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PURPOSE OF REVIEW: This review discusses recent developments in myostatin research, focusing on the basic actions of myostatin on skeletal muscle, the identification of key regulatory elements of the myostatin pathway, and the promise of myostatin as a therapeutic target in muscle-related disorders. RECENT FINDINGS: In addition to a well-characterized role in muscle development, recent research advances have solidified the importance of myostatin in adult muscle, although questions remain. A number of possible regulatory proteins for myostatin have been identified, showing a complex picture of myostatin regulation that requires clarification. The identification of an antimyostatin monoclonal antibody (JA16) shows the promise of myostatin as a target for muscle-wasting disorders; the antibody has already been shown to increase muscle mass in healthy older mice and muscle function in postnatal mdx mice. SUMMARY: Since its discovery in 1997, myostatin has quickly been established as a key regulator of skeletal muscle mass. Recent developments strengthen the idea that myostatin will be an important therapeutic target for muscle-wasting-related disorders, and as more details of myostatin regulation and its mechanisms of action are clarified, myostatin will continue to dominate the skeletal muscle development and muscle-wasting literature. [ABSTRACT FROM AUTHOR]

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy, especially in pediatrics, that can involve the bone marrow, skin, lymph nodes, and central nervous system (CNS). Given its variable clinical presentation, coupled with an immunohistochemistry pattern (CD4, CD56, TCF4, TCL-1, and CD123 positivity) that differs from other myeloid neoplasms, the diagnosis of BPDCN can be missed. Limited data are available to guide the treatment of pediatric BPDCN. Herein, we report a case of a pediatric patient who had BPDCN with central nervous system, orbital, and skin involvement. This patient achieved complete remission after receiving modified hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone with venetoclax and intrathecal chemotherapy. He remains disease-free 200 days after receiving a stem cell transplant. This represents the first known published pediatric case using a modified hyper-CVAD plus venetoclax regimen for treating a pediatric BPDCN patient in the frontline setting., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Severe hypertriglyceridemia is often caused by variants in genes of triglyceride metabolism. These variants include rare, heterozygous pathogenic variants (PVs), or multiple common, small-effect single nucleotide polymorphisms that can be quantified using a polygenic risk score (PRS). The role of genetic testing to examine PVs and PRS in predicting risk for pancreatitis and severity of hypertriglyceridemia is unknown., Methods: We examined the relationship of PVs and PRSs associated with hypertriglyceridemia with the highest recorded plasma triglyceride level and risk for acute pancreatitis in 363 patients from 3 academic lipid clinics who underwent genetic testing (GBinsight's Dyslipidemia Comprehensive Panel). Categories of hypertriglyceridemia included: normal triglyceride (<200 mg/dL), moderate (200-499 mg/dL), severe (500-999 mg/dL), or very severe (≥1000 mg/dL)., Results: PVs and high PRSs were identified in 37 (10%) and 59 (16%) individuals, respectively. Patients with both had increased risk for very severe hypertriglyceridemia compared with those with neither genetic risk factor. Risk for acute pancreatitis was also increased in individuals with both genetic risk factors (odds ratio, 5.1 [ P =0.02] after controlling for age, race, sex, body mass index, and highest triglyceride level), but not in individuals with PV or high PRS alone., Conclusions: The presence of both PV and high PRS significantly increased risk for very severe hypertriglyceridemia and acute pancreatitis, whereas PV or PRS alone only modestly increased risk. Genetic testing may help identify patients with hypertriglyceridemia who have the greatest risk for developing pancreatitis and may derive the greatest benefit from novel triglyceride-lowering therapies.

Purpose: Fungal keratitis (FK) is a serious ophthalmic disease with a potentially devastating outcome that seems to be increasing in recent years. The use of contact lenses (CLs) was evaluated as a risk factor for FK to determine possible differences in course and outcome., Methods: Data from 173 cases reported in the German FK registry until August 2019 were evaluated regarding CL behavior, other ophthalmological and general risk factors, age, sex, identified pathogens, conservative and surgical therapy, visual acuity, and findings at admission and follow-up., Results: One hundred seventy-four eyes from 173 patients between 2000 and 2019 were included [64.4% women, median age 54 (39; 72) years]; 49.7% wore CL, of which 81.3% were soft CL, and 50.3% had no history of contact lens use (NCL). CL users were significantly more often women and otherwise healthy (CL: 80.2% vs. NCL: 48.9%; P < 0.0001). The spectrum of pathogens among CL users showed a significantly higher proportion of infections with filamentous pathogens, in particular Fusarium sp. (total filament: CL 69.8% vs. NCL 27.3%; P = 0.0001; Fusarium sp.: CL 50.0% vs. NCL 14.8%; P < 0.0001). Overall, 54.6% required keratoplasty and 8.6% enucleation., Conclusions: CLS are the most important risk factor for FK in Germany. With CLs, typically, the infection is caused by molds, and patients are comparably younger and otherwise healthy. Often, extensive surgery is needed. To evaluate changes in the pathogen and resistance spectrum and to further monitor possible CL-related risk factors, a consistent collection of data remains paramount., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Overall survival of adolescents with relapsed T-cell lymphoblastic lymphoma (T-LL) remains poor with limited options for salvage therapy. The BCL-2 inhibitor venetoclax combined with hypomethylating agents like decitabine, has shown favorable responses in elderly patients with acute myeloid leukemia., Observation: We present the case of a 19-year-old adolescent with stage III relapsed and refractory T-LL who did not respond to 3 lines of salvage therapy. The patient was treated with venetoclax and decitabine and achieved a dramatic response., Conclusion: This case highlights the potential clinical activity of venetoclax and decitabine in relapsed T-LL., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Purpose- In ischemic stroke, breakdown of the blood-brain barrier (BBB) aggravates brain damage. Pericyte detachment contributes to BBB disruption and neurovascular dysfunction, but little is known about its regulation in stroke. Here, we investigated how loss of RGS5 (regulator of G protein signaling 5) in pericytes affects BBB breakdown in stroke and its consequences. Method- We used RGS5 knockout and control mice and applied a permanent middle cerebral occlusion model. We analyzed pericyte numbers, phenotype, and vessel morphology using immunohistochemistry and confocal microscopy. We investigated BBB breakdown by measuring endothelial coverage, tight junctions, and AQP4 (aquaporin 4) in addition to BBB permeability (fluorescent-conjugated dextran extravasation). Tissue hypoxia was assessed with pimonidazole hydrochloride and neuronal death quantified with the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Results- We demonstrate that loss of RGS5 increases pericyte numbers and their endothelial coverage, which is associated with higher capillary density and length, and significantly less BBB damage after stroke. Loss of RGS5 in pericytes results in reduced vascular leakage and preserved tight junctions and AQP4, decreased cerebral hypoxia, and partial neuronal protection in the infarct area. Conclusions- Our findings show that loss of RGS5 affects pericyte-related BBB preservation in stroke and identifies RGS5 as an important target for neurovascular protection.

Objective: The main objective of this study was to determine if family history of malignant peripheral nerve sheath tumor (MPNST) increases risk of developing an MPNST in patients with neurofibromatosis-1 (NF-1)., Materials and Methods: Individuals with NF-1 registered with the Children's Tumor Foundation's Neurofibromatosis Registry were emailed an anonymous 15-minute survey with regard to personal and family history of NF-1, MPNST, ages of onset, and symptomatology. Participation was voluntary and information was self-reported., Results: The survey was sent to 4801 registrants, 878 responded. Presence of a family history of MPNST was found to be a risk factor for the development of MPNST; 19.4% of respondents confirming a family history of MPNST developed MPNST compared with 7.5% of respondents with no family history (odds ratio, 2.975; 95% confidence interval, 1.232-7.187; P=0.021). NF-1 patients with a positive family history developed MPNST at a younger age than those with no family history (8.3% vs. 0.5% P=0.003 and 13.9% vs. 2.4% P=0.003, for onset before 10 and 20, respectively). In the MPNST population with a known family history, onset prior to age 10 was significantly more prevalent (42.9% vs. 7% P=0.029)., Conclusions: These results suggest a positive family history of MPNST represents a risk factor for the development and early onset of MPNST in individuals with NF-1.

Objective: To describe our experience using the anterior internal pelvic fixator (INFIX) for treating pelvic ring injuries., Design: Case Series., Setting: Level 1 Trauma Center., Patients: Eighty-three patients with pelvic ring injuries were treated with INFIX. Follow-up average was 35 months (range 12-80.33)., Intervention: Surgical treatment of pelvic ring injuries included reduction, appropriate posterior fixation, and INFIX placement., Outcome Measurements: Reduction using the pelvic deformity index and pubic symphysis widening, Majeed functional scores, complications; infection, implant failure, heterotopic ossification (HO), nerve injury, and pain., Results: All patients healed in an appropriate time frame (full weight bearing 12 weeks postoperation). The average pelvic deformity index reduction (injury = 0.0420 ± 0.0412, latest FU = 0.0254 ± 0.0243) was 39.58%. The average reduction of pubic symphysis injuries was 56.92%. The average Majeed score of patients at latest follow-up was 78.77 (range 47-100). Complications were 3 infections, 1 case of implant failure, 2 cases implantation too deep, 7 cases of lateral femoral cutaneous nerve irritation, and 3 cases of pain associated with the device. HO was seen in >50% of the patients, correlated with increased age (P < 0.007), injury severity score (P < 0.05) but only 1 case was symptomatic., Conclusions: The pelvic injuries had good functional and radiological outcomes with INFIX and the appropriate posterior fixation. The downside is removal requiring a second anesthetic, there is a learning curve, HO often occurs, the lateral femoral cutaneous nerve may get irritated which often resolves once the implants are removed. Surgery-specific implants need to be developed., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Thigh muscle weakness is a risk factor for incident radiographic and symptomatic knee osteoarthritis (KOA). The role of thigh muscle weakness in radiographic and/or symptomatic KOA progression remains elusive. Five hundred twenty-seven knees of 527 Osteoarthritis Initiative participants with baseline Kellgren-Lawrence grades 1 to 3 were included in this nested case-control study evaluating whether baseline muscle strength predicted symptomatic and/or radiographic KOA progression. Case knees (n = 173) displayed both medial tibiofemoral joint space loss (≥0.7 mm) and a persistent increase in Western Ontario McMasters Osteoarthritis Index pain (≥9 on a 0- to 100-point scale) over 24 to 48 months from baseline. Control knees (n = 354) included 174 with neither radiographic nor symptomatic progression, 91 with radiographic progression only, and 89 with symptomatic progression only. Isometric knee extensor and flexor strength were recorded at baseline. Using logistic regression models, muscle strength was not associated with case status. However, knee extensor (odds ratio, 1.7; 95% confidence interval, 1.1-3.3; P = 0.035) and flexor weakness (odds ratio, 2.0; 95% confidence interval, 1.1, 3.3; P = 0.016) predicted isolated symptomatic progression in males, but not in females. The results indicate that thigh muscle strength may affect symptomatic and structural progression differently in males with KOA and identify an important window for potentially lowering risk of symptomatic osteoarthritis progression in men., Competing Interests: Potential conflict of interest: Adam Culvenor and Melanie Roth have no conflict of interest to report.

Study Design: Retrospective review of prospectively collected data., Objective: To assess the value of the deformity angular ratio (DAR, maximum Cobb measurement divided by number of vertebrae involved) in evaluating the severity of spinal deformity, and predicting the risk of neurologic deficit in posterior vertebral column resection (PVCR)., Summary of Background Data: Although the literature has demonstrated that PVCR in spinal deformity patients has achieved excellent outcomes, it is still high risk neurologically. This study, to our knowledge, is the largest series of PVCR patients from a single center, evaluating deformity severity, and potential neurologic deficit risk., Methods: A total of 202 consecutive pediatric and adult patients undergoing PVCRs from November 2002 to September 2014 were reviewed. The DAR (coronal DAR, sagittal DAR, and total DAR) was used to evaluate the complexity of the deformity., Results: The incidence of spinal cord monitoring (SCM) events was 20.5%. Eight patients (4.0%) had new neurologic deficits. Patients with a high total DAR (≥25) were significantly younger (20.3 vs. 29.0 yr, P = 0.001), had more severe coronal and sagittal deformities, were more myelopathic (33.3% vs. 11.7%, P = 0.000), needed larger vertebral resections (1.8 vs. 1.3, P = 0.000), and had a significantly higher rate of SCM events than seen in the low total DAR (<25) patients (41.1% vs. 10.8%; P = 0.000). Patients with a high sagittal DAR (≥15) also had a significantly higher rate of SCM events (34.0% vs. 15.1%, P = 0.005) and a greater chance of neurologic deficits postoperatively (12.5% vs. 0, P = 0.000)., Conclusion: For patients undergoing a PVCR, the DAR can be used to quantify the angularity of the spinal deformity, which is strongly correlated to the risk of neurologic deficits. Patients with a total DAR greater than or equal to 25 or sagittal DAR greater than or equal to 15 are at much higher risk for intraoperative SCM events and new neurologic deficits., Level of Evidence: 3.

Objectives: Several mutations of the glucocorticoid receptor (GR) gene cause malfunction of the protein, resulting in steroid resistance. In diseases other than asthma, the GR variants I559N, D641V, and V729I have been linked to steroid resistance. The aim of this study was to evaluate the link of these GR variants in steroid-resistant (SR) asthma in the Chinese Han population., Methods: GR polymorphisms were determined in 64 SR asthma patients, 217 steroid-sensitive (SS) asthma patients and 221 healthy control (CTR) individuals. The analysis of the GR variants was performed using PCR-sequence specific primers according to the European Molecular Biology Laboratory database (NC&#95;000005.8). In addition, ligand binding and serum cortisol levels were determined., Results: Compared with SS asthma patients and CTRs, a significant lower frequency of the GR D641V variant AA genotype (P=0.003, 0.014, respectively) and the A allele (P=0.001, 0.009, respectively) was found in SR asthma patients. Furthermore, the equilibrium dissociation constant (Kd) of GR ligand binding in SR asthma patients with the GR D641V variant AA genotype was significantly lower compared with the AT or the TT genotype carriers (P=0.006, 0.016, respectively). There was no significant difference between the I559N and V729I GR variants on comparing SR asthma patients with SS asthma patients or CTRs., Conclusion: This study suggests that the D641V variant of the GR is probably associated with SR asthma in the Chinese Han population.

Epstein-Barr virus (EBV) viremia (EV) in pediatric solid organ transplant (SOT) recipients is a significant risk factor for posttransplant lymphoproliferative disease (PTLD) but not all patients with EV develop PTLD. We identify predictive factors for PTLD in patients with EV. We conducted a retrospective chart review of all pediatric SOT recipients (0 to 21 y) at a single institution between 2001 and 2009. A total of 350 pediatric patients received a SOT and 90 (25.7%) developed EV. Of EV patients, 28 (31%) developed PTLD. The median age at transplant was 11.5 months in the PTLD group and 21.5 months in the EV-only group (P=0.003). Twenty-three (37%) EV-only patients had immunosuppression increased before EV, compared with 28 (100%) of PTLD patients (P<0.001). The median peak EBV level was 3212 EBV copies/10 lymphocytes for EV-only and 8392.5 EBV copies/10 lymphocytes for PTLD (P=0.005). All patients who developed PTLD had ≥1 clinical symptoms. Younger age at transplant, increased immunosuppression before EV, higher peak EBV level, and presence of clinical symptoms have predictive value in the development of PTLD in SOT patients with EV.

Background: Pulmonary hypertension (PH) is a life-threatening disease characterized by vascular remodeling and increased pulmonary vascular resistance. Chronic alveolar hypoxia in animals is often used to decipher pathways being regulated in PH. Here, we aimed to investigate whether chronic hypoxia-induced PH in mice can be reversed by reoxygenation and whether possible regression can be used to identify pathways activated during the reversal and development of PH by genome-wide screening., Methods and Results: Mice exposed to chronic hypoxia (21 days, 10% O2) were reoxygenated for up to 42 days. Full reversal of PH during reoxygenation was evident by normalized right ventricular pressure, right heart hypertrophy, and muscularization of small pulmonary vessels. Microarray analysis from these mice revealed s-adenosylmethionine decarboxylase 1 (AMD-1) as one of the most downregulated genes. In situ hybridization localized AMD-1 in pulmonary vessels. AMD-1 silencing decreased the proliferation of pulmonary arterial smooth muscle cells and diminished phospholipase Cγ1 phosphorylation. Compared with the respective controls, AMD-1 depletion by heterozygous in vivo knockout or pharmacological inhibition attenuated PH during chronic hypoxia. A detailed molecular approach including promoter analysis showed that AMD-1 could be regulated by early growth response 1, transcription factor, as a consequence of epidermal growth factor stimulation. Key findings from the animal model were confirmed in human idiopathic pulmonary arterial hypertension., Conclusions: Our study indicates that genome-wide screening in mice from a PH model in which full reversal of PH occurs can be useful to identify potential key candidates for the reversal and development of PH. Targeting AMD-1 may represent a promising strategy for PH therapy.

Purpose of Review: To summarize the new knowledge on tissue remodeling in the context of lung diseases. Tissue remodeling includes changes in cells: differentiation; response to growths factors, hormones, or environmental factors; and composition of the extracellular matrix. So, can one trigger cause them all or are they independently regulated?, Recent Findings: New evidence from clinical and experimental studies strengthened the view that a susceptibility to remodeling can be initiated in early life and be re-activated by environmental triggers later in life. Many studies further support the idea that TGF-β plays the central role in the pathogenesis of remodeling and fibrosis. However, the activation pathways and the end-effect of TGF-β activation seems to be distinctive of disease and effecter cell specific patterns. The existing animal models do not properly reflect the human disease and thus have to be further improved., Summary: The central role of TGF-β on pathological mechanisms leading to remodeling and fibrosis has been further confirmed. However, the questions of why TGF-β is activated as well as its disease and cell type specific mode of action remain to be answered. Based on clinical data redefining the term 'tissue remodeling' in a disease and cell type specific way should be considered.

Methadone is effective in the treatment of cancer-related pain in adults. Pediatric oncologists may be reluctant to use methadone, given the paucity of existing research and a lack of familiarity with its use. This study's purpose was to assess pediatric oncologists' experience, comfort and practice of methadone prescription, and determine interest in and appropriate venues for education on methadone. A 22-item survey was sent by electronic mail to 1912 practicing pediatric oncologists. Six hundred thirty-one pediatric oncologists (33%) responded to the survey. Seventy-two percent of respondents reported they prescribe methadone to <10% of their patients receiving opioids. Physicians practicing ≥10 years (84% vs. 76%, P=0.01), at centers that see ≥100 new patients per year (86% vs. 76%, P=0.003), or who have received prior education on methadone (89% vs. 54%, P<0.001) were more likely to have prescribed methadone. The primary reasons respondents did not utilize methadone included a lack of knowledge of methadone's pharmacodynamics (39%), effectiveness (39%), and/or dosing equivalence (34%). Perceived competence with dose equivalence, belief that methadone is effective, and working in a division where >20 patients per year died were all independently associated with having prescribed methadone to >10% of patients on opioids. Eighty-five percent of respondents would like additional education on methadone. Many pediatric oncologists lack experience and education in the use of methadone. Formal education initiatives should be implemented to enhance pediatric oncologists' comfort and expertise in methadone use.

Background: Pediatric oncology patients commonly use complementary and alternative medicine (CAM), yet approximately only 50% of these patients discuss CAM with their oncologist., Objective: The aim of this study is to assess barriers to CAM communication in pediatric oncology., Design/methods: A 33-question survey was sent via electronic mail to 358 pediatric oncologists in the United States., Results: Ninety pediatric oncologists completed the survey. Ninety-nine percent of pediatric oncologists think it is important to know what CAM therapies their patients use. However, less than half of pediatric oncologists routinely ask their patients about CAM. This is primarily because of a lack of time and knowledge. Many physicians think some forms of CAM may improve quality of life, such as massage (74%) and yoga (57%). Over half of physicians thought that dietary supplements, herbal medicine, special diets, vitamins, and chiropractic might be harmful to patients., Conclusions: Pediatric oncologists believe it is important to know which CAM therapies their patients use; however, they are not asking about them owing to lack of time and knowledge. To improve communication about CAM, increased physician education is needed. In addition, physicians should identify patients using potentially harmful CAM therapies. Furthermore, CAM research in pediatric oncology should focus on those modalities physicians believe may improve patient quality of life.

Nonphagocytic NADPH oxidases have recently been suggested to play a major role in the regulation of physiological and pathophysiological processes, in particular, hypertrophy, remodeling, and angiogenesis in the systemic circulation. Moreover, NADPH oxidases have been suggested to serve as oxygen sensors in the lung. Chronic hypoxia induces vascular remodeling with medial hypertrophy leading to the development of pulmonary hypertension. We screened lung tissue for the expression of NADPH oxidase subunits. NOX1, NOXA1, NOXO1, p22phox, p47phox, p40phox, p67phox, NOX2, and NOX4 were present in mouse lung tissue. Comparing mice maintained for 21 days under hypoxic (10% O(2)) or normoxic (21% O(2)) conditions, an upregulation exclusively of NOX4 mRNA was observed under hypoxia in homogenized lung tissue, concomitant with increased levels in microdissected pulmonary arterial vessels. In situ hybridization and immunohistological staining for NOX4 in mouse lungs revealed a localization of NOX4 mRNA and protein predominantly in the media of small pulmonary arteries, with increased labeling intensities after chronic exposure to hypoxia. In isolated pulmonary arterial smooth muscle cells (PASMCs), NOX4 was localized primarily to the perinuclear space and its expression levels were increased after exposure to hypoxia. Treatment of PASMCs with siRNA directed against NOX4 decreased NOX4 mRNA levels and reduced PASMC proliferation as well as generation of reactive oxygen species. In lungs from patients with idiopathic pulmonary arterial hypertension (IPAH), expression levels of NOX4, which was localized in the vessel media, were 2.5-fold upregulated. These results support an important role for NOX4 in the vascular remodeling associated with development of pulmonary hypertension.

Background and Purpose: This study investigates dynamic cerebral autoregulation assessed from spontaneous blood pressure (ABP) and cerebral blood flow velocity (CBFV) fluctuations and its time course in acute ischemic stroke., Methods: Forty patients admitted with acute ischemic stroke in the territory of the middle cerebral artery (MCA) were enrolled. Admission National Institutes of Health Stroke score was 6+/-4. Study 1 was performed within 22 (+/-11) hours and study 2 was performed within 134 (+/-25) hours of ictus. The final analysis comprised 33 and 29 patients for study 1 and study 2, respectively. Twenty-five age- and sex-matched controls were studied. ABP (Finapres method) and CBFV in both MCAs (transcranial Doppler) were recorded over 10 minutes. Correlations between diastolic and mean ABP and CBFV fluctuations were averaged, yielding the correlation coefficient indices (Dx, Mx). Transfer function analysis was applied to obtain phase shift and gain between ABP and CBFV oscillations., Results: No disturbance of autoregulation was indicated by all parameters at study 1. Separate analyses for clinical severity, stroke side, and size did not reveal significant differences for the various autoregulatory indices at study 1 and 2. At study 2, MCA flow velocity was significantly increased on both sides, the autoregulation index Mx was slightly but significantly (P<0.05) worse on both sides in comparison to study 1, and phase showed a trend toward poorer values on affected sides. No significant differences to controls occurred. Clinical outcome in patients completing both studies was good in all but one patient., Conclusions: Dynamic cerebral autoregulation assessed from spontaneous blood pressure fluctuations does not seem to be relevantly disturbed in early minor MCA stroke. At the subacute stage, slight autoregulatory disturbance may be present.

The network of cortical and subcortical regions that contribute to articulation was examined in bilinguals using functional magnetic resonance imaging. Participants were all fluent in French and English: half were bilingual from birth and half were 'late bilinguals' who had learned French after the age of 12. Overt articulation resulted in the bilateral activation of the motor cortex, basal ganglia and cerebellum, and also the supplementary motor area, independent of the language spoken. Furthermore, the threshold and extent of the network involved in articulation was identical for the two bilingual groups with the exception of greater variation in the left putamen for the late bilinguals. These data challenge claims that age of acquisition results in fundamental differences in the neural substrates that subserve language in bilinguals.

Background: Obliterative bronchiolitis (OB) is the major cause of morbidity and mortality after lung transplantation. The potential role of immunosuppressive drugs in the development of OB is uncertain, but there are limited data indicating that cyclosporine A (CsA) may have a direct fibrogenic effect on various human cell types. Epithelium-fibroblast interactions have been suggested to play a crucial role in the course of fibroproliferation, which is a major feature of OB., Methods: We studied the effect of CsA and FK506 on primary human lung fibroblast proliferation in a human epithelial-fibroblast interactive model., Results: Clinically relevant concentrations of CsA (0.1-1 microg/mL) and FK506 (0.001-0.01 microg/mL) did not affect fibroblast proliferation in monocultures. Conditioned medium (CM) from untreated epithelial cells (Calu-3) stimulated fibroblast proliferation. CM from FK506-treated (0.001-0.1 microg/mL) epithelial cells had no significant additive effect on fibroblast proliferation compared with CM of untreated epithelial cells. In contrast, CM obtained from epithelial cells treated with 0.1 microg/mL CsA significantly enhanced fibroblast proliferation compared with CM of untreated epithelial cells. This proliferative effect of 0.1 microg/mL CsA was mediated by epithelial-derived factors greater than 100 kDa., Conclusions: These data demonstrate that a clinically relevant concentration of CsA stimulates fibroblast proliferation through mediators produced by airway epithelial cells, raising the possibility that CsA may contribute to the development of OB after lung transplantation.

Background and Purpose: Analysis of dynamic cerebral autoregulation (DCA) from spontaneous blood pressure fluctuations might contribute to prognosis of severe internal carotid artery stenosis, but its response to carotid recanalization has not been investigated so far. This study investigates the effect of carotid endarterectomy or stenting on various DCA parameters., Methods: In 58 patients with severe unilateral stenosis undergoing carotid endarterectomy (n=41) or stenting (n=17), cerebral blood flow velocity (CBFV, transcranial Doppler) and arterial blood pressure (ABP, Finapres method) were recorded over 10 minutes before and on average 3 days after carotid recanalization. Nineteen patients were additionally examined after 7 months. Correlations between diastolic and mean ABP and CBFV fluctuations were averaged to form the correlation coefficient indices (diastolic [Dx] and mean values [Mx]). Transfer function parameters (low-frequency phase and high-frequency gain between ABP and CBFV oscillations) were calculated over the same 10 minutes. CO2 reactivity was assessed via inhalation of 7% CO2., Results: Before recanalization, all DCA parameters were clearly impaired ipsilaterally compared with contralateral sides. Phase, Dx, and Mx indicated early normalization of DCA after both endarterectomy and stenting. By multiple regression, the degree of DCA improvement was highly significantly related to the extent of impairment before recanalization. No significant change in DCA was found at follow-up. Ipsilateral gain and CO2 reactivity increased significantly less after endarterectomy than after stenting (P<0.05)., Conclusions: Dynamic cerebral dysautoregulation in patients with severe carotid obstruction is readily and completely remedied by carotid recanalization.

Background: Dysregulated fibroblast proliferation is thought to play an important role in the progression of bronchiolitis obliterans (BO) after lung transplantation. Augmented immunosuppression is often used to treat BO. We investigated the effect of methylprednisolone (mPRED), cyclosporine A (CsA), tacrolimus (FK506), azathioprine (AZA), mycophenolate mofetil (MMF), and everolimus (rapamycin derivative [RAD]) on the proliferative capacity of fibroblasts cultured from transbronchial biopsies of lung transplant recipients., Methods: Primary cultures of human lung fibroblasts were obtained from 14 transbronchial biopsies of lung transplant recipients. Subconfluent cells were serum starved for 24 hr followed by growth stimulation in the presence or absence of the respective drug in six concentrations ranging as follows: 0.01 to 100 mg/L for mPRED; 0.01 to 50 mg/L for CsA and AZA; 0.001 to 5 mg/L for FK506 and MMF; and 0.00001 to 1 mg/L for RAD. Proliferation was quantified by [3H]thymidine incorporation and direct cell count. A toxic drug effect was excluded by trypan blue., Results: Drug concentrations (mg/L) causing a 50% inhibition of fibroblast proliferation were mPRED 4; CsA 20; FK506 0.3; AZA 7; MMF 0.3; and RAD 0.0006. Drug concentrations (mg/L) causing inhibition of fetal bovine serum-induced proliferation were mPRED 60; CsA 45; FK506 3; AZA 35; MMF 1; and RAD 0.003., Conclusions: RAD and MMF were the most potent antifibroproliferative drugs and were effective at concentrations achieved clinically, supporting their use for the treatment of patients with early BO. Our method holds promise as an in vitro model to assess the likely in vivo responses of human lung fibroblasts to specific immunosuppressive drugs.

Background and Purpose: Estimation of dynamic cerebral autoregulation from spontaneous fluctuations of arterial blood pressure (ABP) and cerebral blood flow velocity (CBFV) is an attractive monitoring option for cerebral hemodynamic impairment. We evaluated the correlation coefficient index method in patients with severe obstructive carotid disease and compared it with transfer function analysis (frequency domain approach to cerebral autoregulation) and CO2 vasomotor reactivity., Methods: In 139 patients with severe unilateral carotid stenosis (>or=70%) or occlusion, CBFV (transcranial Doppler) and ABP (Finapres method) were recorded over 10 minutes. Correlations between systolic pressure, diastolic pressure, and mean ABP and CBFV oscillations over 1-minute epochs were averaged over 10 minutes to form the correlation coefficient indexes (Sx, Dx, Mx, respectively). Transfer function parameters (phase shift and gain between ABP and CBFV oscillations) were determined from the entire 10-minute period. CO2 reactivity was assessed by inhalation of 7% CO2., Results: The correlation indexes Dx and Mx were significantly higher ipsilateral to stenosis and increased with degree of stenosis, indicating increasing dependence of CBFV on ABP and thus impairment of cerebral autoregulation. Dx and Mx correlated moderately but highly significantly with transfer function parameters and CO2 reactivity and showed a good level of agreement in detecting pathological values. Patients with a small variance of the 1-minute source correlations of Dx and Mx showed clearly better correlation values. Transfer function parameters and CO2 reactivity but not Dx and Mx were significantly poorer in patients with symptomatic stenosis or occlusion., Conclusions: The potential of the correlation coefficient indexes Dx and Mx in detecting hemodynamic impairment in patients with carotid stenosis is comparable to that of transfer function analysis and CO2 reactivity testing. In future, a combination of various hemodynamic tests might help to identify patients at risk for ischemic events.

The brain areas involved in music reading were investigated using fMRI. In order to evaluate the specificity of these areas we compared reading music notation to reading verbal and number notations in a task that required professional pianists to play the notes (in musical and verbal notations) and the numbers displayed on a 5-key keyboard. Overall, the three tasks revealed a similar pattern of activated brain areas. However, direct contrasts between the music notation and the verbal or the numerical notation tasks also revealed specific major foci of activation in the right occipito-temporal junction, superior parietal lobule and the intraparietal sulcus. We interpret the right occipito-temporal difference as due to differences at the encoding level between notes, words and numbers. This area might be analogous to one described for words, called the visual word form area. The parietal activations are discussed in terms of visuo-motor transcoding pathways that differ for the three types of notations used. Finally, we present a model of music reading that can possibly explain our findings.

The insulin resistance syndrome, consisting of resistance to insulin and several metabolic abnormalities, is associated with an increased risk of symptomatic coronary artery disease. Asymptomatic persons with increased coronary calcification have increased coronary plaque and an increased likelihood of future cardiovascular events. Electron-beam computed tomography-derived coronary artery calcium scores, metabolic and anthropometric parameters, and fasting and stimulated concentrations of glucose and insulin were measured in 1160 asymptomatic men and women. Coronary artery calcium scores were positively correlated with glucose, insulin, and homeostasis model assessment (HOMA) insulin resistance. Calcium scores were positively correlated with intra-abdominal adiposity, age, total cholesterol/high density lipoprotein (HDL) ratio, low density lipoprotein, triglycerides, blood pressure, and HOMA beta cell function and inversely correlated with HDL and peripheral fat. These correlations, except for 2-hour glucose, remained significant for all subjects with fasting serum glucose <126 mg/dL or all subjects with fasting serum glucose 110 mg/dL. In a multivariate analysis, age, sex, family history of premature coronary artery disease, intra-abdominal adiposity, low density lipoprotein, and smoking independently predicted calcium scores. Blood pressure, HDL, triglycerides, glucose, insulin, and HOMA insulin resistance or beta cell function were not independently correlated with coronary artery calcium scores. Asymptomatic individuals with insulin resistance have elevated coronary calcium scores. The association between insulin resistance and coronary calcification persists with impaired glucose tolerance and normal fasting serum glucose. Central/visceral adiposity may be a determinant of insulin resistance and atherosclerosis even in asymptomatic nondiabetic persons.

Disorders in the fibrinolytic and renin-angiotensin-aldosterone systems and excessive extracellular matrix (ECM) deposition are determinant factors in several pathologic manifestations of vascular and cardiac tissue. We used primary human vascular smooth muscle cells (VSMC) and studied the effects of losartan on angiotensin II (Ang II)-mediated (a) DNA synthesis, (b) secretion of tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1), (c) secretion of matrix metalloprotease-2 (MMP-2) activity and tissue inhibitors of MMPs (TIMPs), and (d) synthesis of glycosaminoglycans. VSMC cultures, established from human pulmonary arteries, were treated with Ang II (0.1 nM -1 microM ) and/or losartan (0.1-10 microM ), for 24 or 48 h. DNA synthesis was assessed by incorporation of 3 H-thymidine into VSMC, secreted tPA, PAI-1, and TIMPs by enzyme-linked immunosorbent assay, MMP-2 activity by gelatin zymography, and glycosaminoglycan synthesis by 3 H-glucosamine incorporation. Ang II (1 microM ) enhanced DNA synthesis and secretion of PAI-1 and glycosaminoglycans and decreased secretion of MMP-2 activity and tPA, whereas it had no effect on secretion of TIMPs and glycosaminoglycans associated with cell layers. The Ang II-mediated effects were reversed by losartan, in a concentration-dependent manner. Losartan alone increased secretion of tPA, MMP-2 activity, and TIMPs and decreased secretion of PAI-1. These results indicate that AT 1 receptors are implicated in Ang II-mediated disorders of fibrinolysis and excessive ECM deposition by VSMC.

Background: Survival after lung transplantation is limited by the development of bronchiolitis obliterans (BO) that is a fibroproliferative process and regarded as the histological marker of chronic rejection. To study further the pathogenesis of BO we attempted to establish primary fibroblast cell cultures from transbronchial lung biopsies (TBBs)of lung transplant recipients., Methods: One to two TBB samples from each patient were collected in sterile phosphate-buffered saline. Biopsies were cut into small pieces and placed onto 25-cm2 culture flasks for cell culture and kept under standard cell culture conditions (21% O2, 5% CO2, 37 degrees C). Culture medium consisted of RPMI 1640, 10% fetal calf serum, L-glutamine, HEPES, and antibiotics. After reaching confluence, fibroblasts were passaged into 75-cm2 flasks., Results: The success rate of establishing fibroblast cultures from transbronchial lung biopsies was 54% (27/50). Cell growth was independent of patient age, transplant type, underlying lung disease, indication for transbronchial lung biopsies, grade, or type of re jection and infection., Conclusions: We have established a novel method of culturing fibroblasts from lung transplant recipients. We consider this method as an unique human in vitro model to study the pathogenetic mechanisms leading to BO.

Inflammatory or malignant diseases are associated with elevated levels of cytokines and abnormal low density lipoprotein (LDL) cholesterol metabolism. In the acute-phase response to myocardial injury or other trauma or surgery, total and LDL cholesterol levels are markedly decreased. We investigated the effects of the proinflammatory cytokine interleukin (IL)-6 on LDL receptor (LDL-R) function and gene expression in HepG2 cells. IL-6 dose-dependently increased the binding, internalization, and degradation of (125)I-LDL. IL-6-stimulated HepG2 cells revealed increased steady-state levels of LDL-R mRNA. In HepG2 cells transiently transfected with reporter gene constructs harboring the sequence of the LDL-R promoter extending from nucleotide -1563 (or from nucleotide -234) through -58 relative to the translation start site, IL-6 dose-dependently increased promoter activity. In the presence of LDL, a similar relative stimulatory effect of IL-6 was observed. Studies using a reporter plasmid with a functionally disrupted sterol-responsive element (SRE)-1 revealed a reduced stimulatory response to IL-6. In gel-shift assays, nuclear extracts of IL-6-treated HepG2 cells showed an induced binding of SRE binding protein (SREBP)-1a and SRE binding protein(SREBP)-2 to the SRE-1 that was independent of the cellular sterol content and an induced binding of Sp1 and Sp3 to repeat 3 of the LDL-R promoter. Our data indicate that IL-6 induces stimulation of the LDL-R gene, resulting in enhanced gene transcription and LDL-R activity. This effect is sterol independent and involves, on the molecular level, activation of nuclear factors binding to SRE-1 and the Sp1 binding site in repeat 2 and repeat 3 of the LDL-R promoter, respectively.

Background: Calcium channel blockers (CCB) of all subclasses: the dihydropyridines, benzothiazepines, and phenylalkylamines, at nanomolar concentrations, have been shown to up-regulate interleukin-6 (IL-6) mRNA. We investigated the underlying molecular mechanism responsible for IL-6 induction in response to the CCB amlodipine, diltiazem, and verapamil in primary human vascular smooth muscle cells (VSMC)., Methods and Results: All 3 CCB directly activated transcription of the human IL-6 gene in primary human VSMC in a time- and dose-dependent manner, as demonstrated by luciferase reporter gene assays using a 651-bp fragment of the human IL-6 gene promoter. Deletion analysis of the IL-6 promoter revealed that CCB inducible promoter activity was localized to a 160-bp fragment directly upstream of the transcriptional start site of the IL-6 gene. Known transcription factor consensus sequences within this fragment include a NF-IL6 and a NF-kappaB site. Site-directed mutagenesis suggested that both transcription factors had positive regulatory activity and cooperatively transmitted induction of the IL-6 gene by CCB. The data are confirmed by electrophoretic mobility shift analyses using nuclear extracts from CCB-stimulated and control primary VSMC. CCB of all subclasses increased DNA binding of NF-IL6 and NF-kappaB as early as 30 minutes after stimulation with the drugs. This effect was independent of intracellular calcium concentrations because calcium-free medium did not increase NF-IL6 or NF-kappaB activity., Conclusions: The results demonstrate that CCB of all 3 subclasses are capable of activating NF-IL6 and NF-kappaB. CCB may thus directly regulate cellular functions by affecting the activity of transcription factors independent of changes of intracellular calcium concentrations, an observation that is of interest considering the biological effects induced by CCB.

Purpose: Electron beam CT (EBCT)-derived coronary artery calcium scores correlate with the extent of atherosclerosis, but there is a substantial variance about the general relationship between coronary calcification and coronary atherosclerosis. The relationship between calcification and atherosclerosis may also differ in various arteries. This study was designed to evaluate whether the relation between carotid artery intima-media thickness (IMT) and carotid artery calcium could be used as a correction factor to improve the correlation between coronary calcification and coronary atherosclerosis., Method: We measured atherosclerosis in the coronary and carotid arteries by angiography and ultrasonography, respectively, and quantified coronary and carotid calcium deposition with EBCT in 50 subjects. The correlation between the findings in the carotid and coronary arteries was investigated., Results: Coronary artery calcium score correlated with coronary angiography and with carotid calcium score. Coronary stenosis correlated with carotid IMT. There was no meaningful correlation of carotid IMT and carotid calcium., Conclusion: There is an intraindividual variation in the relationship of plaque mass to calcification among different vessels. The relation between carotid artery calcification and carotid IMT is not predictive of the relation between coronary artery calcification and coronary obstruction.

Objective: To define an optimal dose of hirudin that would improve early coronary artery Thrombolysis in Myocardial Infarction grade 3 (TIMI 3) patency and prevent reocclusions in patients with acute myocardial infarction treated with front-loaded recombinant tissue-type plasminogen activator (rt-PA)., Methods: Recombinant hirudin (HBW 023) was tested in a sequential dose-escalating study as adjunct to front-loaded rt-PA in 143 patients with acute myocardial infarction. The sequential model was assigned two 'decision boundaries': it triggered an increase in dosage if the 60-min TIMI 3 flow rate in a dosage group was statistically not consistent with a target patency rate of 75%, or if the deterioration in coronary blood flow (of at least one TIMI grade, from TIMI 2 or 3, from one angiography to the next) exceeded 5%., Results: The decision boundary for TIMI 3 flow grade at 60 min was crossed when 18 patients were treated with 0.1/0.06 mg/kg (bolus/infusion per hour over 48 h) r-hirudin (dosage group I), 42 patients treated with 0.2/0.1 mg/kg (dosage group II), and 83 patients with 0.4/0.15 mg/kg (dosage group III). TIMI 3 flow at 60 min was 50%, 58%, and 63% in dosage groups I-III, respectively (P = 0.15). Early, complete, and sustained patency (TIMI 3 flow at 60 min, 90 min and 48 h) were 44%, 55% and 64% (P = 0.07). Reocclusion between 90-min and 48-h angiograms or reinfarction occurred in 0 to 15, two of 36, and one of 72 patients, respectively (P = 0.5). Four patients (2.8%) died in hospital and 14 patients suffered a major bleeding event, but no intracranial bleeding was encountered., Conclusions: With increasing doses of hirudin, there was a trend towards greater early and complete patency, but no clear dose--response relationship was observed. A borderline significant effect was observed with respect to early, complete, and sustained patencies. In all groups, reocclusions or reinfarctions were rare. Neither clinical nor laboratory data predicted the imbalance in haemorrhagic events observed in a subsequent, prematurely terminated, phase III trial with hirudin and rt-PA.

Background: The amount of coronary artery calcification, measured using electron beam computed tomography, is correlated with the volume of coronary artery atherosclerotic plaque, the severity of stenosis by angiography, and with the likelihood of future cardiovascular events. The deposition of calcium in atherosclerotic plaques may also be influenced by determinants of calcium metabolism, thus contributing to the variance of the relation between coronary artery calcification and extent of atherosclerosis. Our objective was to determine whether this variance could be explained by differences in the parameters of calcium metabolism., Design and Methods: We measured serum concentrations of calcium, 1,25(OH)2 vitamin D and parathyroid hormone (PTH) in 50 subjects undergoing angiography for clinical indications, and evaluated the correlations between these concentrations and calcium deposition in the coronary arteries, and the ratio of calcium deposition to extent of atherosclerosis using coronary angiography., Results and Conclusions: Serum concentrations of calcium 1,25(OH)2 vitamin D and PTH were not correlated with coronary calcification or the ratio of coronary calcification to the extent of coronary stenosis. We conclude that, in subjects undergoing coronary angiography, the variance of the relationship between coronary atherosclerosis and coronary calcium is not a result of differences in serum concentrations of calcium, 1,25(OH)2 vitamin D or PTH.

Background: The VERAS study (VErringerung der Restenoserate nach Angioplastie durch ein Somatostatin-analogon [Prevention of Restenosis Following Angioplasty With a Somatostatin Analogue]) was a placebo-controlled trial to evaluate the effects of octreotide for the prevention of restenosis after coronary angioplasty. Octreotide is a somatostatin analogue with antiproliferative properties on smooth muscle cell growth in vitro that limits myointimal thickening of arteries in balloon injury models., Methods and Results: Patients received either octreotide or placebo, starting 1 hour before angioplasty and continued for 3 weeks. The minimal luminal diameters before and after angioplasty and at 6-month follow-up were analyzed with a digital quantitative algorithm. Of the initial 274 patients recruited, 217 (108 in the octreotide group and 109 in the placebo group) could be analyzed after a complete 6-month evaluation: the minimal luminal diameters were 1.67+/-0.57 mm in the octreotide-treated group and 1.66+/-0.64 mm in the placebo group (two-paired P=.70), and the relative losses were 0.16+/-0.22 and 0.13+/-0.21 (two-paired P=.27). The restenosis rates were also identical in both treatment groups: final diameter stenosis > or =50% (34.3% versus 33.9%, two-paired P=1.0), loss of > or =50% of the initial gain (34.3% versus 33.9%, two-paired P=1.0), and absolute reduction of minimal luminal diameter >0.72 mm (29.6% versus 24.8%, two-paired P=.45). Likewise, there was no difference with regard to the incidence of clinical events (death, myocardial infarction, bypass operations, reintervention). Octreotide was well tolerated, with the exception of gastrointestinal side effects, which were three times more common than in the placebo group., Conclusions: Octreotide did not reduce the angiographically determined restenosis rate or the incidence of major clinical events after coronary angioplasty.

Village health rooms (VHRs) were established in villages with no on-site health facilities in the Hebron District of the West Bank, beginning in 1985. By 1991, the program served a total population of 40,000 in 49 VHRs and by the end of 1996 covered 69 villages in Hebron and 20 in other districts that were previously served by visiting vaccination teams and nearby clinics. The VHRs provide close contact with the population of mothers for well child and pregnancy care, health education and provide visiting doctor/nurse teams for backup services and supervision. Data on coverage, utilization, costs, and outcome measures are presented. The program is accepted and grows despite adverse social and political conditions.

The role of the primary motor cortex (M1) during mental simulation of movement is open to debate. In the present study, functional magnetic resonance imaging (fMRI) signals were measured in normal right-handed subjects during actual and mental execution of a finger-to-thumb opposition task with either the right or the left hand. There were no significant differences between the two hands with either execution or simulation. A significant involvement of contralateral M1 (30% of the activity found during execution) was detected in four of six subjects. Premotor cortex (PM) and the rostral part of the posterior SMA were activated bilaterally during motor imagery. These findings support the hypothesis that motor imagery involves virtually all stages of motor control.

Juvenile active ossifying fibroma (JAOF) is a lesion characterized by early age of onset, slow growth, frequent recurrence, and locally aggressive behavior. Histologically, it consists of three major components: cellular fibrous stroma, osteoid bodies, and myxomatous matrix, which may become cystic. This article describes a case of a slowly growing destructive lesion of the mastoid in a 2-year-old girl with histologic features resembling those of juvenile active ossifying myxoma (JAOM). Histologically, its prominent features were myxoid and fibromyxoid stroma with cystic areas, vascular spaces, bone, and multinucleated giant cells. This is the first pediatric temporal bone lesion with these features recorded These histologic components led to the diagnosis of JAOM of the temporal bone, probably developing in relation to the development of the mastoid air spaces.

Retrospective analysis of 103 samples of amniotic fluid was performed. Twenty-four samples were obtained prior to midtrimester abortion, 31 were from patients who delivered spontaneously, 14 were from patients in whom labor was induced, and the remaining samples were obtained from patients who were delivered by cesarean section. In all normal pregnancies, there was a rising trend in corticosteroid levels in amniotic fluid as the gestation advanced. This was less marked in abnormal pregnancies. There is a suggestive fetal role in initiation of normal spontaneous labor, as reflected by a significant increase in amniotic fluid corticosteroid levels, in patients immediately prior to vaginal delivery as opposed to abdominal delivery. There was a significant correlation between the birthweight of babies born vaginally with the amniotic fluid corticosteroid levels, as compared to the weight of babies born by cesarean section.

The estriol concentration of a morning sample of urine from high-risk pregnant women was correlated with the total 24-hour estriol excretion. One hundred seventy sample pairs compared the estriol concentration of the morning specimen with those of a 24-hour specimen of the previous day, while 110 sample pairs compared the value of morning specimen with those of a 24-hour specimen of the following day. Although there is highly significant statistical correlation between those sample pairs, they are of modest magnitude. The mean values of the sample pairs are significantly different. Also, the morning sample estriol concentrations are significantly more variable than those of the 24-hour specimen.