Here, we report novel yet undescribed localization of NUCB2/nesfatin-1 at the mRNA and protein level SBI-0206965 in the rat central nervous system. Immunohistochemical staining revealed the localization of NUCB2/nesfatin-1 in the piriform and insular cortex, endopiriform

nucleus, nucleus accumbens, lateral septum, bed nucleus of stria terminalis, central amygdaloid nucleus, medial preoptic area, dorsal raphe nucleus, ambiguus nucleus, ventrolateral medulla and gigantocellular reticular nucleus, as well as Purkinje-cells of the cerebellum. In the spinal cord, nesfatin-1 immunoreactivity (IR) was found in both sympathetic and parasympathetic preganglionic neuronal groups and in the dorsal area X from lower thoracic to sacral segments. The immunohistochemical results were confirmed by RT-PCR

in the central amygdaloid nucleus, nucleus accumbens, cerebellum and lumbar spinal cord microdissected by punch technique. The features and distributions of nesfatin-1 IR and mRNA expression in the brain and spinal cord suggest that NUCB2/nesfatin-1 could play a wider role in autonomic regulation of visceral-endocrine functions besides food intake. Published by Elsevier Ireland Ltd.”
“The copepod Calanus finmarchicus is a marine ecological key species in the Northern Atlantic food web. This species was exposed to an artificially weathered North Sea oil buy LY411575 dispersion (oil droplets and water-soluble fractions [WSF]) and a filtered dispersion Sitaxentan (containing only WSF) in serial dilution. Female copepods were divided into lipid-rich and lipid-poor for each exposure followed by gene expression analyses of glutathione S-transferase (GST) and cytochrome P-450 330A1 (CYP330A1). Lipid-rich copepods exhibited elevated transcription of GST and reduced transcription of CYP330A1 after exposure to both dispersed oil and WSF. In contrast, lipid-poor copepods exhibited increased transcription of CYP330A1 following exposure to WSF but not the dispersion. Data suggested that small lipid storage promotes increased bioavailability of accumulated oil compounds.

Variations in response in CYP330A1 gene expression indicate that oil constituents may exert different modes of toxic action in copepods depending on their reproductive stages. The contribution of oil droplets to the observed effects seemed to be low as GST gene expression was similar after exposure to both dispersed oil and WSF. However, feeding rate in copepods exposed to dispersed oil was reduced, and this may have decreased the uptake of oil constituents via the diet. Although quantitatively higher mortality was observed in copepods exposed to the highest dispersion levels, this may result from smothering of animals by oil droplets. Furthermore, increasing dilution of both the dispersions and the WSF altered their distributions and chemical composition, which may influence the bioavailability of spilled crude oil to pelagic marine organisms.

(C) 2011 Elsevier Ireland Ltd. All rights reserved.”
“Fibroblasts act as important immune regulatory cells via their ability to cross-talk with T cells accumulating in lesions. Our previous study showed that fibroblasts produce several cytokines and chemokines by crosslinking HLA class II (HLA-II) molecules with monoclonal antibodies or by making T-cell receptor-peptide-HLA complexes.

It is thus conceivable that the interaction of T cells and fibroblasts via HLA-II affects fibroblast responses to stimuli. This study used human gingival fibroblasts (HGF) to investigate possible effects of these fibroblast-derived soluble factors on the differentiation of naive T cells and on the subsequent fibroblast responses. After mixed lymphocyte reaction culture between naive T cells and allogeneic dendritic cells in the presence of culture supernatant from HGF stimulated via HLA-DQ molecules (DQ-sup), INCB018424 cost but not via DR, T cells exhibited a Th2-shifted phenotype, thereby producing quantitatively more IL-13 and IL-5 compared with interferon-gamma. Astonishingly, analyses to identify possible factors affecting the

Th2 polarization secreted from HLA-II-stimulated HGF, prostaglandin E-2, was detected only in DQ-sup. The Th2 polarization of naive Selleckchem S3I-201 T cells was blocked in the presence of supernatants from indomethacin-treated HGF with HLA-DQ stimulation. In addition, Celastrol we found that the culture supernatants of Th cells activated following mixed lymphocyte reaction culture in the presence of DQ-sup had the potential to induce gene expression of type I and III collagens in HGF. These results suggested that

fibroblasts stimulated via HLA-DQ molecules promote Th2 polarization in Th-cell responses and showed the counter activation of collagen synthesis, implicating orchestrated responses among these cells in the fibrosis of chronic inflammatory lesions. Laboratory Investigation (2010) 90, 1747-1756; doi:10.1038/labinvest.2010.128; published online 2 August 2010″
“Perseveration refers to maladaptive persistence of behavior outside appropriate contexts and despite negative outcomes. In humans, perseveration is a symptom of a variety of psychiatric disorders. In rats, perseveration has been observed in reversal learning tasks following lesions of the prefrontal cortex (PFC). However, the exact nature of the impairment underlying this effect remains unclear. Male Sprague-Dawley rats were trained on a novel reversal task that requires switching between two rewarded options varying in effort (concurrent fixed and progressive ratios) necessary to obtain the reward. Following initial training, bilateral lesions of the dorsal PFC. medial PFC, or orbitofrontal cortex were produced by NMDA infusions.

Measures of tau and beta-amyloid in CSF, MTL atrophy on MRI, and performance on delayed memory tasks were extracted from the papers or obtained from the investigators.

Results. Twenty-one MRI studies and 14 CSF Studies

were retrieved. The effect sizes of total tau (t-tau), phosphorylated tau (p-tau) and amyloid beta 42 (a beta 42) ranged from 0.91 to 1.11. The effect size of MTL atrophy was 0.75. Memory performance had an effect size of 1.06. MTL atrophy and memory impairment tended to increase Selleck PHA-848125 when assessed closer to the moment of diagnosis, whereas effect sizes of CSF biomarkers tended to increase when assessed longer before the diagnosis.

Conclusions. Memory impairment is a more accurate predictor of early AD than atrophy of MTL on MRI, whereas CSF abnormalities

and memory impairment are about equally predictive. Consequently, the CSF and MRI biomarkers are not very sensitive to preclinical AD. CSF markers remain promising, but studies with long follow-up periods in elderly subjects who are normal at baseline are needed to evaluate this promise.”
“Background. Panic disorder (PD) is generally considered to be a chronic or intermittent disorder. This view may be biased because of a lack of general population studies investigating panic from the onset of an episode onwards. Data regarding the course of subthreshold panic disorder (sub-PD) and predictors of its course are lacking.

Method. Using data from a large community-based survey, the Netherlands Rapamycin molecular weight Mental Health and Incidence Study (NEMESIS), OICR-9429 that retrospectively assessed

the 2-year course of panic with a Life Chart Interview (LCI), this Study investigated remission, chronicity and recurrence in subjects with new episodes of PD or sub-PD. Predictor variables of remission consisted of sociodemographics, psychobiological, environmental, psychiatric and panic-related factors.

Results. In PD, remission of panic attacks occurred in 64.5% of subjects, mean time to remission was 5.7 months, and the remission rate was 5.8/100 person-months. In 43.3%, of subjects panic was still present after 1 year. Recurrence of panic attacks occurred in 21.4%, of those with PD who had achieved remission and for whom sufficient follow-tip time was available. In general, the Course of sub-PD was more favourable. Predictors of remission were female gender, the absence of ongoing difficulties, subthreshold panic and a low initial frequency of attacks.

Conclusions. These results Suggest that the Course of panic is diverse in the general population, thereby underlining the need for accurate predictors. This requires further research including biological data and additional psychological data. In addition, given the large proportion with a relapse, relapse prevention should be part of any treatment programme.

“
“Objective: The optimal treatment for chronic type B selleck products dissection remains controversial. This study reports early and midterm results of thoracic endovascular aortic repair for chronic type B aortic dissection.

Methods: From June 2001 to September 2007, a total of 84 patients with chronic type B aortic dissection underwent thoracic endovascular aortic repair. The time between onset of dissection and thoracic endovascular aortic repair was 13.9 +/- 22.0 months (range, 1-120 months). All patients were followed up from 6 to 86 months (mean, 33.2 +/- 19.2 months).

Results: The entry tear was completely sealed in 77 cases (91.7%)

during thoracic endovascular aortic repair. The incidence of incomplete seal was 8.3%. Poziotinib purchase The 1-month mortality was 1.2%. One patient had retrograde type A dissection 1 month after the operation. Four patients underwent a second thoracic endovascular aortic repair during follow-up, for endoleak in 3 patients and for newly formed intimal tear in 1 patient. Seven patients (8.3%) died during follow-up. Three died of rupture of the thoracic aorta because of endoleak. The Kaplan-Meier actuarial survival curve showed a 5-year survival of 84.4%. At 5 years, 75.2% of patients were alive with neither endoleak nor reintervention.

Conclusions: Early and midterm results show that thoracic endovascular aortic repair was effective in the treatment of chronic type B aortic dissection. Endoleak was the main cause of death during follow-up.

With increased surgical experience and refinement of the stent graft, results are likely to improve in the future. (J Thorac Cardiovasc Surg 2010;139:1548-53)”
“‘By far the best proof is experience,’ wrote Francis Bacon. Given the experience of countries – both developing and developed -

that have used intellectual property (IP), IP protection and IP management to stimulate innovation, there is ample proof that 17-DMAG (Alvespimycin) HCl good IP management has benefited multitudes of people around the world with new technologies, products and services. Innovations in health and agriculture have greatly enriched lives. But does this experience apply to all countries? If the best proof is experience, then what can be said authoritatively about the effects of using IP systems wisely in developing countries?”
“Objectives: Our objective was to determine the contribution of endobronchial ultrasound in the diagnostic yields of acid-fast bacillus smear, nucleic acid amplification tests, and culture in bronchoalveolar lavage fluid for pulmonary tuberculosis.

Methods: During a 1-year interval, 99 patients who had initial sputum-negative acid-fast bacillus smears or no sputum but were later proven to have a positive culture for Mycobacterium tuberculosis in their sputum or bronchoalveolar lavage fluid were retrospectively studied. Among them, 56 patients underwent bronchoscopy with endobronchial ultrasound (EBUS group) and 43 patients received conventional bronchoscopy for bronchoalveolar lavage (non-EBUS group).

Patients were randomly assigned to receive chest compression alone or chest compression plus rescue breathing. The primary outcome was survival to hospital discharge. Secondary outcomes included a favorable neurologic outcome at discharge.

Results: Of the 1941 patients who met the inclusion criteria, 981 were randomly assigned to receive chest compression alone and 960 to receive chest compression plus rescue breathing. We observed no significant difference between the two groups in the proportion of patients who survived to hospital discharge (12.5% with chest compression

alone and 11.0% with chest compression plus rescue breathing, P=0.31) or in the proportion who survived with a favorable neurologic outcome in the two sites that assessed this secondary outcome (14.4% and 11.5%, respectively; ACP-196 P=0.13). Prespecified subgroup analyses showed a trend toward a higher proportion of patients surviving to hospital discharge with chest compression alone as compared with chest compression plus rescue breathing for patients

with a cardiac cause of arrest (15.5% vs. 12.3%, P=0.09) and selleck inhibitor for those with shockable rhythms (31.9% vs. 25.7%, P=0.09).

Conclusions: Dispatcher instruction consisting of chest compression alone did not increase the survival rate overall, although there was a trend toward better outcomes in key clinical subgroups. The results Sucrase support a strategy for CPR performed by laypersons that emphasizes chest compression and minimizes the role of rescue breathing. (Funded in part by the Laerdal Foundation for Acute Medicine and the Medic One Foundation; ClinicalTrials.gov number, NCT00219687.)

N Engl J Med 2010;363:423-33.”
“Immunosuppressants are considered critical dose/narrow therapeutic index drugs and there is the lingering suspicion among physicians and patients that generic versions may differ in quality and therapeutic efficacy from the brand name drug. The innovator’s and the generic active drug molecule are exactly the same and are produced following exactly the same tight rules of good

manufacturing practice. Upon oral administration, the drug molecule separates from the formulation and passes the membranes of gut mucosa cells; from this point on, the formulation has no influence on the kinetics of a drug and its biological effects. As formulations may differ, bioequivalence testing in healthy volunteer studies establishes equal relative oral bioavailability. Due to the number of patients required to achieve sufficient statistical power, to test the therapeutic equivalence of two formulations of the same drug with the same bioavailability is an unrealistic goal. An often overlooked fact is that the approval by drug regulatory agencies of several post-approval versions of the innovators’ immunosuppressants is based on the identical guidelines used for approval of generics.

(c) 2007 Elsevier Ireland Ltd. All rights reserved.”
“Neurons are arguably the most varied cell type both morphologically and functionally. Their fate during differentiation and development and the activity of mature neurons are significantly determined

and regulated by chromatin. The nucleus is compartmentalized and the arrangement of these compartments, termed the nuclear architecture, distinguishes one cell type from another and dictates many nuclear processes. Nuclear architecture determines the arrangement of chromosomes, the positioning of genes within chromosomes, SGC-CBP30 in vivo the distribution of nuclear bodies and the interplay between these different factors. Importantly, chromatin regulation has been shown to be the basis for a variety of central nervous system processes including grooming and nursing, depression and stress, and drug abuse, among others. Here we review the regulation and function of nuclear architecture Torin 1 mw and chromatin structure in the context of the nervous system and discuss the potential use of histone deacetylase inhibitors as chromatin-directed therapy for nervous system disorders.”
“Previous electrophysiological evidence

supports categorical perception of Chinese lexical tones at the preattentive stage (Xi and colleagues). In this study, we examined participants’ attentive responses to tonal continua in an event-related potential experiment that recorded their N2b and P3b oddball responses. We found that for both the N2b and the P3b component, the responses elicited by the within-category deviants were similar in the left and the right recording sites. However, the across-category deviants elicited larger responses in the left recording sites than in the right sites, reflecting conscious phonological processing of lexical tones. These results provide electrophysiological correlates of categorical

perception of Chinese lexical tones in later stages associated with controlled processes. NeuroReport Thiamet G 23: 35-39 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.”
“The influenza virus RNA-dependent RNA polymerase is capable of initiating replication but mainly catalyzes abortive RNA synthesis in the absence of viral and host regulatory factors. Previously, we reported that IREF-1/minichromosome maintenance (MCM) complex stimulates a de novo initiated replication reaction by stabilizing an initiated replication complex through scaffolding between the viral polymerase and nascent cRNA to which MCM binds. In addition, several lines of genetic and biochemical evidence suggest that viral nucleoprotein (NP) is involved in successful replication. Here, using cell-free systems, we have shown the precise stimulatory mechanism of virus genome replication by NP.

Prions passaged once in Gps from cases of sporadic (s) CreutzfeldtJakob disease (CJD) and Gerstmann-Straussler-Scheinker (GSS) disease caused by the P102L mutation were used, as well as human prions from a variant (v) CJD case, bovine prions from bovine spongiform encephalopathy (BSE) and mousepassaged scrapie prions. Variant

CJD and BSE prions transmitted to all the inoculated Gps with incubation times of 367 +/- 4 and 436 +/- 28 days, respectively. On second passage in Gps, vCJD and BSE prions caused disease LY2874455 cost in 287 +/- 4 and 310 +/- 4 days, whereas sCJD and GSS prions transmitted in 237 +/- 4 and 279 +/- 19 days, respectively. Although hamster Sc237 prions transmitted to two of three Gps after 574 and 792 days, mouse-passaged RML and 301V prion strains, the latter derived from BSE prions, failed to transmit disease to Gps. Those Gps inoculated with vCJD or BSE prions exhibited ‘type 2′ unglycosylated, rPrP(Sc) (19 kDa), whereas those receiving FK506 in vitro sCJD or GSS prions displayed ‘type 1′ prions (21 kDa), as determined by western blotting.

Such strain-specific properties were maintained in Gps as well as mice expressing a chimeric human/mouse transgene. Gps may prove particularly useful in further studies of novel human prions such as those causing vCJD. Laboratory Investigation (2011) 91, 1326-1336; doi: 10.1038/labinvest.2011.89; published online 4 July 2011″
“Filamins are large actin-binding proteins that stabilize delicate three-dimensional actin filament networks and link them to cellular membranes where they integrate cell architectural and signaling Morin Hydrate functions important for cell locomotion. Filamins have been shown to bind to proteins with diverse functions and are implicated in human genetic diseases including malformations of the skeleton, brain, and heart. Mouse models of filamin deficiency have advanced our understanding of the important roles filamins play in embryonic development

and disease progression. These studies provide clear evidence that cytoskeletal filamin proteins integrate cell signaling, transcription and organ development. This review focuses on the emerging roles of filamins in cell signaling and transcription, with emphasis on cell motility and organ development.”
“The influence of the selective 5-HT4 receptor agonist prucalopride on acetylcholine release from cholinergic nerve endings innervating pig gastric circular muscle and the possible regulation of this effect by phosphodiesterases (PDEs) was investigated, as PDEs have been shown to control the response to 5-HT4 receptor activation in pig left atrium. Circular muscle strips were prepared from pig proximal stomach and either submaximal cholinergic contractions or tritium outflow after incubation with [H-3]-choline, induced by electrical field stimulation, were studied.

05) and protein levels of MMP-2 (p <0.05). In contrast, there were no significant

changes in membrane-type 1 Cytoskeletal Signaling inhibitor MMP protein and tissue inhibitors of MMP activity after insulin treatment. Thus, these results suggest a mechanism by which insulin inhibits SMC migration and supports a vasculoprotective role for insulin in vivo. copyright (C) 2013 S. Karger AG, Basel”
“This article reviews the literature on co-occurring mental disorders and substance use disorders. The co-occurrence of mental disorders with substance use disorders presents a major challenge to those who provide psychiatric services. Despite the clinical and social burdens caused by this complex problem, research in this area is still insufficient. We found 18 studies showing potential predictors of co-occurring disorders (COD). Poor outcomes have been associated with: (i) COD compared to single disorders and (ii) COD with prior mental disorder compared to COD with prior substance use disorders. Poorer outcomes were reported for substance use disorder patients with comorbid major depressive disorder, and patients with substance use disorder and post-traumatic stress disorder. Furthermore, more negative outcomes were related to

COD patients with temporally prior onset of mood disorders. Comorbidity between major depressive disorder or post-traumatic stress disorder and substance use disorder is suggested in the literature as a potential predictor of COD problems. (C) 2010 Elsevier Ireland Ltd. All rights reserved.”
“The internal nnicroenvironment in peripheral nerves is highly https://www.selleckchem.com/products/sbe-b-cd.html regulated in order to maintain normal axonal impulse very transmission to or from the central nervous system. In humans, this regulation is facilitated by specialized tight junction (TJ)-forming endoneurial nnicrovascular endothelial cells and perineurial myofibroblasts that form multiple concentric layers around nerve fascicles. The endoneurial endothelial cells come in direct contact with circulating blood and, thus, can be considered the blood-nerve barrier (BNB). Studies on the molecular and biophysical properties of the human BNB in vivo or in situ are limited. Owing

to the recent isolation of primary human endoneurial endothelial cells and the development of simian virus 40 large T-antigen immortalized cell lines, data are emerging on the structural and functional characteristics of these cells. These data aim to increase our understanding of how solutes, macromolecules, nutrients and hennatogenous leukocytes gain access into or are restricted from the endoneurium of peripheral nerves. These concepts have clinical relevance in understanding normal peripheral nerve homeostasis, the response of peripheral nerves to external insult and stresses such as drugs and toxins and the pathogenesis of peripheral neuropathies. This review discusses current knowledge in this nascent and exciting field of microvascular biology. (C) Copyright 2013 S.

8 +/- 3.3 vs 9.3 +/- 3.1; P = .38), progression of original neurologic insult (7.5% vs 4.6%; 11 = .61) or mortality (28.1% vs 19%; P = .08). When comparing open surgical to endovascular interventions (46 open, 34 endovascular, including 3 combined), the only significant differences were in the total Injury Severity learn more Score (22.4 +/- 12.2 vs 31.4 +/- 15.4; P = .01) and length of intensive care unit (ICU) and hospital stay (5.0 +/- 6.0 days vs 10.7 +/- 10.4 days; P = .01,

and 10.3 +/- 9.2 days vs 19.3 +/- 17.7 days; P = .01). Multivariate regression analysis confirmed that neither Functional Independence Measure (FIM) nor mortality was associated with conservative: or operative treatment.

Conclusion: BCI is rare and carries a poor prognosis. Operative intervention is not associated with functional

improvement or a survival advantage. This study was unable to support that less invasive endovascular treatment improves treatment outcome when compared to open surgery. (J Vasc Surg 2010;51:593-9.)”
“The alternation of sounds in the left and right ears induces motion perception of a static visual stimulus (SIVM: Sound-Induced Visual Motion). In this case, binaural cues were of considerable benefit in perceiving locations and movements of the sounds. The present study investigated how a spectral cue – another important cue for sound localization and motion perception – contributed Foretinib price to the SIVM. In experiments, two alternating sound sources aligned in the vertical plane were presented, synchronized with a static visual stimulus. We found that the proportion of the SIVM and the STK38 magnitude of the perceived movements of the static visual stimulus increased with an increase of retinal eccentricity

(1.875-30 degrees), indicating the influence of the spectral cue on the SIVM. These findings suggest that the SIVM can be generalized to the whole two dimensional audio-visual space, and strongly imply that there are common neural substrates for auditory and visual motion perception in the brain. (C) 2010 Elsevier Ireland Ltd. All rights reserved.”
“Chronic constriction injury (CCI) is a peripheral mononeuropathic pain model that is caused by an injury to the peripheral nervous system and refractory to available conventional treatment. Mechanisms involved in neuropathic pain are still unclear. Previous studies reveal that proinflammatory cytokines contribute to CC-induced peripheral nerve pathology. Ghrelin, a novel identified gastric peptide, has been shown to have antinociceptive activity and also anti-inflammatory properties by decreasing proinflammatory cytokines. Therefore, the aim of the present study was to investigate the effects of ghrelin on the CCI and its relationship with proinflammatory cytokines in rats. Wistar rats underwent sciatic nerve ligation to induce CCI fallowed by repeated ghrelin administrations (50 and 100 mu g/kg i.p., once daily) for a period of 14 days.

Levels of radioactivity in tumors were maintained at steady levels (from 5.40 to 5.67 %ID/g) after 4 to 24 h. In pharmacokinetics, the AUC((0 ->infinity)) and MRT(0 ->infinity) and Cl of Re-188-liposome in blood via intravenous route were 998 h %ID/ml, 28.7 h and 0.1 ml/h, respectively. The total excreted fractions of feces and urine were 0.61 and 0.26, respectively. Absorbed doses for Re-188-liposome

in the liver and red marrow were 0.31 and 0.08 mSv/MBq, respectively. Tumor-absorbed closes for Re-188-liposome ranged from 48.4 to 1.73 mGy/MBq at 10 to 300 g tumor spheres. In therapeutic efficacy, the survival times of mice after Re-188-liposome [80% maximum tolerated dose (MTD);29.6 MBq], 5-FU (80% MTD; 144 mg/kg), liposome or normal saline treatments were evaluated. MDV3100 cost Consequently, radiotherapeutics of Re-188-liposome attained a longer lifespan (increase of 34.9%; P=.005) in mice than in the normal saline group. The increase in lifespan of the Re-188-liposome group was 2.5-fold greater than that of the 5-FU group. Therefore, intravenous administration

of Re-188-liposome could provide a benefit and it is a promising strategy for delivery of passive nanotargeted radiotherapeutics in oncology applications. (C) 2012 Elsevier Inc. All rights reserved.”
“Objective: Pulmonary arteriovenous malformations are an important but uncommon complication of cavopulmonary connection, particularly CB-839 clinical trial in patients with heterotaxy. Absence of hepatic venous effluent in pulmonary arterial blood seems to be a predisposing factor. Pulmonary arteriovenous malformations are most common after superior cavopulmonary anastomosis, but may develop, progress, or persist

in 1 lung after Fontan completion if hepatic venous blood streams completely or primarily to the contralateral lung.

Methods: Among 53 patients with heterotaxy and inferior vena cava interruption who underwent a modified Fontan procedure from 1985 to 2005, 8 had unilateral streaming Abiraterone in vitro of hepatic venous flow and clinically significant pulmonary arteriovenous malformations after hepatic venous inclusion and underwent reconfiguration of the cavopulmonary pathway. In all 8 patients, the hepatic vein-pulmonary artery pathway was contralateral to and offset from the pulmonary artery anastomosis of the single or dominant superior vena cava. Pathway reconfiguration included pulmonary arterial stenting (n = 2), revision of the superior vena cava-pulmonary artery connection (n = 1), construction of a branched hepatic vein-pulmonary artery conduit (n = 2), and surgical or transcatheter construction of a direct hepatic vein-azygous vein pathway (n = 5).

Results: Hepatic vein-azygous vein connection led to improvement in 4 of 5 patients; other approaches typically did not lead to improvement.