stenosis (eg, C5 displacement: controls [n = 18], 0.54 [SD, 0.16] mm; patients [n = 29], monosegmental stenosis [n = 10], 1.86 [SD, 0.92] mm; P < .001) and even in segments remote from the level of the stenosis (eg, C2 displacement: controls [n = 18], 0.36 [SD, 0.09] mm; patients [n = 52]; stenosis: C3, n = 21; C4, n = 11; C5, n = 18; C6, n = 2; 0.85 [SD, 0.46] mm; P < .001). Motion at C2 differed with the distance to the next stenotic segment and the number of stenotic segments. The motion pattern in most patients showed continuous spinal cord motion throughout the cardiac cycle. CONCLUSIONS: Patients with degenerative cervical myelopathy show altered spinal cord motion with increased and ongoing oscillations at and also beyond the focal level of stenosis. Phase-contrast MR imaging has promise as a biomarker to reveal mechanical stress to the cord and may be applicable to predict disease progression and the impact of surgical interventions.

Extrapyramidal plasticity predicts recovery after spinal cord injury.

Spinal cord injury (SCI) leads to wide-spread neurodegeneration across the neuroaxis. We explored trajectories of surface morphology, demyelination and iron concentration within the basal ganglia-thalamic circuit over 2 years post-SCI. This allowed us to explore the predictive value of neuroimaging biomarkers and determine their suitability as surrogate markers for interventional trials. Changes in markers of surface morphology, myelin and iron concentration of the basal ganglia and thalamus were estimated from 182 MRI datasets acquired in 17 SCI patients and 21 healthy controls at baseline (1-month post injury for patients), after 3, 6, 12, and 24 months. Using regression models, we investigated group difference in linear and non-linear trajectories of these markers. Baseline quantitative MRI parameters were used to predict 24-month clinical outcome. Surface area contracted in the motor (i.e. lower extremity) and pulvinar thalamus, and striatum; and expanded in the motor thalamus and striatum in patients compared to controls over 2-years. In parallel, myelin-sensitive markers decreased in the thalamus, striatum, and globus pallidus, while iron-sensitive markers decreased within the left caudate. Baseline surface area expansions within the striatum (i.e. motor caudate) predicted better lower extremity motor score at 2-years. Extensive extrapyramidal neurodegenerative and reorganizational changes across the basal ganglia-thalamic circuitry occur early after SCI and progress over time; their magnitude being predictive of functional recovery. These results demonstrate a potential role of extrapyramidal plasticity during functional recovery after SCI.

Segmental differences of cervical spinal cord motion: advancing from confounders to a diagnostic tool.

Increased cranio-caudal spinal cord motion is associated with clinical impairment in degenerative cervical myelopathy. However, whether spinal cord motion holds potential as a neuroimaging biomarker requires further validation. Different confounders (i.e. subject characteristics, methodological problems such as phase drift, etc.) on spinal cord motion readouts have to be considered. Twenty-two healthy subjects underwent phase contrast MRI, a subset of subjects (N = 9) had repeated scans. Parameters of interest included amplitude of velocity signal, maximum cranial respectively maximum caudal velocity, displacement (=area under curve of the velocity signal). The cervical spinal cord showed pulse synchronic oscillatory motions with significant differences in all readouts across cervical segments, with a maximum at C5. The Inter-rater reliability was excellent for all readouts. The test-retest reliability was excellent for all parameters at C2 to C6, but not for maximum cranial velocity at C6 and all readouts at C7. Spinal cord motion was correlated with spinal canal size, heart rate and body size. This is the first study to propose a standardized MRI measurement of spinal cord motion for further clinical implementation based on satisfactory phase drift correction and excellent reliability. Understanding the influence of confounders (e.g. structural conditions of the spine) is essential for introducing cord motion into the diagnostic work up.

Fate of rubrospinal neurons after unilateral section of the cervical spinal cord in adult macaque monkeys: effects of an antibody treatment neutralizing Nogo-A.

The present study describes in primates the effects of a spinal cord injury on the number and size of the neurons in the magnocellular part of the red nucleus (RNm), the origin of the rubrospinal tract, and evaluates whether a neutralization of Nogo-A reduces the lesioned-induced degenerative processes observed in RNm. Two groups of monkeys were subjected to unilateral section of the spinal cord affecting the rubrospinal tract; one group was subsequently treated with an antibody neutralizing Nogo-A; the second group received a control antibody. Intact animals were also included in the study. Counting neurons stained with a monoclonal antibody recognizing non-phosphorylated epitopes on neurofilaments (SMI-32) indicated that their number in the contralesional RNm was consistently inferior to that in the ipsilesional RNm, in a proportion amounting up to 35%. The lesion also induced shrinkage of the soma of the neurons detected in the contralesional RNm. Infusing an anti-Nogo-A antibody at the site of the lesion did not increase the proportion of SMI-32 positive rubrospinal neurons in the contralesional RNm nor prevent shrinkage.

Static mechanical allodynia (SMA) is a paradoxical painful hypo-aesthesia: observations derived from neuropathic pain patients treated with somatosensory rehabilitation.

The present study aimed at investigating the time span it takes to remove a static mechanical allodynia (SMA) in humans suffering from chronic peripheral neuropathic pain. Forty-three subjects were included in the study and, during somatosensory rehabilitation, their SMA territory was precisely mapped. They then underwent distant vibrotactile counter stimulation (DVCS) treatment. It was observed that, with DVCS, SMA disappeared in all cases, and was transformed into an underlying hypoaesthesia. It was found that the "tenderness to touch" symptom (which is SMA) was located in the same territory as the underlying hypoaesthesia, which was located on a part of the cutaneous territory of a partially damaged nerve. These results demonstrate that treating patients suffering from neuropathic pain with DVCS revealed a skin territory of denervation that was previously masked by SMA. Thus, SMA can be considered as a paradoxical painful hypoaesthesia. Furthermore, mapping SMA is a valuable source of information for our understanding of abnormal sensory processing in neuropathic pain patients. We conclude that the mapping of the zone of hypersensitivity on the skin in humans suffering from chronic peripheral neuropathic pain improves diagnosis. The mapping of the zone of hypersensitivity is a tool to presume which branch of the peripheral nerve is damaged. The location of the axonal lesions is at the periphery, while the mechanism of pain sensitization is probably central and referred peripherally to the skin by a painful hypoaesthesia.

O-GlcNAcylation of STAT5 controls tyrosine phosphorylation and oncogenic transcription in STAT5-dependent malignancies.

The signal transducer and activator of transcription 5 (STAT5) regulates differentiation, survival, proliferation and transformation of hematopoietic cells. Upon cytokine stimulation, STAT5 tyrosine phosphorylation (pYSTAT5) is transient, while in diverse neoplastic cells persistent overexpression and enhanced pYSTAT5 are frequently found. Post-translational modifications might contribute to enhanced STAT5 activation in the context of transformation, but the strength and duration of pYSTAT5 are incompletely understood. We found that O-GlcNAcylation and tyrosine phosphorylation act together to trigger pYSTAT5 levels and oncogenic transcription in neoplastic cells. The expression of a mutated hyperactive gain-of-function (GOF) STAT5 without O-GlcNAcylation resulted in decreased tyrosine phosphorylation, oligomerization and transactivation potential and complete loss of oncogenic transformation capacity. The lack of O-GlcNAcylation diminished phospho-ERK and phospho-AKT levels. Our data show that O-GlcNAcylation of STAT5 is an important process that contributes to oncogenic transcription through enhanced STAT5 tyrosine phosphorylation and oligomerization driving myeloid transformation. O-GlcNAcylation of STAT5 could be required for nutrient sensing and metabolism of cancer cells.

Discrepancy between perceived pain and cortical processing: A voxel-based morphometry and contact heat evoked potential study.

OBJECTIVES: The purpose of this study was to determine if local gray and white matter volume variations between subjects could account for variability in responses to CHEP stimulation. METHODS: Structural magnetic resonance imaging was used to perform voxel-based morphometry (VBM) of gray and white matter in 30 neurologically healthy subjects. Contact heat stimulation was performed on the dorsum of the right hand at the base of the thumb. Evoked potentials were acquired from a vertex-recording electrode referenced to linked ears. RESULTS: Controlling for age, total intracranial volume, and skull/scalp thickness, CHEP amplitude and pain rating were not significantly correlated between subjects. A VBM region of interest approach demonstrated a significant interaction between pain rating and N2 amplitude in the right insular cortex (p<0.05, family-wise error corrected, FWE). In white matter, a significant interaction was localized in the right inferior frontal occipital fasciculus (IFOF, p<0.05 FWE). CONCLUSIONS: Accounting for gray matter volume in the right insular cortex, resulted in a significant relationship between CHEP amplitude and pain rating. SIGNIFICANCE: This finding suggests that the discrepancy between pain ratings and the amplitude of evoked potentials is not solely related to measurement artifact, but rather attributable, in part, to anatomical differences between subjects.

(-)-BM 13.0913: a new oral antidiabetic agent that improves insulin sensitivity in animal models of type II (non-insulin-dependent) diabetes mellitus.

Insulin resistance is one of the key features of non-insulin-dependent diabetes mellitus (NIDDM). Therefore, a drug that causes an improvement in insulin sensitivity would be of great interest for the treatment of NIDDM. In addition to the insulin-sensitizing thiazolidinediones, we have found another class of insulin-sensitizing agents: the alpha-activated carbonic acids. (-)-BM 13.0913, a member of this class, was effective in improving insulin resistance in hyperinsulinemic and hypoinsulinemic insulin-resistant animal models of NIDDM. The 50% effective dose (ED50) for the glucose-lowering action was 4, 2.4, and 8 mg/kg in ob/ob, yellow KK, and db/db mice, respectively. The ED50 for the insulin-lowering action was 14.5, 5, and 26 mg/kg. This rightward shift of the dose-response curve for insulin indicates that improving glucose homeostasis is the primary effect of the drug, followed by an insulin-decreasing action. This effect on glucose homeostasis may be brought about by sensitizing peripheral target tissues to the effects of insulin. An increase in deoxyglucose uptake and glucose oxidation measured in adipocytes from rats that had been treated for 14 days with (-)-BM 13.0913 supports this conclusion. Glucose uptake and oxidation was increased at all insulin concentrations tested, suggesting an improved responsiveness. Insulin sensitivity in adipocytes was not influenced by the drug. Studies in the moderately hypoinsulinemic, low-dose streptozotocin (STZ) diabetic rat with a residual insulin concentration showed a decrease in blood glucose concentrations, as well as a decrease in urinary glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of the new oral antidiabetic agent (-)-BM 13.0913.Na on insulin resistance in lean and obese Zucker rats.

The new antidiabetic agent (-)-BM 13.0913.Na (BM) was administered to 12-week-old lean and obese Zucker rats, an animal model of insulin resistance, at a daily dose of 50 mg/kg for 14 days. Hyperinsulinemic-euglycemic clamps were performed on treated and untreated lean and obese Zucker rats. Basal hepatic glucose production (HGP) rates were similar in lean and obese untreated animals. Insulin-induced suppression of HGP was significantly less effective in obese animals. In addition, these animals exhibited the characteristic impaired glucose utilization. In obese animals, drug treatment improved insulin suppression of HGP and total glucose utilization (GU) during clamp studies. Furthermore, drug treatment decreased insulin levels during clamp studies, suggesting an acceleration of insulin clearance. Drug treatment also decreased basal plasma insulin levels and serum and liver concentrations of cholesterol in both fasted lean and obese rats. Additionally, blood glucose, plasma nonesterified fatty acids (NEFA), and serum triglyceride levels were reduced in fasted obese rats, but only minor changes in liver triglycerides were observed in lean and obese rats. On the basis of these results, we suggest that BM is an effective antidiabetic agent that may reduce abnormalities of glucose and lipid metabolism.

Plasma renin activity and forearm blood flow in paraplegic humans.

We recently found that paraplegic humans respond to hyperthermia with subnormal increase in skin blood flow (SkBF), based on measurements of forearm blood flow (FBF). Is this inhibition of SkBF a defect in thermoregulation or a cardiovascular adjustment necessary for blood pressure control? Since high resting plasma renin activity (PRA) is found in unstressed individuals with spinal cord lesions and since PRA increases during hyperthermia in normal humans, we inquired whether the renin-angiotensin system is responsible for the attenuated FBF in hyperthermic resting paraplegics. Five subjects, 28-47 yr, with spinal transections (T1-T10), were heated in water-perfused suits. Blood samples for PRA determinations were collected during a control period and after internal temperature reached approximately 38 degrees C. Some subjects with markedly attenuated FBF had little or no elevation of PRA; those with the best-developed FBF response exhibited the highest PRA. Clearly, circulating angiotensin is not the agent that attenuates SkBF. Rather, increased activity of the renin-angiotensin system may be a favorable adaptation that counters the locally mediated SkBF increase in the lower body and thus allows controlled active vasodilation in the part of the body subject to centrally integrated sympathetic effector outflow.

Sweat rate vs. forearm blood flow during lower body negative pressure.

Skin blood flow is inhibited when hyperthermia and added hypovolemic stresses are superimposed. We tested the hypothesis that part of this inhibition is a reduced drive for cutaneous active vasodilatation (AVD) with sweat rate (SR) taken as an indirect measure of the efferent drive for cutaneous AVD. We also inquired whether SR itself changes with redistribution of blood volume. Six healthy supine men were subjected to lower body negative pressure (LBNP) after heating in water-perfused suits increased esophageal temperatures (Tes) to a mean of 37.2 degrees C and at least doubled SR and forearm vascular conductance (FVC). Heating continued throughout LBNP and recovery. Sweat rate did not decrease with LBNP onset, although SR-Tes slopes during LBNP were reduced 28% from control. In four subjects the SR-Tes slope did not recover when LBNP was discontinued. These observations suggest that SR is not an effector of the low-pressure baroreflex. In contrast to SR, FVC abruptly fell 22% at the onset of LBNP. Thereafter, FVC-Tes slopes near zero or less occurred. The major effector for FVC inhibition with LBNP appears to be the neural vasoconstrictor system. A minor component due to reduced drive for cutaneous AVD probably occurs as well.

Unaltered norepinephrine-heart rate relationship in exercise with exogenous heat.

We measured plasma norepinephrine (NE) concentration, an index of sympathetic nervous activity, and epinephrine (E), an index of adrenal medulla activity, in six normal young men during mild to severe exercise, with and without superimposed heat stress. The primary objective was to observe whether the normally close relationship between heart rate and log NE concentration in upset when heart rate at a given work load is increased by heat stress. Exercise, beginning at 50 W, was graded in 50-W increments lasting 10 min each up to 200 W, which lasted 5-10 min. Each subject went through the protocol twice, once with skin temperature kept low by a water-perfused suit and then with skin temperature raised to 38 degrees C. Exogenous heart stress raised log circulating NE concentration in proportion to the rise in heart rate at a given work load so that the usual relationship between these variables, previously observed during other stresses, was preserved. In contrast to some other stresses, heat stress had no added effect on E concentration, indicating that this stress during exercise raises sympathetic neural activity (as reflected in the rise in NE) without stimulating additional adrenal release of E.

Cystic fibrosis, vasoactive intestinal polypeptide, and active cutaneous vasodilation.

The transmitter substance for the active cutaneous vasodilation that accompanies sweating during hyperthermia in humans is unknown. Hökfelt et al. (Nature Lond. 284: 515-521, 180) hypothesized that it is vasoactive intestinal polypeptide (VIP) that is cotransmitted with acetylcholine. Heinz-Erian et al. (Science Wash. DC 229: 1407-1408, 1985) reported that VIP innervation is sparse in the skin of persons with cystic fibrosis (CF). A corresponding attenuation of active vasodilation in these subjects would be evidence that VIP is involved in this effector mechanism of human thermor-regulation. Immunocytochemical analysis of skin biopsies from four men with CF confirmed that VIP innervation was sparse. We also analyzed immunoreactivity for calcitonin gene-related peptide (CGRP; normal), substance P (normal), and neuropeptide Y (low). VIP-immunoreactive Merkel cells were abnormal. Despite sparse VIP-immunoreactive innervation, our CF subjects' cutaneous vascular responses to hyperthermia were normal. Because VIP was not completely absent, this evidence is insufficient to rule out VIP as the vasodilator transmitter. However, the CGRP and substance P innervation we observed could mean that release of one or both of these peptides was the mechanism of the fully developed active cutaneous vasodilation.

Does acute hypoxemia blunt sympathetic activity in hyperthermia?

Sympathetic alpha-adrenergic function is depressed by hypoxemia per se; does addition of another sympathoexcitatory stimulus elicit normal responses in other sympathetic effector pathways? We activated by hyperthermia four sympathetic pathways: alpha-adrenergic [norepinephrine (NE) release], beta-adrenergic [plasma renin activity (PRA)], cholinergic (sweating), and peptidergic (active vasodilation). In the first test, five normothermic men were exposed to hypoxemia for 10 min (control), then hypoxemia plus heat for 30 min, and then heat with normoxia for 8-10 min over a continuous 48- to 50-min period. Heating was controlled with a water-perfused suit. Time courses and magnitudes of heat-induced increments in body temperature, forearm blood flow, and sweat rate were normal during hypoxemia and unaffected by switching to normoxia. Hypoxemia exaggerated increases in plasma NE, epinephrine, PRA, and heart rate but had no additional effects on blood pressure. In a second 50-min test (2 men) with normoxic control (10 min), heating plus normoxia (20 min), and heating plus hypoxemia (20 min), effects of hypoxemia on all variables were as in the first test. Thus, acute moderate hypoxemia did not blunt active cutaneous vasodilation or sweating and exaggerated increases in catecholamines and heart rate, indicating maintained peripheral autonomic function.

Implantation of the automatic defibrillator: the subxiphoid approach.

The automatic implantable defibrillator is an electronic device capable of diagnosing and correcting malignant venticular arrhythmias. While major thoracic surgery was required in the original 24 implants, a new technique for implanting the device has been developed. The first subxiphoid implantations have been accomplished with the defibrillatory function successfully tested intraoperatively. The advantages and indications of the subxiphoid technique are reviewed.

Ca2+-sensitizing effect of BM 14.478 on skinned cardiac muscle fibres of guinea-pig papillary muscle.

A concentration-dependent increase in force development was obtained with BM 14.478 (10(-9)-5 X 10(-4) M) in skinned fibres of guinea-pig papillary muscles. Guinea-pig papillary muscles are standard preparations for evaluating inotropic effects and they were also used in the present case for evaluating the positive inotropic effect of BM 14.478. We therefore conclude that a marked calcium-sensitizing effect contributes to the positive inotropic effect obtained with BM 14.478 even at very low concentrations.

Transesophageal Doppler scanning versus thermodilution during general anesthesia. An initial comparison of cardiac output techniques.

Measurement of cardiac output has become an essential feature of anesthetic management of patients with cardiac disease requiring operation. Thermodilution by way of a Swan-Ganz catheter is the current popular technique for cardiac output determination. Unfortunately, this method is costly and has an associated irreducible morbidity rate and has, in rare instances, resulted in death. The suprasternal ultrasonographic Doppler technique has shown promise for measuring cardiac output noninvasively; however, it is too cumbersome for continuous intraoperative use. In an effort to overcome this limitation, the esophageal stethoscope was modified to accept a Doppler probe. Herein, we have reported an initial comparison of transesophageal Doppler scanning and thermodilution in 23 adult men during general anesthesia. The average difference between thermodilution and descending cardiac output was 0.16 +/- 0.81 liters/min. The correlation between thermodilution and descending cardiac output increased with operator experience. In the last 13 patients, there was an average correlation of 0.85. After the equipment was mastered and improvements in design were made, descending cardiac output had a high correlation with thermodilution and appeared to track the dynamic changes during general anesthesia.

Health care in a declining economy: the case of Zambia.

The severe and worsening economic crisis in Zambia has set into motion various adjustment measures (subsidy withdrawal or reduction, adjustment of exchange rates, import control, a foreign exchange auction system and retrenchment of government expenditure) which is making it increasingly difficult for the government to maintain the network of health and other social services developed in the 20 years since Independence. The situation became critical particularly after the decline of copper prices which provided Zambia with 90% of its foreign exchange earnings. The resulting fall in the GNP along with rapid inflation, population growth and urbanization has had a number of consequences for health care delivery. These effects are described with particular attention to health manpower/facilities, disease morbidity, malnutrition, expenditure patterns and health policy. Finally, some proposed strategies being considered by the government are presented.

Local politicization of Primary Health Care as an instrument for development: a case study of community health workers in Zambia.

The integrated approach of the Primary Health Care Concept has obvious implications for development. In view of Zambia's commitment to Primary Health Care it is important to evaluate the effectiveness of present institutional frameworks and the problems that may arise in shifting towards community responsibility for the provision of health. It is often assumed that the Primary Health Care approach of working through the community should be free of serious implementation problems. However, experience from community participation projects in a wide variety fields carried out in many countries, including Zambia has shown that failure to account for local institutional arrangements and political interests has hindered success. This article presents the theoretical issues involved in community participation research, reviews relevant literature and presents a case study of a community health worker in Western Province, Zambia. The case study derives from an on-going UNICEF/Government of Zambia sponsored project which is monitoring and evaluating the impact of child health and nutrition services in rural areas. The study illustrates some of the problems encountered by a CHW because of clashes with local political interests. An alternative model is proposed which if implemented can help alleviate and/or avoid these types of conflicts.