Vitamin D and Vulnerable Carotid Plaque.

BACKGROUND AND PURPOSE: MR imaging-detected carotid intraplaque hemorrhage indicates vulnerable plaque with high stroke risk. Angiotensin II stimulates intraplaque hemorrhage in animal models, and the angiotensin system is highly regulated by vitamin D. Our purpose was to determine whether low vitamin D levels predict carotid intraplaque hemorrhage in humans. MATERIALS AND METHODS: In this cross-sectional study, 65 patients with carotid disease underwent carotid MR imaging and blood draw. Systemic clinical confounders and local lumen imaging markers were recorded. To determine the association of low vitamin D levels with MR imaging detected intraplaque hemorrhage, we performed multivariable Poisson regression by using generalized estimating equations to account for up to 2 carotid arteries per patient and backward elimination of confounders. MR imaging detected intraplaque hemorrhage volume was also correlated with vitamin D levels and maximum plaque thickness. Thirty-five patients underwent carotid endarterectomy, and histology-detected intraplaque hemorrhage was correlated with vitamin D levels and total plaque area. RESULTS: Low vitamin D levels (<30 ng/mL, prevalence ratio = 2.05, P = .03) were a significant predictor of MR imaging detected intraplaque hemorrhage, along with plaque thickness (prevalence ratio = 1.40, P < .001). MR imaging detected intraplaque hemorrhage volume linearly correlated with plaque thickness (partial r = 0.45, P < .001) and low vitamin D levels (partial r = 0.26, P = .003). Additionally, histology-detected intraplaque hemorrhage area linearly correlated with plaque area (partial r = 0.46, P < .001) and low vitamin D levels (partial r = 0.22, P = .03). The association of intraplaque hemorrhage volume with low vitamin D levels was also higher with ischemic stroke. CONCLUSIONS: Low vitamin D levels and plaque thickness predict carotid intraplaque hemorrhage and outperform lumen markers of vulnerable plaque. This research demonstrates a significant link between low vitamin D levels and carotid intraplaque hemorrhage.

Long-term maintenance therapy for post-cardiac transplant monoclonal lymphoproliferative disorder: caveat mammalian target of rapamycin.

A 53-year-old Caucasian male suffering from idiopathic dilated cardiomyopathy underwent cardiac transplantation. Fifty-seven days following transplant, he developed posttransplant lymphoproliferative disorder (PTLD), which was Epstein-Barr virus positive. The initial episode of PTLD was treated with a dose reduction in cyclosporine (CsA) and a 4-week course of rituximab. Subsequent biopsies showed resolution of PTLD. One year posttreatment, his evaluation revealed severe cardiac allograft vasculopathy (CAV). The patient was switched to sirolimus-based immunosuppression regimen with gradual up-titration of sirolimus in combination with complete withdrawal of previously administered Calcineurin-based immunosuppression approach. The switchover was carried out over a 6-week period. In the following 3 years, there was CAV regression as well as PTLD remission, without any significant episode of rejection. Despite frequent relapses with this form of PTLD, the patient remains in remission, 8 years posttransplantation. In summary, sirolimus has been demonstrated to attenuate the progression of CAV, and this case report illustrates that regression of CAV is possible. In addition to preventing rejection, mammalian target of rapamycin inhibitors directly suppress signaling pathways leading to PTLD and may be effective monotherapy for preventing rejection and suppressing PTLD.

Proteinase-activated receptor-2 activation evokes oesophageal longitudinal smooth muscle contraction via a capsaicin-sensitive and neurokinin-2 receptor-dependent pathway.

BACKGROUND: Intraluminal acid evokes sustained oesophageal longitudinal smooth muscle (LSM) contraction and oesophageal shortening, which may play a role in oesophageal pain and the aetiology of hiatus hernia. In the opossum model, this reflex has been shown to involve mast cell activation and release of neurokinins from capsaicin-sensitive neurons. The aim of this study was to determine whether proteinase-activated receptor-2 (PAR-2) activation evokes reflex LSM contraction via similar mechanisms. METHODS: Tension recording studies were performed using opossum oesophageal LSM strips in the presence and absence of pharmacological agents. In addition, the effect of trypsin on single isolated LSM cells was determined using videomicroscopy, and the expression of PAR-2 in oesophageal tissue was examined using immunohistochemistry. KEY RESULTS: The PAR-2 agonist trypsin evoked sustained, concentration-dependent contraction of LSM muscle strips, but had no effect on isolated LSM cells. The trypsin-induced contraction was blocked by capsaicin desensitization, substance P (SP) desensitization or application of the selective neurokinin-2 (NK-2) receptor antagonist MEN 10376. Immunohistochemistry revealed co-localization of SP, calcitonin gene-related peptide and PAR-2 in axons of opossum oesophageal LSM. CONCLUSIONS & INFERENCES: Longitudinal smooth muscle contraction induced by trypsin involves capsaicin-sensitive neurons and subsequent activation of NK-2, which is identical to the pathway involved in acid-induced LSM contraction and oesophageal shortening. This suggests that acid-induced LSM contraction may involve mast cell-derived mediators that activate capsaicin-sensitive neurons via PAR-2.

TREK-1 channels do not mediate nitrergic neurotransmission in circular smooth muscle from the lower oesophageal sphincter.

BACKGROUND AND PURPOSE: The ionic mechanisms underlying nitrergic inhibitory junction potentials (IJPs) in gut smooth muscle remain a matter of debate. Recently, it has been reported that opening of TWIK-related K(+) channel 1 (TREK-1) K(+) channels contributes to the nitrergic IJP in colonic smooth muscle. We investigated the effects of TREK-1 channel blockers on nitrergic neurotransmission in mouse and opossum lower oesophageal sphincter (LOS) circular smooth muscle (CSM). EXPERIMENTAL APPROACH: The effects of TREK-1 channel blockers were characterized pharmacologically in murine and opossum gut smooth muscle using conventional intracellular and tension recordings. KEY RESULTS: In LOS, L-methionine depolarized the resting membrane potential (RMP) but did not inhibit the nitrergic IJP. Cumulative application of theophylline hyperpolarized the RMP and inhibited the nitrergic IJP concentration dependently. The induced membrane hyperpolarization was prevented by pre-application of caffeine, but not by 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one. 8-Br-cAMP significantly hyperpolarized membrane potential and increased the amplitude of the nitrergic IJP. In opossum LOS muscle strips, L-methionine increased resting tone but had no effect on nerve-mediated LOS relaxation. On the other hand, theophylline markedly inhibited tone. In CSM from mouse proximal colon, L-methionine caused modest inhibition of nitrergic IJPs. CONCLUSIONS AND IMPLICATIONS: TREK-1 channels were not involved in the nitrergic IJP in LOS CSM. Not only does L-methionine have no effect on the nitrergic IJP or LOS relaxation, but the effect of theophylline appears to be due to interruption of Ca(2+)-releasing pathways (i.e. caffeine-like effect) rather than via blockade of TREK-1 channels.

Primary central nervous system vasculitis: comparison of patients with and without cerebral amyloid angiopathy.

OBJECTIVES: To describe the clinical features and outcomes of patients with primary central nervous system vasculitis (PCNSV) and cerebral amyloid angiopathy (CAA) from a large cohort of consecutive patients with PCNSV treated at a single institution. METHODS: We identified 101 consecutive patients with PCNSV admitted between January 1983 and December 2003. PCNSV diagnoses were based on findings from a central nervous system (CNS) biopsy (n = 31) and conventional angiography (n = 70). CNS tissue specimens from 49 cases were examined histologically, and 49 were stained for amyloid deposits. Those with vascular amyloid deposits (CAA) were compared with those without histological evidence of amyloid deposition. RESULTS: Eight cases (26%) with CNS biopsy specimens positive for PCNSV also showed findings of CAA. Compared with patients with PCNSV only, these patients were older at diagnosis, predominantly male, had a more acute onset, a higher frequency of cognitive dysfunction and showed prominent gadolinium-enhanced leptomeningeal lesions with MRI. Histologically, all had a granulomatous vascular inflammatory pattern. Six patients responded promptly to therapy. Outcomes at last follow-up were similar in the two groups. CONCLUSIONS: PCNSV with CAA appears to form a clinical subset of PCNSV. The vasculitis influences the clinical findings to a greater degree than the presence of amyloid deposits in the vessels.

Primary CNS vasculitis with spinal cord involvement.

BACKGROUND: Primary CNS vasculitis (PCNSV) is an uncommon disease in which lesions are limited to the brain and spinal cord. Our objective was to evaluate the frequency, clinical features, and outcome of spinal cord involvement in PCNSV. METHODS: We retrospectively identified 101 consecutive patients with PCNSV. Spinal cord involvement was documented for five. Clinical findings, laboratory studies, and outcomes of patients with spinal cord involvement were assessed and compared with those without spinal cord manifestations. RESULTS: Spinal cord symptoms developed before cerebral symptoms in one patient, concurrently in two, and after cerebral symptoms in two. CNS biopsy specimens showed necrotizing vasculitis in three patients and granulomatous vasculitis in two. MRI of the spinal cord showed enhanced thoracic lesions in all five. Cerebral angiograms from four patients had normal findings. One patient had a fatal clinical course. The other four had relapses during follow-up but responded well to therapy and had favorable overall outcomes. At the last follow-up (median, 19 months after diagnosis), the four patients had recovered with slight or moderate residual disability. No significant differences in clinical and laboratory features were observed when comparing patients with or without spinal cord involvement. Cerebral angiograms with evidence of vasculitis were significantly more frequent for patients without spinal cord involvement (p = 0.002). CONCLUSION: Spinal cord involvement was documented in 5% of patients with primary CNS vasculitis. The thoracic cord was the predominantly affected site. Other than myelopathy, clinical characteristics were similar to those of the patients without spinal cord involvement.

Role of platelet-activating factor in acid-induced esophageal mucosal injury.

Studies on the pathophysiology of reflux esophagitis have focused on the associated motility and/or structural abnormalities, with relatively little attention directed to inflammatory mediators involved in the acid-induced mucosal injury. Mast cells line the subepithelial lamina propria in both humans and the opossum model, and are ideally positioned to respond to luminal agents that cross the mucosal barrier. To determine whether certain mast cell mediators are involved in acid-induced mucosal injury, epithelial injury scores following 60 min of luminal perfusion of the opossum esophagus with 100 mM HCl were compared in the presence and absence of two different mast cell stabilizers (disodium cromoglycate and doxantrazole) or the selective platelet-activating factor antagonist TCV-309. In control animals acid perfusion caused release of PAF and significant epithelial injury, characterized by epithelial sloughing and cleft formation. This injury was unaffected by pretreatment with disodium cromoglycate or doxantrazole but was completely prevented by TCV-309 (histology damage score, 2.40+/-0.28 in controls vs 0.50 +/- 0.14 in TCV-309-treated animals). These studies suggest that platelet-activating factor is an important mediator of acid-induced esophageal mucosal damage.

Role of cADPR in sodium nitroprusside-induced opossum esophageal longitudinal smooth muscle contraction.

Nitric oxide (NO) relaxes most smooth muscle, including the circular smooth muscle (CSM) of the esophagus, whereas in the adjacent longitudinal smooth muscle (LSM), it causes contraction. The second messenger pathways responsible for this NO-induced LSM contraction are unclear, given that these opposing effects of NO are both cGMP dependent. In intestinal LSM, but not CSM, cADP ribose (cADPR)-dependent pathways participate in Ca(2+) mobilization and muscle contraction; whether similar differences exist in the esophagus is unknown. The purpose of this study was to determine whether cADPR plays a role in the NO-mediated contraction of opossum esophageal LSM. Standard isometric tension recordings were performed using both LSM and CSM strips from opossum distal esophagus that were hung in 10-ml tissue baths perfused with oxygenated Krebs solution. cADPR produced concentration-dependent contraction of LSM strips with an EC(50) of 1 nM and peak contraction of 57 +/- 18% of the 60 mM KCl-induced contraction. cADPR had no effect on CSM strips at concentrations up to 10(-6) M. The EC(50) of cADPR caused contraction (18 +/- 2% from initial resting length) of isolated LSM cells. Sodium nitroprusside (SNP; 300 muM) induced contraction of LSM strips that averaged 67 +/- 5% of the KCl response. cADPR antagonists 8-bromo-cADPR and 8-amino-cADPR, as well as ryanodine receptor antagonists ryanodine and tetracaine, significantly inhibited the SNP-induced contraction. In conclusion, in the opossum esophagus, 1) cADPR induces contraction of LSM, but not CSM, and 2) NO-induced contraction of LSM appears to involve a cADPR-dependent pathway.

Heterotopic ossification after lateral epicondylectomy.

Lateral epicondylitis is a common affliction that can be treated nonsurgically. However, surgical treatment is rarely indicated, and results are usually effective in more than 90% of patients. Although complications have been described, ours is the first report of heterotopic ossification after an uncomplicated lateral epicondylectomy.

Opposing roles of K(+) and Cl(-) channels in maintenance of opossum lower esophageal sphincter tone.

The ionic basis underlying the maintenance of myogenic tone of lower esophageal sphincter circular muscle (LES) was investigated in opossum with the use of standard isometric tension and conventional intracellular microelectrode recordings in vitro. In tension recording studies, nifedipine (1 microM) reduced basal tone to 27.7 +/- 3.8% of control. The K(+) channel blockers tetraethylammonium (TEA, 2 mM), charybdotoxin (100 nM), and 4-aminopyridine (4-AP, 2 mM) enhanced resting tone, whereas apamin and glibenclamide were without affect. Cl(-) channel blockers DIDS (500 microM) and 5-nitro-2-(3-phenylpropylamino)-benzoic acid (500 microM), as well as niflumic acid (0.1-300 microM), decreased basal tone, but tamoxifen was without effect. Intracellular microelectrode recordings revealed ongoing, spontaneous, spike-like action potentials (APs). Nifedipine abolished APs and depolarized resting membrane potential (RMP). Both TEA and 4-AP significantly depolarized RMP and augmented APs, whereas niflumic acid dose-dependently hyperpolarized RMP and abolished APs. These data suggest that, in the opossum, basal tone is associated with continuous APs and that K(+) and Ca(2+)-activated Cl(-) channels have important opposing roles in the genesis of LES tone.

Genetic polymorphisms of group B streptococcus scpB alter functional activity of a cell-associated peptidase that inactivates C5a.

Many group B Streptococcus agalactiae strains and other pathogenic streptococci express a cell-associated peptidase that inactivates C5a (C5a-ase), the major neutrophil chemoattractant produced by activation of the complement cascade. Type III group B streptococci (GBS) can be classified genotypically into three restriction digest pattern types. Functional C5a-ase activity of GBS correlates with this genetic typing; therefore, we sought to identify a genetic basis for this phenomenon. Southern hybridization confirms that all type III GBS contain scpB, the gene encoding GBS C5a-ase. GBS strains with high C5a-ase functional activity and those with no or very low activity both express immunoreactive C5a-ase. The scpB sequence of strain I30, which has high C5a-ase activity, is 98.2% homologous to the previously reported serotype II GBS scpB sequence. The scpB sequences of strains I25 and GW, which have low or no C5a-ase activity, are identical. The predicted I25 and GW C5a-ase proteins share a four-amino-acid deletion affecting the protease histidine active-site consensus motif. Recombinant I30 C5a-ase has good functional activity, whereas recombinant I25 C5a-ase has low activity. These data demonstrate that functional C5a-ase differences between type III GBS strains are attributable to a genetic polymorphism of scpB. The ubiquitous expression of C5a-ase, irrespective of functional activity, suggests that C5a-ase may have a second, as yet unidentified, function.

ECG Quiz: Chest Pain in a College Football Player.

A 21-year-old college athlete was seen on the first day of football practice because of an acute onset of severe chest pain. The pain was noted during conditioning drills before any body contact had begun. The sharp, intermittent, left inframammary pain was aggravated by twisting or turning. The pain did not radiate and was not associated with shortness of breath, palpitations, nausea, or vomiting.

Slipped capital femoral epiphysis. The case for internal fixation in situ.

The traditional method of treating slipped capital femoral epiphysis by in situ pinning is being challenged. The complication of chondrolysis has been correlated with unrecognized pin penetration into the hip joint. Several studies have shown that black children may be more susceptible to developing chondrolysis. Fifty-five children (89% black) with 80 slipped epiphyses agreed to return for evaluation by the authors at an average of 3.3 years after in situ pinning. The results were classified according to clinical and roentgenographic parameters. The results were excellent or good in 56 (70%) of the 80 slips. Excellent or good results were found in 86% of mild slips, 55% of moderate, and 27% of severe. The complication of chondrolysis developed in three slips (4%) and avascular necrosis in two (3%). Poor pin position could be correlated with the complication in one of the three patients who developed chondrolysis and in both who developed avascular necrosis. Poor pin position was also associated with 12 (60%) of the 20 poor results. The majority of pin problems were secondary to technical problems associated with attempting in situ pinning from the lateral approach. In this study, black children were not more susceptible to chondrolysis than nonblack children.

The contact neodymium-yttrium aluminum garnet laser. A new approach to arthroscopic laser surgery.

Arthroscopic treatment of meniscal lesions has been modified as technological advances have occurred. However, alternatives to conventional arthroscopic cutting tools, including electrocautery and CO2 lasers, have thus far met with limited success. The recent development of a sapphire tip has enabled the use of the neodymium-yttrium aluminum garnet (Nd-YAG) laser in a contact mode in a saline medium. This study compares the biology of the Nd-YAG laser to that of electrocautery and scalpel techniques with respect to its effects on articular cartilage and the meniscus. The contact Nd-YAG laser has advantages over both scalpel and electrocautery with regard to its effects on articular cartilage. It also has significant biologic advantages over electrocautery for meniscal lesions. Although in its infancy in the clinical setting, the contact Nd-YAG laser represents the possible beginning of a new era for application of laser energy in arthroscopy.

Two-stage reimplantation for the salvage of total knee arthroplasty complicated by infection. Further follow-up and refinement of indications.

Thirty-eight total knee replacements (in thirty-five patients) that were complicated by infection were treated with a two-stage protocol for reimplantation. The clinical results in these knees (nine of which have been previously reported on) were evaluated at an average follow-up of four years (range, 2.5 to ten years). There was only one documented recurrence of infection with the original organism. Three patients in whom the immunological system was suppressed had a subsequent hematogenous infection with a different organism. According to the knee-rating system of The Hospital for Special Surgery, there were eleven excellent, thirteen good, six fair, and seven poor results. For one patient who had severe polyarticular rheumatoid arthritis, the result could not be rated. The results of this study suggested that the two-stage protocol for reimplantation, with a six-week interval of intravenous antibiotic therapy, is the procedure of choice for the treatment of an infection around a total knee arthroplasty. A patient who has polyarticular rheumatoid arthritis and in whom the immunological system is suppressed may not be an ideal candidate for the protocol. Gram-negative bacterial infection may be treated with this protocol, provided the organism is sensitive to relatively non-toxic antibiotic medication.

The use of the contact Nd:YAG laser in arthroscopic surgery: effects on articular cartilage and meniscal tissue.

The contact Nd:YAG laser's small size, tip variety, fiberoptic application, and suitability for use in a saline medium make it a particularly appealing tool for use in arthroscopic procedures. This study was performed to investigate the laser's effects on articular cartilage and meniscal tissue with respect to depth of damage (canine cadaver model) and healing response (rabbit model). Depth of damage in the canine cadaver model was greater in meniscal tissue than in articular cartilage at each wattage level. In the presence of a saline bath, depth damage in both tissues was diminished. Scalpel articular cartilage lesions showed no response over time. Electrocautery lesions uniformly showed significant wide margins of hyaline cartilage necrosis which increased over time. Laser articular cartilage lesions showed vigorous healing responses characterized by fibrocartilage healing by 6 weeks. Scalpel meniscectomies showed characteristic fibrocartilagenous remodeling by 6 weeks, while electrocautery meniscectomies showed wide margins of necrosis with no specimen showing remodeling capability. Laser meniscectomies showed an intermediate response with a small number of menisci remodeling in a normal fashion. This article represents the first comprehensive look at the effects of the Nd:YAG laser on articular cartilage and meniscal tissue in terms of depth of damage and healing response over time, and indicates this laser's biological advantage over scalpel and electrocautery in arthroscopic procedures.