Muscle pathology in upper motor neuron paraplegia

During the last 30 years acceptance of the muscle biopsy by paraplegic patients have accumulated a large body of knowledge on effects of spinal cord injury (SCI) on the skeletal muscle microstructure. Light and electron microscopy analyses combined with computerized methods provided a large body of knowledge on the progression of muscle atrophy and on the effects of rehabilitation strategies. Beside a summary of normal human muscle results, we will here discuss the time-course of muscle events related to SCI affecting the upper motor neuron. Furthermore the concomitant events on the microcirculation of skeletal muscle will be described in relation to the frequent complications of deep venous thrombosis, decubitus ulcers and paraosteoarthrosis

Muscle pathology in upper motor neuron paraplegia

During the last 30 years acceptance of the muscle biopsy by paraplegic patients have accumulated a large body of knowledge on effects of spinal cord injury (SCI) on the skeletal muscle microstructure. Light and electron microscopy analyses combined with computerized methods provided a large body of knowledge on the progression of muscle atrophy and on the effects of rehabilitation strategies. Beside a summary of normal human muscle results, we will here discuss the time-course of muscle events related to SCI affecting the upper motor neuron. Furthermore the concomitant events on the microcirculation of skeletal muscle will be described in relation to the frequent complications of deep venous thrombosis, decubitus ulcers and paraosteoarthrosis

Pilot Study of the Mechanism of Action of Preoperative Trastuzumab in Patients with Primary Operable Breast Tumors Overexpressing HER2

Abstract Purpose: To elucidate the mechanism by which trastuzumab, a humanized monoclonal antibody against HER2 with proven survival benefit in women with HER2-positive metastatic breast cancer, mediates its antitumor activity. Experimental Design: A pilot study including 11 patients with HER2-positive tumors treated in a neo-adjuvant setting with trastuzumab was performed. Trastuzumab was administered i.v. at a dose of 4 mg/kg followed by three weekly i.v. doses of 2 mg/kg. The primary tumor was surgically removed 7 days after the last treatment. Surgical samples, tumor biopsies, and lymphocytes from these patients were collected for biological studies. Result: Clinical data indicated one complete pathological remission and four partial remissions using RECIST (Response Evaluation Criteria in Solid Tumors). Trastuzumab was well tolerated and neither serious adverse events nor changes in cardiac function were observed during this short-term treatment and after surgery. The biological data showed that, independent of response, (a) all patients showed high levels of circulating trastuzumab; (b) saturating level of trastuzumab was present in all of the tumors; (c) no down-modulation of HER2 was observed in any tumors; (d) no changes in vessel diameter was observed in any tumors; (e) no changes in proliferation was observed in any tumors; and (f) a strong infiltration by lymphoid cells was observed in all cases. Patients with complete remission or partial remission were found to have a higher in situ infiltration of leukocytes and a higher capability to mediate in vitro antibody-dependent cellular cytotoxicity activity. Conclusions: The results of this pilot study argue against trastuzumab activity in patients through down-modulation of HER2 but in favor of antibody-dependent cellular cytotoxicity guiding efforts to optimize the use of trastuzumab in breast cancer patients

Echocardiographically defined haemodynamic categorization predicts prognosis in ambulatory heart failure patients treated with sacubitril/valsartan

Aim: Echo-derived haemodynamic classification, based on forward-flow and left ventricular (LV) filling pressure (LVFP) correlates, has been proposed to phenotype patients with heart failure and reduced ejection fraction (HFrEF). To assess the prognostic relevance of baseline echocardiographically defined haemodynamic profile in ambulatory HFrEF patients before starting sacubitril/valsartan. Methods and results: In our multicentre, open-label study, HFrEF outpatients were classified into 4 groups according to the combination of forward flow (cardiac index; CI:< or ≥2.0 L/min/m2 ) and early transmitral Doppler velocity/early diastolic annular velocity ratio (E/e': ≥ or <15): Profile-A: normal-flow, normal-pressure; Profile-B: low-flow, normal-pressure; Profile-C: normal-flow, high-pressure; Profile-D: low-flow, high-pressure. Patients were started on sacubitril/valsartan and followed-up for 12.3 months (median). Rates of the composite of death/HF-hospitalization were assessed by multivariable Cox proportional-hazards models. Twelve sites enrolled 727 patients (64 ± 12 year old; LVEF: 29.8 ± 6.2%). Profile-D had more comorbidities and worse renal and LV function. Target dose of sacubitril/valsartan (97/103 mg BID) was more likely reached in Profile-A (34%) than other profiles (B: 32%, C: 24%, D: 28%, P < 0.001). Event-rate (per 100 patients per year) progressively increased from Profile-A to Profile-D (12.0%, 16.4%, 22.9%, and 35.2%, respectively, P < 0.0001). By covariate-adjusted Cox model, profiles with low forward-flow (B and D) remained associated with poor outcome (P < 0.01). Adding this categorization to MAGGIC-score and natriuretic peptides, provided significant continuous net reclassification improvement (0.329; P < 0.001). Intermediate and high-dose sacubitril/valsartan reduced the event's risk independently of haemodynamic profile. Conclusions: Echocardiographically-derived haemodynamic classification identifies ambulatory HFrEF patients with different risk profiles. In real-world HFrEF outpatients, sacubitril/valsartan is effective in improving outcome across different haemodynamic profiles

Microvasculature of the Unconditioned Latissimus Dorsi Muscle after Vascular Delay and Postmobilization for Cardiomyoplasty

Vascular deafferentation of the Latissimus Dorsi Muscle (LDM) for dynamic cardiomyoplasty is an important cause of ischemia in the distal portion of the muscle with degeneration of muscle fibres and consequent reduction in the effectiveness of the surgery. Experimental studies suggest that a vascular delay procedure and a 10-day delay adaptation significantly improve the distal perfusion and function of the LDM flap for cardiomyoplasty. We here report a comparative histological and ultrastructural study of biopsies from unconditioned LDM flaps of two patients, taken 30 days after vascular deafferentation and dynamic cardiomyoplasty, and 10 days after a vascular delay procedure, respectively. In the first case, in the distal part of LDM we found muscle atrophy and degeneration, necrosis of capillaries, with swelling of endothelial cells and disruption of cytoplasmic organelles, and capillary neoangiogenesis. In the second patient, the distal LDM after vascular delay procedure show minimal muscle fibre degeneration, dilatation of capillaries with endothelial cell preservation, and scarce capillary neoangiogenesis. The present results seem to confirm that a vascular delay procedure on LDM for use with cardiomyoplasty may improve the LDM perfusion and function, inducing moderate morphological changes in muscle fibres and vasculature in comparison to the deafferentated LDM

Neuropatie tossiche occupazionali: quadri morfologici in biopsie del nervo periferico

Many peripheral neuropathies are caused by the (acute or chronic) toxic action of metals, solvents, pesticides, and other occupational and environmental contaminants. These agents often reproduce the anatomoclinical pictures of hereditary (e.g., Charcot-Marie-Tooth disease), autoimmune (Guillain-Barrè syndrome), or dysmetabolic (thiamine deficiency, diabetic neuropathy) forms. Toxic peripheral neuropathies can be classified on the basis of etiology, clinical features (sensitive, motor, sensitive-motor), or histopathology: neuronopathies (uncommon, mostly secondary to retrograde axonal degeneration; e.g., arsenic, thallium), axonopathies (acrylamide, esacarbons, carbon disulphide, organophosphate-induced delayed neuropathy), myelinopathies (trichloroethylene), mixed forms (axonal and demyelinating: lead). For many substances, experimental research has led to the identification of the molecular and cellular targets of neurotoxicity. Several compounds are active by biotransformation (e.g., the esacarbons n-hexane and MnBK are neurotoxic since they are metabolized to 2,5-hexanedione), Genetic, physiological and environmental factors determine the individual metabolic set-up, and they may give origin to differences in the workers' sensitivity. Cessation of exposure is often followed by (microscopically observable) regenerative phenomena and clinical improvement. The morphology of neuropathies can be studied through peripheral nerve biopsy. Samples of sural nerve (or other nervous trunks of the limbs), adequately fixed, sectioned, and stained, allow the observation of alterations in axonal fibres (e.g., giant-axonal neuropathy, dying back neuropathy), myelin (demyelination), Schwann cells, interstitium, and blood vessels; possible inflammatory infiltrates; fibre density; regenerative phenomena (growth cone, remyelination). In occupational medicine, biopsy is indicated when the anamnestic-clinical picture, laboratory tests, and instrumental exams leave doubts about the nature, type, and entity of the neurological damage. In such cases, current optical and electron microscopy techniques can be very useful for injury evaluation, prognosis, and follow-up