Smooth Muscle Degeneration Research Articles

An Unusual Case of Nausea, Vomiting, Diarrhea and Urinary Retention in a Healthy Female

Purpose: Hollow visceral myopathy (HVM) is a form of chronic idiopathic intestinal pseudo obstruction (CIIP). It rarely involves other systems including the urinary tract. Methods: A 45 year old female was transferred to our hospital with 3 months of nausea, vomiting and watery diarrhea. She had a tender, distended abdomen on physical exam. CT enterography demonstrated thickening and distension of the large and small intestines without a transition point. Bilateral hydroureter/nephrosis was noted. Results: EGD and colonoscopy were grossly and histologically normal. Ureteral stents were placed without resolution of her hydronephrosis. Laparotomy did not reveal a mechanical obstruction. A full thickness rectal biopsy showed vacuolar smooth muscle degeneration with loss of a majority of muscle fibers c/w HVM. A PET scan and testing for amyloid, scleroderma and HIV were negative. A venting gastrostomy was placed and TPN started with resolution of symptoms. She was discharged to a rehabilitation facility. Conclusion: Secondary chronic intestinal pseudo obstruction (CIP) is usually due to a paraneoplastic syndrome, scleroderma, amyloidosis or HIV. In contrast, CIIP is due to either a HVM or hollow visceral neuropathy. Involvement of other visceral smooth muscle including the urinary tract and gallbladder has been reported. Although CIIP is usually seen as a familial syndrome, rare sporadic cases have been reported. Treatment of CIIP is primarily supportive with venting, surgical resecton and TPN as needed. Chronic nausea, vomiting and diarrhea with small intestinal dilation and hydroureter should prompt consideration of CIIP.Figure

Signs of herniosis in women with vaginal prolapse and/or stress incontinence

Gynecological literature pertaining to prolapse or stress urinary incontinence published over the past four decades was reviewed to determine whether signs of herniosis, the systemic connective tissue co-morbidity known to play a significant role in abdominal herniation, were present and differed from controls. A total of eight indications were reported: (1) Genetic factors, i.e., family history and race, were predictive. (2) An increase in the incidence was observed in association with heritable diseases of collagen and their formes frustes (e.g., joint laxity). (3) Recurrence rate after repair was high (30%). (4) Fragmentation and degeneration of smooth muscle and collagen fibers were observed histologically. (5) Biochemistry demonstrated a decline of 24-40% in collagen content of skin, round ligament, cardinal ligament, periurethral vaginal wall, cervix, pubocervical, cervicococcygeal, and vesicovaginal fasciae. (6) In patients with stress urinary incontinence, collagen content decreased 60%. This change was independent of age, parity, menopausal status, and weight. (7) Matrix metalloproteinase (MMP-2 and MMP-9) activity increased fourfold and that of their inhibitor TIMP-1 decreased. (8) Cigarette smoking, an acquired factor, increased the incidence of stress urinary incontinence. This commonality with the etiology of abdominal herniae explains why gynecologists have decreased their emphasis on childbirth injury and, like herniologists, have moved to discard the dogma "prolapse" as a designate for extraperitoneal herniation in the pelvis.

Lipid mapping in human dystrophic muscle by cluster-time-of-flight secondary ion mass spectrometry imaging

Human striated muscle samples, from male control and Duchenne muscular dystrophy-affected children, were subjected to cluster-time-of-flight secondary ion mass spectrometry (cluster-ToF-SIMS) imaging using a 25 keV Bi(3)(+) liquid metal ion gun under static SIMS conditions. Spectra and ion density maps, or secondary ion images, were acquired in both positive and negative ion mode over several areas of 500 x 500 microm(2) (image resolution, 256 x 256 pixels). Characteristic distributions of various lipids were observed. Vitamin E and phosphatidylinositols were found to concentrate within the cells, whereas intact phosphocholines accumulated over the most damaged areas of the dystrophic muscles, together with cholesterol and sphingomyelin species. Fatty acyl chain composition varied depending on the region, allowing estimation of the local damage extent.

Corpus Cavernosum Electromyography with Revised Methodology: An Explorative Study in Patients with Erectile Dysfunction and Men with Reported Normal Erectile Function

A lack of standardization of the recording techniques of corpus cavernosum electromyography (CC-EMG) and objective criteria to characterize the recorded signals (CC-potentials) are the main difficulties hindering the clinical application of this method. These difficulties have been recently overcome by revising the recording and interpretation methodology of CC-EMG AIM: To assess if CC-EMG performed with the revised methodology is discriminative for well-defined clinical conditions in patients with erectile dysfunction (ED). Based on blinded clinical diagnosis, ED patients were catalogued into five subgroups: severe penile fibrosis, cavernous arterial insufficiency (CAI), cardio-vascular comorbidity (CVCM) without proven CAI, post-radical retropubic prostatectomy (RRP), and psychogenic ED. With four electrodes placed on the penile shaft bilaterally, CC-EMG was recorded monopolarly for 30 minutes during flaccidity. After evaluation of the recordings by visual inspection, CC-potentials were analyzed using cross- and autocorrelation techniques. The parameters evaluated were amplitude, duration, dominant frequency (DF), and maximum cross-correlation coefficient (Rmax) of CC-potentials recorded from proximal and distal parts of the CC. Comparison of the values of parameters amplitude, duration, DF, and Rmax between patient and control groups. A total of 119 patients with ED and 43 men with reported normal erectile function were studied. Thirteen out of 14 patients with severe penile fibrosis did not show any distinguishable CC-potential. Patients with CAI had significantly decreased amplitude compared with the potent controls, as well as the patients with CVCM but without proven CAI. Significantly decreased amplitude and Rmax were detected in ED patients following RRP compared with the controls. Corpus cavernosum electromyography performed with the revised methodology is able to discriminate ED patients with conditions that are associated with cavernous smooth muscle degeneration and/or autonomic neuropathy from men with reported normal erectile function.

Null mutation in macrophage migration inhibitory factor prevents muscle cell loss and fibrosis in partial bladder outlet obstruction

Idiopathic detrusor underactivity (DU) and detrusor decompensation which develops following partial bladder outlet obstruction (pBOO) are both associated with smooth muscle degeneration and fibrosis. Macrophage migration inhibitory factor (MIF), an important mediator of bladder inflammation, has been shown to promote fibroblast survival and muscle death in other tissues. We evaluated the hypothesis that MIF has similar actions in the bladder by studying detrusor responses to pBOO or sham surgery in anesthetized female mice rendered null for the mif gene (MIF KO) and in wild-type (WT) controls, all killed 3 wk after surgery. WT mice revealed intense MIF immunoreactivity in urothelial cells which decreased, without change in overall mif mRNA levels. Stereologically sound quantitative morphometric measurements were performed in the middetrusor region of each bladder. MIF KO bladders were normal in appearance, yet were 30-40% heavier, with increased middetrusor collagen and muscle, compared with WT controls. In WT mice, pBOO increased the collagen-to-muscle ratio 1.9-fold and middetrusor collagen 1.8-fold, while nucleated muscle counts were 22% lower. In MIF KO mice, by contrast, pBOO had no significant effect on any of these parameters. In primary bladder muscle cultures, treatment with rMIF protein increased TUNEL staining, raising the proportion of early and late apoptotic cells on flow cytometry. Our studies implicate MIF in the sequence of events leading to detrusor muscle loss and fibrosis in obstruction. They raise the possibility that strategies designed to antagonize MIF synthesis, release, or biological activity could prevent or delay DU and urinary retention.

Differential deposition of amyloid β peptides in cerebral amyloid angiopathy associated with Alzheimer’s disease and vascular dementia

Cerebral amyloid angiopathy (CAA) caused by deposition of amyloid beta (Abeta) peptides in the cerebrovasculature, involves degeneration of normal vascular components and increases the risk of infarction and cerebral hemorrhage. Accumulating evidence suggests that sporadic CAA is also a significant contributor to cognitive decline and dementia in the elderly. However, the mechanisms by which CAA arises are poorly understood. While neuronal sources of Abeta peptides are sufficient to cause CAA in transgenic mice overexpressing the amyloid precursor protein, there is reason to believe that in aging man, vascular disease modulates the disease process. To better understand CAA mechanisms in dementia, we assessed the frontal cortex of 62 consecutive cases of Alzheimer's disease (AD), vascular dementia (VaD), and mixed dementia (MD) using immunohistochemistry with antibodies to Abeta, smooth muscle actin and the carboxyl-terminal peptides to detect Abeta(40) and Abeta(42). While vascular Abeta deposition was invariably associated with smooth muscle degeneration as indicated by absence of smooth muscle cell actin reactivity, VaD/MD cases exhibited markedly more vascular Abeta(42) deposits and smooth muscle actin loss compared to AD cases with similar degrees of CAA and Abeta(40) deposition. This suggests that distinct mechanisms are responsible for the differential deposition of Abeta in CAA associated with AD and that associated with ischemic/cerebrovascular disease. It is plausible that experimental studies on the effects of cerebrovascular disease on Abeta production and elimination will yield important clues on the pathogenesis of CAA.

Corpus cavernosum electromyography, a usable clinical diagnostic method for erectile dysfunction?

Corpus cavernosum electromyography (CC-EMG) has been intensively studied as a potential clinical tool for evaluating the function of the cavernous smooth muscle and its autonomic innervations since 1989. Both basic and clinical studies have shown promising results. However, its application as a diagnostic tool with clinical relevance was hindered by insufficient knowledge of cavernous smooth muscle electrophysiology and a series of technical and practical difficulties. Recently, major progress has been made to overcome these difficulties. Multichannel monopolar recording method has been proved to be superior to traditional one or two-channel bipolar recording. Correlation techniques have been applied as a comprehensive, objective and easy-to-use method to analyze CC-EMG recordings. Using these newly developed techniques, CC-EMG has been demonstrated to be discriminative in erectile dysfunction patients with conditions that are associated with cavernous smooth muscle degeneration and/or autonomic neuropathy from men with normal erectile function. However, before CC-EMG can be used as a robust method for erectile dysfunction-diagnostics, some basic and clinical issues are still to be solved. This review presents an overview of the latest advances in CC-EMG studies, mainly focusing on the clinical application of this method as a diagnostic tool. Furthermore, the background knowledge of cavernous electrophysiology, the problems to be overcome and future perspectives are also discussed.

The pathogenesis of CADASIL: an update

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) appears to be the most common form of hereditary stroke disorder. CADASIL is associated with arterial smooth muscle degeneration linked to mutations in the Notch3 gene, whose product is a transmembrane receptor that functions in cell–cell communication. The pathogenesis of CADASIL remains unclear. Current research efforts are directed towards the elucidation of various features of the disorder including investigations on CADASIL-like disorders, early cognitive changes, specificity of neuroimaging for diagnosis, discovery of de novo mutations, the development of Notch3 transgenic mouse models and molecular cellular studies in Notch3 signaling. The genetics of cerebrovascular disorders (CVD) was virtually unknown until recently. Genetic associations may have been evaded because of widely variable phenotypes, even within monogenic disorders such as CADASIL. Several investigators have attempted genotype–phenotype correlation in CADASIL cases but the relationship between genetic alterations and overt manifestation of phenotype remains elusive. However, the elucidation of the genetics and pathogenesis of CADASIL have been important in further understanding of the primary vascular mechanisms that lead to ischemic blood flow and its consequences on neuronal survival. This report summarizes some of the highlights of the satellite symposium on CADASIL at Vas-Cog 2003.

Inhibition of Platelet-Derived Growth Factor Promotes Pericyte Loss and Angiogenesis in Ischemic Retinopathy

We investigated whether inhibition of platelet-derived growth factor (PDGF) receptor tyrosine kinase activity would affect pericyte viability, vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor-2 (VEGFR-2) expression and angiogenesis in a model of retinopathy of prematurity (ROP). ROP was induced in Sprague Dawley rats by exposure to 80% oxygen from postnatal (P) days 0 to 11 (with 3 hours/day in room air), and then room air from P12-18 (angiogenesis period). Shams were neonatal rats in room air from P0-18. STI571, a potent inhibitor of PDGF receptor tyrosine kinase, was administered from P12-18 at 50 or 100 mg/kg/day intraperitoneal (i.p.). Electron microscopy revealed that pericytes in the inner retina of both sham and ROP rats appeared normal; however STI571 induced a selective pericyte and vascular smooth muscle degeneration. Immunolabeling for caspase-3 and alpha-smooth muscle cell actin in consecutive paraffin sections of retinas confirmed that these degenerating cells were apoptotic pericytes. In all groups, VEGF and VEGFR-2 gene expression was located in ganglion cells, the inner nuclear layer, and retinal pigment epithelium. ROP was associated with an increase in both VEGF and VEGFR-2 gene expression and blood vessel profiles in the inner retina compared to sham rats. STI571 at both doses increased VEGF and VEGFR-2 mRNA and exacerbated angiogenesis in ROP rats, and in sham rats at 100 mg/kg/day. In conclusion, PDGF is required for pericyte viability and the subsequent prevention of VEGF/VEGFR-2 overexpression and angiogenesis in ROP.

Estimation of time of fetal death in the second trimester by placental histopathological examination.

It has been suggested that certain placental histopathological changes may be useful in predicting the time of death in stillborn fetuses. We retrospectively evaluated 36 placentas from therapeutic terminations in which the time interval between fetal death and delivery was relatively short and well-documented to determine the earliest stillbirth-associated changes and the utility of placental examination in timing death in the second trimester. In each case, termination had been initiated by creating fetal asystole with intracardiac KCl injections. The gestational age ranged from 18-23 wk. The time from asystole to placental delivery range was 2.8-52.0 h. Placental groups were categorized by time intervals from asystole to delivery: I, <12 h [n = 4 (11%)]; II, 12-24 h [n = 15 (42%)]; III, 24-36 h [n = 14 (39%)]; IV, > 36 h [n = 3 (8%)]. Among eight histopathologic changes involving the umbilical cord or chorionic villi evaluated, only three were present in a significant number of cases and also appeared to be the result of stillbirth. Degeneration of cord vascular smooth muscle was present in 33% of umbilical cords in group I, but was seen in 100% of cords in groups II-IV; the extent of these changes increased significantly with increasing time intervals. Intravascular karyorrhexis was present in villous blood vessels in 75, 73, 64, and 100%, respectively, for groups I-IV. Villous blood vessel luminal abnormalities were seen in 25, 7, 21, and 67%, respectively, for groups I-IV. These findings indicate that these are the earliest morphological changes in stillbirth in second trimester placentas, but they cannot be used to accurately predict time of death in the relatively short time intervals evaluated in this study.

Effect of Dexamethasone on the Metabonomics Profile Associated with Phosphodiesterase Inhibitor-Induced Vascular Lesions in Rats

Metabonomics is the evaluation of the multiparametric metabolic response of biological systems to pathophysiological stimuli. High-resolution nuclear magnetic resonance (NMR) spectroscopy of biofluids coupled with pattern recognition-based chemometric analysis is an emerging approach to the study of metabonomics and may be used for the prediction of toxicity in vivo and for identification of surrogate markers of toxicity. Previously, we established that metabonomic analysis of urine samples has significant potential for identification of phosphodiesterase type 4 (PDE-4) inhibitor-induced vascular lesions in rats. It was not clear, however, whether the observed changes in metabonomics profile were related mechanistically to the pathogenesis of these vascular lesions or whether these changes were reflective primarily of the ensuing inflammatory response. In the present study, dexamethasone was used to suppress inflammation associated with vascular lesions induced in rats by the PDE-4 inhibitor CI-1018 and urine samples were evaluated for resultant changes in metabonomic profile. Female Wistar rats were given CI-1018 by gavage at 750 mg/kg with or without concurrent intraperitoneal administration of dexamethasone at 1 mg/kg for 4 days. Dexamethasone induced a characteristic lymphoid depletion and lymphocytolysis but no evidence of vascular lesions. Rats dosed with CI-1018 had mild vascular changes in liver and/or marked vascular lesions in mesentery characterized by medial necrosis, hemorrhage, and/or edema accompanied by perivascular mixed inflammatory cell infiltrates. Inflammatory infiltrates associated with these lesions were eliminated in rats given dexamethasone, yet minimal medial smooth muscle necrosis and degeneration still occurred, suggestive of etiologic changes rather than effects secondary to the inflammatory response. Principle component analysis of urine NMR spectra produced a clear pattern separation within 48 to 72 h between CI-1018-treated rats with vascular lesions and vehicle controls or rats given dexamethasone alone. There was no pattern separation, however, between rats given CI-1018 alone and rats given CI-1018 and dexamethasone concurrently, suggesting that CI-1018-induced urine spectral changes were associated with the vascular lesions, yet were independent of the inflammatory response. These findings provide new insight into the mechanism(s) of PDE inhibitor-induced vasculitis and support the potential use of metabonomics for developing reliable noninvasive methods for detecting vascular changes in rats.

Effect of Dexamethasone on the Metabonomics Profile Associated with Phosphodiesterase Inhibitor-Induced Vascular Lesions in Rats

Metabonomics is the evaluation of the multiparametric metabolic response of biological systems to pathophysiological stimuli. High-resolution nuclear magnetic resonance (NMR) spectroscopy of biofluids coupled with pattern recognition-based chemometric analysis is an emerging approach to the study of metabonomics and may be used for the prediction of toxicity in vivo and for identification of surrogate markers of toxicity. Previously, we established that metabonomic analysis of urine samples has significant potential for identification of phosphodiesterase type 4 (PDE-4) inhibitor-induced vascular lesions in rats. It was not clear, however, whether the observed changes in metabonomics profile were related mechanistically to the pathogenesis of these vascular lesions or whether these changes were reflective primarily of the ensuing inflammatory response. In the present study, dexamethasone was used to suppress inflammation associated with vascular lesions induced in rats by the PDE-4 inhibitor CI-1018 and urine samples were evaluated for resultant changes in metabonomic profile. Female Wistar rats were given CI-1018 by gavage at 750 mg/kg with or without concurrent intraperitoneal administration of dexamethasone at 1 mg/kg for 4 days. Dexamethasone induced a characteristic lymphoid depletion and lymphocytolysis but no evidence of vascular lesions. Rats dosed with CI-1018 had mild vascular changes in liver and/or marked vascular lesions in mesentery characterized by medial necrosis, hemorrhage, and/or edema accompanied by perivascular mixed inflammatory cell infiltrates. Inflammatory infiltrates associated with these lesions were eliminated in rats given dexamethasone, yet minimal medial smooth muscle necrosis and degeneration still occurred, suggestive of etiologic changes rather than effects secondary to the inflammatory response. Principle component analysis of urine NMR spectra produced a clear pattern separation within 48 to 72 h between CI-1018-treated rats with vascular lesions and vehicle controls or rats given dexamethasone alone. There was no pattern separation, however, between rats given CI-1018 alone and rats given CI-1018 and dexamethasone concurrently, suggesting that CI-1018-induced urine spectral changes were associated with the vascular lesions, yet were independent of the inflammatory response. These findings provide new insight into the mechanism(s) of PDE inhibitor-induced vasculitis and support the potential use of metabonomics for developing reliable noninvasive methods for detecting vascular changes in rats.

Secondary smooth muscle degeneration with inclusion bodies in slow transit constipation

Secondary smooth muscle degeneration with inclusion bodies in slow transit constipation

Effects of ligation of the internal iliac artery on blood flow to the bladder and detrusor function in rat.

Ischaemia induced by atherosclerosis is a common cause of disorders in the elderly, including impairment of bladder function. To evaluate experimentally the effects of ischaemia on detrusor function, we performed infusion cystometry and evaluated the morphologic findings in the bladder of the rat. Blood flow to the bladder of the rat was evaluated with a Doppler flowmeter before and after the unilateral or bilateral ligation of the internal iliac arteries. Reevaluation was done at one and two weeks after surgery. Bladder function was studied by infusion cystometry performed in vivo under urethane anaesthesia. Finally, histological examination was performed. Blood flow at mid-dorsal wall of the control bladder was inversely related to intravesical volume. Unilateral or bilateral ligation of the internal iliac arteries decreased blood flow to the bladder, which showed a complete recovery two weeks postoperatively. Infusion cystometry of the ischaemic bladder with bilateral ligation of the internal iliac arteries demonstrated a decrease in voiding pressure, an increase in bladder capacity, and an increase in pressure at which micturition was initiated vs. the control. The bladder with unilateral ligation of the artery showed a decrease in voiding pressure, with no change in the other parameters. Histological examination indicated that the bilateral ischaemia and ischaemic side of unilateral ischaemia led to a degeneration of the mucosa, and severe oedema in submucosal and muscle layers one week postoperatively. Degeneration of smooth muscle was predominant at 2 weeks. Contralateral side of the unilaterally ischaemic bladder showed oedema and congestion of the submucosa and smooth muscle. Ligation of the internal iliac artery decreased blood flow to the bladder significantly, which resulted in smooth muscle degeneration. Consequently, in vivo voiding pressure was impaired in the ischaemic bladder.

Amyloid-beta protein angiopathies masquerading as Alzheimer's disease?

Current evidence from genetic and epidemiological studies supports the view that Alzheimer's disease (AD) is a heterogeneous disorder. While the disease is pathologically defined by the presence of specified lesions in form of amyloid plaques and neurofibrillary tangles within the parenchyma, other features of pathology are often either neglected or considered coincidental. Our studies suggest that cerebrovascular pathology is inherently part of the disorder, which could be an important factor in a cause or effect manner. We have recently identified subjects having died with severe amyloid beta (A beta) protein cerebral amyloid angiopathy (CAA) in the absence of a profound Alzheimer pathology. These subjects, diagnosed with dementia had a late onset disease and were found at autopsy to exhibit severe CAA but paucity of typical AD changes. Immunocytochemical studies showed numerous microvascular abnormalities as well as characteristic degeneration of the vascular smooth muscle in both surface and intracortical vessels. The pathology was also characterized by occasional intracerebral hemorrhages and multiple infarcts. Further assessment of the abnormalities and amyloid infiltrated cerebral vessels with antibodies to the carboxyl terminus of A beta indicated that the longer, more pathogenic form of A beta(1-42) was found to be highly associated with intracerebral hemorrhages. Our observations suggest that these mild AD cases with a predominantly vascular pathology are variants of AD and bear resemblance to the familial Dutch and Flemish versions of cerebral amyloidosis. We propose that AD is a group of diseases with a variable pathology analogous to the prion diseases, in which a vascular variant also exists.

Primary degeneration of the internal anal sphincter as a cause of passive faecal incontinence

Faecal incontinence is usually attributed to pelvic-floor denervation of striated muscle or direct sphincter trauma. We have identified a cause of passive faecal incontinence related to degeneration of the internal anal sphincter smooth muscle, in the absence of denervation, structural damage, external-sphincter weakness, or sensory abnormalities. Patients were included on the basis of: passive faecal incontinence, no urge faecal incontinence, low anal pressure whilst at rest, normal anal-squeeze pressure, endosonographically confirmed circumferentially intact internal and external anal sphincters, and normal pudendal nerve terminal nerve latencies. In a second analysis done to assess the proportion of patients with this disorder, we recorded the cause of incontinence in consecutive patients seen during a 6-month period. 45 patients (35 women, median age 63 years, range 23-80 years) fulfilled the diagnostic criteria. Median duration of symptoms was 2 years (3 months to 20 years). Nine of the 35 women were nulliparous. The median resting anal pressure was 40 cm water (16-56 cm water, normal > 60 cm water). Endosonography revealed an internal sphincter that was thin and hyperechogenic, and had a poorly defined edge. The normal increase in the thickness of the internal anal sphincter with age was not seen. Anal-squeeze pressure, sensitivity, and pudendal nerve latencies were normal. In the second analysis the condition was identified in eight of 230 patients, representing 4% of new referrals. Primary degeneration of the internal anal sphincter smooth muscle is a discrete clinical condition causing passive faecal incontinence.

Megacystic microcolon intestinal hypoperistalsis syndrome: Evidence of a primary myocellular defect of contractile fiber synthesis

Two infant boys with megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) are reported. Presenting with neonatal intestinal obstruction, they underwent laparotomies that showed megacystis, microcolon, and aperistaltic shortened small bowel without any mechanical obstruction. Patient 1 gradually improved and is developing normally at home, on a normal diet without genitourinary or gastrointestinal complaints (now 11 years old). Patient 2, who underwent vesicoamniotic drainage antenatally, nerver developed adequate gastrointestinal or genitourinary function in spite of appropriate diversion and pharmacologic support. He showed progressive deterioration and died at the age of 7 months. Detailed histo-immuno- and ultrastructural pathology assessment, although confirming results in the existing literature in some aspects, showed previously unreported neuronal dysplastic changes associated with increased laminin and fibronectin. Although patient 1 showed ultrastructural features of vacuolar degeneration of smooth muscle as reported in the literature, patient 2 showed ultrastructural and histochemical evidence of excessive smooth muscle cell glycogen storage with severely reduced contractile fibres displaced to the extreme periphery of the cells, suggesting a fundamental defect of glycogen-energy utilization. A deficiency of fiber synthesis as the alternative primary defect is discussed. In both cases, a two-step genetic defect may explain the variability in clinical outcome and pathological findings.

Functional electromyostimulation of the corpus cavernosum penis--preliminary results of a novel therapeutic option for erectile dysfunction.

Transcutaneous application of low-frequency electric current in the treatment of partially or temporarily denervated striated muscles is widely used to prevent or treat muscular atrophy. Due to the high regenerative capacity of smooth-muscle cells, this approach should be beneficial in the treatment of diseases with smooth-muscle degeneration due to partial denervation. Our study was done to evaluate the possible beneficial effect of transcutaneously applied low-frequency electric current on the corpus cavernosum penis in the treatment of erectile dysfunction. After a comprehensive workup, 21 patients with chronic erectile dysfunction (20/21 vasoactive nonresponders) received daily (3-5 x 20 min) transcutaneous functional electromyostimulation of the corpus cavernosum smooth muscles [FEMCC; zero-line symmetric impulses of trapezoid shape, 2-channel device with alternating stimulations; frequency (f), 10-20 Hz for channel I and 20-35 Hz for channel II; impulse duration (ti), 100-150 microseconds; approx. 12 mA; rise time, 0.5 s; stimulation time, 5 s/channel; pause between stimulations, 0.5 s. In all, 4/21 patients (19%) regained full spontaneous erections and another 3/21 (14%) responded to vasoactive drugs after FEMCC. Overall, 14/21 were FEMCC failures, including 2 who subjectively "improved." In a similar group of patients who were evaluated during the same period but received no therapy, no spontaneous improvement in erectile function was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Radiation-induced arteritis.

Injuries to human vessels in various anatomic sites exposed to therapeutic doses of radiation have shown a remarkably consistent pattern including the following findings: (1) subendothelial connective tissue proliferation; (2) disruption of the elastic lamina; (3) accumulation of intimal and subintimal fibrinoid substances; (4) degeneration of smooth muscle; (5) dense fibrosis of the adventitia; (6) aggregates of foamy histiocytes in the damaged wall; and (7) obliteration of vasa vasorum, z,3 The mechanism of delayed radiation injury of vessels has been hypothesized as endothelial cell damage and the resultant destruction of the microcirculation. 4 In smaller arteries or arterioles, less than 100 ixm, delayed postradiation changes consist of subendothelial fibrosis, subendothelial foam cells, hyaline medial change, and adventitial fibrosis. Obliteration of the arteriolar lumen is observed in advanced cases. In medium-sized arteries, 100-500/xm, accumulation of foam ceils in the subendothelial and

Coronary Artery Toxicity in Beagle Dogs Given Indolidan, a Type III Phosphodiesterase Inhibitor

Coronary Artery Toxicity in Beagle Dogs Given Indolidan, a Type III Phosphodiesterase Inhibitor. Sandusky, G. E., Means, J. R., and Yeager, H. K. (1993). Fundam. Appl. Toxicol. 21, 228-235. The hemodynamic changes and cardiovascular lesions produced by a single iv dose of 2.0 mg/kg indolidan were evaluated in four beagle (two male, two female) dogs. Four additional dogs (two male, two female) served as vehicle controls. This was followed by a multidose study in which the same dose of indolidan or vehicle was given iv to clogs (4/group) on 4 consecutive days. Both studies were followed for 4 days postdose before termination. Clinical signs, mean arterial blood pressure, and heart rate were evaluated. Seven sections of the heart, approximately 25 sections of the coronary arteries, and 3 sections of the carotid, subclavian, spermatic or ovarian, renal, and femoral arteries were examined. Mean blood pressure was decreased 20 to 25% over a 24-hr period and heart rates were increased 40 to 50% after treatment and remained elevated for at least a 24-hr period in both single and multidose treated groups. The earliest lesions occurred in three of four treated dogs after a single intravenous dose of 2.0 mg/kg. The main lesion was sporadic in distribution and seen in the outer one-half of the smooth muscle media of the coronary arteries. Smooth muscle degeneration and necrosis were present, with little secondary inflammation. No lesions were observed in the peripheral arteries or the myocardium. The coronary arterial lesions observed after the multidose study were more extensive and severe. The lesions were seen in large extramural and large intramural coronary arteries. These were characterized by marked smooth muscle necrosis involving most of the media, destruction of the internal elastic membrane, and marked adventitial fibroplasia. The inflammatory infiltrate varied from mild to moderate and was usually seen in the adventitia. No lesions were observed in the peripheral arteries or the myocardium in the multidose study.