PIEZO2-dependent rapid pain system in humans and mice.

The PIEZO2 ion channel is critical for transducing light touch into neural signals but is not considered necessary for transducing acute pain in humans. Here, we discovered an exception - a form of mechanical pain evoked by hair pulling. Based on observations in a rare group of individuals with PIEZO2 deficiency syndrome, we demonstrated that hair-pull pain is dependent on PIEZO2 transduction. Studies in control participants showed that hair-pull pain triggered a distinct nocifensive response, including a nociceptive reflex. Observations in rare Aß deafferented individuals and nerve conduction block studies in control participants revealed that hair-pull pain perception is dependent on Aß input. Single-unit axonal recordings revealed that a class of cooling-responsive myelinated nociceptors in human skin is selectively tuned to painful hair-pull stimuli. Further, we pharmacologically mapped these nociceptors to a specific transcriptomic class. Finally, using functional imaging in mice, we demonstrated that in a homologous nociceptor, Piezo2 is necessary for high-sensitivity, robust activation by hair-pull stimuli. Together, we have demonstrated that hair-pulling evokes a distinct type of pain with conserved behavioral, neural, and molecular features across humans and mice.

Concomitant gastroparesis negatively affects children with functional gallbladder disease.

OBJECTIVES: The aim of the present study was to determine whether concomitant gastroparesis and biliary dyskinesia (BD) occur in children, and if so, to determine whether concomitant gastroparesis affects clinical outcome in children with BD. METHODS: We conducted a retrospective chart review of children with BD (ejection fraction <35% on cholescintigraphy, with no other metabolic or structural cause) who completed a solid-phase gastric emptying scintigraphy scan within 12 months of abnormal cholescintigraphy. Children were classified into 1 of 4 clinical outcome groups (excellent, good, fair, poor). RESULTS: Thirty-five children with a mean follow-up time of 23.1±17.3 (standard deviation) months were included. Twenty (57%) children were identified as having concomitant gastroparesis (GP) with BD. Children with concomitant GP were more likely to have a poor clinical outcome compared with those with BD alone (P<0.005). In children undergoing cholecystectomy, those with concomitant GP were more likely to have a fair or poor clinical outcome compared with those with BD alone (P<0.01). Factors predicting a more favorable clinical outcome were having BD alone and not having limitations in activity (eg, school absences) at the time of presentation. CONCLUSIONS: Concomitant GP may occur in children with functional gallbladder disorders. Concomitant GP may negatively affect clinical outcome in children with BD.

Randomized, double-blind pilot study of transendocardial injection of autologous aldehyde dehydrogenase-bright stem cells in patients with ischemic heart failure.

BACKGROUND: The optimal type of stem cell for use in patients with ischemic heart disease has not been determined. A primitive population of bone marrow-derived hematopoietic cells has been isolated by the presence of the enzyme aldehyde dehydrogenase and comprises a multilineage mix of stem and progenitor cells. Aldehyde dehydrogenase-bright (ALDH(br)) cells have shown promise in promoting angiogenesis and providing perfusion benefits in preclinical ischemia studies. We hypothesize that ALDH(br) cells may be beneficial in treating ischemic heart disease and thus conducted the first randomized, controlled, double-blind study to assess the safety of the transendocardial injection of autologous ALDH(br) cells isolated from the bone marrow in patients with advanced ischemic heart failure. METHODS: Aldehyde dehydrogenase-bright cells were isolated from patients' bone marrow on the basis of the expression of a functional (aldehyde dehydrogenase) marker. We enrolled 20 patients (treatment, n = 10; control, n = 10). Safety (primary end point) and efficacy (secondary end point) were assessed at 6 months. RESULTS: No major adverse cardiovascular or cerebrovascular events occurred in ALDH(br)-treated patients in the periprocedural period (up to 1 month); electromechanical mapping-related ventricular tachycardia (n = 2) and fibrillation (n = 1) occurred in control patients. Aldehyde dehydrogenase-bright-treated patients showed a significant decrease in left ventricular end-systolic volume at 6 months (P = .04) and a trend toward improved maximal oxygen consumption. The single photon emission computed tomography delta analysis showed a trend toward significant improvement in reversibility in cell-treated patients (P = .053). CONCLUSIONS: We provide preliminary evidence that treatment with the novel cell population, ALDH(br) cells, is safe and may provide perfusion and functional benefits in patients with chronic myocardial ischemia.

A randomized study of transendocardial injection of autologous bone marrow mononuclear cells and cell function analysis in ischemic heart failure (FOCUS-HF).

BACKGROUND: Autologous bone marrow mononuclear cell (ABMMNC) therapy has shown promise in patients with heart failure (HF). Cell function analysis may be important in interpreting trial results. METHODS: In this prospective study, we evaluated the safety and efficacy of the transendocardial delivery of ABMMNCs in no-option patients with chronic HF. Efficacy was assessed by maximal myocardial oxygen consumption, single photon emission computed tomography, 2-dimensional echocardiography, and quality-of-life assessment (Minnesota Living with Heart Failure and Short Form 36). We also characterized patients' bone marrow cells by flow cytometry, colony-forming unit, and proliferative assays. RESULTS: Cell-treated (n = 20) and control patients (n = 10) were similar at baseline. The procedure was safe; adverse events were similar in both groups. Canadian Cardiovascular Society angina score improved significantly (P = .001) in cell-treated patients, but function was not affected. Quality-of-life scores improved significantly at 6 months (P = .009 Minnesota Living with Heart Failure and P = .002 physical component of Short Form 36) over baseline in cell-treated but not control patients. Single photon emission computed tomography data suggested a trend toward improved perfusion in cell-treated patients. The proportion of fixed defects significantly increased in control (P = .02) but not in treated patients (P = .16). Function of patients' bone marrow mononuclear cells was severely impaired. Stratifying cell results by age showed that younger patients (≤60 years) had significantly more mesenchymal progenitor cells (colony-forming unit fibroblasts) than patients >60 years (20.16 ± 14.6 vs 10.92 ± 7.8, P = .04). Furthermore, cell-treated younger patients had significantly improved maximal myocardial oxygen consumption (15 ± 5.8, 18.6 ± 2.7, and 17 ± 3.7 mL/kg per minute at baseline, 3 months, and 6 months, respectively) compared with similarly aged control patients (14.3 ± 2.5, 13.7 ± 3.7, and 14.6 ± 4.7 mL/kg per minute, P = .04). CONCLUSIONS: ABMMNC therapy is safe and improves symptoms, quality of life, and possibly perfusion in patients with chronic HF.

Morphological features of advanced hepatocellular carcinoma as a predictor of downstaging and liver transplantation: an intention-to-treat analysis.

In selected patients, locoregional therapy (LRT) has been successful in downstaging advanced hepatocellular carcinoma (HCC) so that the conventional criteria for liver transplantation (LT) can be met. However, the factors that predict successful treatment are largely unidentified. To determine these factors, we analyzed our experience with multimodal LRT in downstaging advanced HCC before LT in a retrospective cohort study. Thirty-two patients with advanced HCC exceeding conventional and expanded criteria for LT underwent therapy, but only those patients whose tumors were successfully downstaged were considered for LT. Eighteen patients (56%) had their tumors successfully downstaged; 14 patients (44%) did not. No intergroup differences existed with respect to patient characteristics or the types and number of treatments. However, mean alpha-fetoprotein levels were significantly higher in the non-downstaged group than in the downstaged group (P < 0.048), and significantly more patients in the non-downstaged group had infiltrative tumors (P = 0.0001). The median survival time was 42 and 7 months for the downstaged and non-downstaged groups, respectively (P = 0.0006). Fourteen patients (43.3%) underwent LT. After a median follow-up period of 35 months (range, 1.5-50 months) after LT, 2 patients (14.2%) developed tumor recurrence. The Kaplan-Meier survival rates after LT were 92% at 1 year and 75% at 2 years. The noninfiltrative expanding tumor type was the sole predictor of successful downstaging and improved outcome on univariate and multivariate analyses. Our study suggests that, in patients with advanced HCC, morphological characteristics of the tumor may predict a good response to downstaging and an improved outcome after LT.

Safety and efficacy of radionuclide therapy with high-activity In-111 pentetreotide in patients with progressive neuroendocrine tumors.

The intent of this study was to evaluate the safety and efficacy of high-activity 111In-pentetreotide in patients with neuroendocrine tumors. Thirty-two patients with pentetreotide-avid neuroendocrine tumors received therapy from August 2005 to November 2006. Fourteen (14) patients received 1 treatment and 18 patients received 2 treatments. Patients were followed an average of 12.73 months (range 1.2-24.5). Seventeen (17) patients (53%) had grade I or II hematologic toxicities, and 1 patient had grade III thrombocytopenia. One patient had grade II liver toxicity, which appeared 4 weeks after therapy and resolved on week 5. No patient had renal toxicity. Of the patients who completed 2 treatment cycles, 2 of 18 patients had partial disease regression, and 16 of 18 patients with previously progressive disseminated neuroendocrine disease achieved stable disease by imaging criteria. A decrease in serum tumor markers was observed in 14 of 18 patients given 2 therapies. A clinical response was achieved in 84% of the patients. Upon interim analysis, median survival was approximately 13 months (range 1.2-24.5). These results show that high-activity 111In-pentetreotide therapy is effective in patients with progressive disseminated neuroendocrine tumors.

Low back pain: prediction of short-term outcome of facet joint injection with bone scintigraphy.

PURPOSE: To prospectively evaluate use of bone scintigraphy with single photon emission computed tomography (SPECT) for identification of patients with low back pain who would benefit from facet joint injections. MATERIALS AND METHODS: The protocol was reviewed and approved by the institutional review board. All patients provided informed consent. Forty-seven patients (23 men and 24 women) with low back pain, who were scheduled for facet joint injections, were prospectively enrolled and randomized into groups A and B (mean ages, 43.3 and 44.2 years, respectively) with a group A-group B ratio of 2:1. Group A patients underwent bone scintigraphy with SPECT prior to injection. Group A patients with bone scans positive for facet joint abnormalities received injections at the levels where abnormalities were identified on the scan (group A1). Group A patients with negative scans (group A2) received injections at the levels that were decided as in group B. Group B patients received injections at the levels indicated by the referring physician and did not undergo bone scintigraphy. All patients completed a pain and function questionnaire before injection and at 1, 3, and 6 months afterward. The change in the American Academy of Orthopaedic Surgeons pain scores after 1, 3, and 6 months compared with baseline scores was analyzed with analysis of variance and post hoc Bonferroni multiple-comparison tests between groups. Cost analysis was performed. RESULTS: The change in the pain score at 1 month was significantly higher (P < .004) in group A1 than it was in the other two groups. In group A1, 13 of 15 patients had improvement in pain score of greater than 1 standard deviation at 1 month, whereas improvement occurred in only two of 16 patients in group A2 and five of 16 patients in group B. In patients with positive scans, the number of facets treated with injection was decreased from 60, which was the number originally indicated by the referring physician, to 27. The Medicare cost was reduced from $2191 per patient to $1865 with the use of SPECT. CONCLUSION: Bone scintigraphy with SPECT can help identify patients with low back pain who would benefit from facet joint injections.

Molecular imaging in transplantation: basic concepts and strategies for potential application.

BACKGROUND: The potential applications of molecular imaging in the clinical arena are diverse and expanding rapidly. One such area of application is transplantation. Currently, biopsy is the gold standard for monitoring allograft well-being after transplantation of organs or tissues. However, biopsies are invasive, associated with morbidity if performed on a routine basis and can potentially miss focal rejection. AIM: It is notable that none of the existing studies in the literature have examined the possible role of molecular imaging in transplantation-related indications. In this direction, this paper aims to discuss imaging strategies that could be of pertinence in monitoring immune events and improving long-term outcomes after solid organ or tissue transplantation. METHODS: This paper discusses the currently available direct/surrogate imaging techniques/agents that can be used to detect chemokine receptors/ligands, leucocyte endothelial events and ischaemia-reperfusion injury in transplantation. CONCLUSION: Molecular imaging methods can non-invasively detect, quantify and monitor immune phenomena, such as rejection or graft-versus-host disease, after transplantation. Molecular imaging could help in targeted biopsy and could improve graft survival by allowing for early intervention with tailored immunosuppressive regimens. Given the unprecedented progress in the field, the potential benefits of molecular imaging to the speciality of organ and tissue transplantation cannot be underestimated.

A double-blind placebo-controlled trial of botulinum toxin B for sialorrhea in Parkinson's disease.

BACKGROUND: Injections of botulinum toxin A are an effective treatment for sialorrhea in Parkinson's disease (PD). Based on the relatively high rates of dry mouth seen with botulinum toxin B, there is reason to suspect that it may also improve sialorrhea. OBJECTIVE: To determine whether botulinum toxin B (Myobloc; Elan Pharmaceuticals, New York, NY) is a safe and effective treatment for sialorrhea in patients with PD. METHODS: Demographics, PD treatments, head posture, the Unified Parkinson's Disease Rating Scale (UPDRS), two questionnaires regarding drooling, Visual Analogue Scale, global impressions, salivary gland imaging, and a dysphagia questionnaire were assessed in 16 PD subjects with problematic sialorrhea. Patients were then randomized to receive either botulinum toxin B (1,000 units into each parotid gland and 250 units into each submandibular gland) or a pH-matched placebo, using only anatomic landmarks. Patients returned 1 month later to undergo an identical assessment. RESULTS: Compared with placebo, those randomized to drug reported improvement on the Visual Analogue Scale (p < 0.001), global impressions of change (p < 0.005), Drooling Rating Scale (p < 0.05), and Drooling Severity and Frequency Scale (p < 0.001). There was no change in UPDRS, head posture, or Dysphagia Scale. Adverse events were mild and included dry mouth (three patients), worsened gait (two), diarrhea (one), and neck pain (one) in the botulinum toxin B group. CONCLUSION: Anatomically guided injections of botulinum toxin B into the parotid and submandibular glands appear to effectively improve sialorrhea without compromising dysphagia in patients with PD.

Congenital sucrase-isomaltase deficiency presenting with failure to thrive, hypercalcemia, and nephrocalcinosis.

BACKGROUND: Disaccharide Intolerance Type I (Mendelian Interance in Man database: *222900) is a rare inborn error of metabolism resulting from mutation in sucrase-isomaltase (Enzyme Catalyzed 3.2.1.48). Usually, infants with SI deficiency come to attention because of chronic diarrhea and nutritional evidence of malabsorption. CASE PRESENTATION: We describe an atypical presentation of this disorder in a 10-month-old infant. In addition to chronic diarrhea, the child displayed severe and chronic hypercalcemia, the evaluation of which was negative. An apparently coincidental right orbital hemangioma was detected. Following identification of the SI deficiency, an appropriately sucrose-restricted, but normal calcium diet regimen was instituted which led to cessation of diarrhea, substantial weight gain, and resolution of hypercalcemia. CONCLUSIONS: This case illustrates that, similar to congenital lactase deficiency (Mendelian Interance in Man database: *223000, Alactasia, Hereditary Disaccharide Intolerance Type II), hypercalcemia may complicate neonatal Sucrase-Isomaltase deficiency. Hypercalcemia in the presence of chronic diarrhea should suggest disaccharide intolerance in young infants.