Fetal craniofacial structure and intracranial morphology in a case of Apert syndrome.

Apert syndrome is characterized by craniosynostosis, midfacial hypoplasia and bilateral syndactyly. We document in detail the intrauterine natural history of Apert syndrome by serial sonographic examination. Ultrasound examination of a 19-week fetus revealed an abnormal appearance of the skull. The subsequent examination including transvaginal brain scanning demonstrated a deformed occipital part of the cerebrum and lateral ventricles, frontal bossing, a low nasal bridge and an abnormal appearance of the fetal hands and feet. The distortion of the fetal profile became progressively worse with advancing gestation. Towards the end of pregnancy, anterior prominence of the cerebrum, ventricles and corpus callosum was demonstrated and mild non-progressive ventriculomegaly was seen. The female 3152-g newborn with the typical facial appearance of Apert syndrome, bilateral syndactyly of the fingers and toes and isolated cleft palate was delivered at 37 weeks. Postnatal three-dimensional computed tomography scan demonstrated the fusion of the coronal suture and a wide mid-line calvarial defect, and cranial magnetic resonance imaging confirmed the prenatal sonographic findings. Although the karyotype was normal, genomic DNA analysis of the fibroblast growth factor receptor 2 revealed Ser252Trp, which is specified in the mutational basis of Apert syndrome. The time course of the prenatal findings in this case may help increase understanding of the intrauterine natural history of Apert syndrome.     

Apert's syndrome: differential in vitro production of matrix macromolecules and its regulation by interleukins

During embryonic development, variations in the composition of the extracellular matrix (ECM) macromolecules influence bone tissue differentiation. We present novel findings on the in vitro phenotypic expression of periosteal fibroblasts obtained from patients affected by Apert’s syndrome, a rare craniofacial malformation, and the effects that interleukins (ILs) induce on the phenotype. Apert fibroblasts synthesized greater quantities of glycosaminoglycans (GAGs) and intracellular type I collagen, and also produced more type III collagen and fibronectin. The amount of hyaluronic acid (HA) secreted by Apert fibroblasts was much higher than that secreted by normal fibroblasts, but, as the absolute values of heparan sulphate (HS), chondroitin sulphate (CS) and dermatan sulphate (DS) also rose in Apert media, the HA–sulphated GAG ratio was similar in the media obtained from both populations. Both ILs triggered elevations of HA in normal cells, although relative percentage secretion remained unaltered, but significantly reduced HA secretion by Apert cells. IL-1 significantly increased CS in normal and Apert media, whereas IL-6 enhanced HS and DS in media of both populations. HA–sulphated GAG ratio decreased in Apert media after IL treatment. Both ILs boosted fibronectin production by Apert fibroblasts, whereas IL-1 increased type III but not type I collagen. Taken together, these data demonstrate that the synthesis and secretion of ECM macromolecules are markedly altered in Apert fibroblasts. The fact that treatment with ILs further modifies the Apert phenotype suggests that ILs may be implicated in the pathophysiology of the malformations during skull morphogenesis.     

Apert's syndrome: differential in vitro production of matrix macromolecules and its regulation by interleukins

During embryonic development, variations in the composition of the extracellular matrix (ECM) macromolecules influence bone tissue differentiation. We present novel findings on the in vitro phenotypic expression of periosteal fibroblasts obtained from patients affected by Apert's syndrome, a rare craniofacial malformation, and the effects that interleukins (ILs) induce on the phenotype. Apert fibroblasts synthesized greater quantities of glycosaminoglycans (GAGs) and intracellular type I collagen, and also produced more type III collagen and fibronectin. The amount of hyaluronic acid (HA) secreted by Apert fibroblasts was much higher than that secreted by normal fibroblasts, but, as the absolute values of heparan sulphate (HS), chondroitin sulphate (CS) and dermatan sulphate (DS) also rose in Apert media, the HA–sulphated GAG ratio was similar in the media obtained from both populations. Both ILs triggered elevations of HA in normal cells, although relative percentage secretion remained unaltered, but significantly reduced HA secretion by Apert cells. IL-1 significantly increased CS in normal and Apert media, whereas IL-6 enhanced HS and DS in media of both populations. HA–sulphated GAG ratio decreased in Apert media after IL treatment. Both ILs boosted fibronectin production by Apert fibroblasts, whereas IL-1 increased type III but not type I collagen. Taken together, these data demonstrate that the synthesis and secretion of ECM macromolecules are markedly altered in Apert fibroblasts. The fact that treatment with ILs further modifies the Apert phenotype suggests that ILs may be implicated in the pathophysiology of the malformations during skull morphogenesis.     

胎儿Apert综合征产前超声诊断研究

目的：探讨Apert综合征胎儿产前超声声像图特征。方法对2010年1月至2014年2月在深圳市妇幼保健院产前超声诊断为Apert综合征的4例胎儿超声影像检查资料进行总结,并与引产胎儿尸体解剖和产后诊断结果进行对照分析。结果4例Apert综合征胎儿产前超声声像图特征及临床结局：（1）头颅异常：4例胎儿均表现为尖头、冠状缝早闭、前额隆凸,其中3例（例1~3）头颅形态呈“三叶草征”。（2）面部异常：4例胎儿中1例（例4）颜面部无明显异常,3例（例1~3）两眼眼距增宽和颜面部正中矢状切面轮廓线异常,1例（例2）鼻梁塌陷。（3）肢体异常：4例胎儿双手均呈对称性并指畸形（表现为“手套征”）,产前超声检出1例（例2）双足并趾畸形。（4）伴发其他系统畸形：1例（例1）伴永久性右脐静脉,1例（例2）伴脊椎胸段椎管狭窄,1例（例3）伴双肾实质回声增强,1例（例4）伴左侧膈疝。（5）胎儿临床结局：4例胎儿超声检查后引产3例,胎儿标本外观检查发现产前超声漏诊2例（例1、2）双足并趾畸形;足月出生1例（例3）,产后检查发现产前超声漏诊Ⅰ度腭裂伴双足并趾畸形,新生儿2d后死亡。除漏诊Ⅰ度腭裂及双足并趾畸形外4例胎儿产前超声与产后检查结果均符合。结论 Apert综合征临床罕见,冠状缝早闭、尖头、颜面部正中矢状切面轮廓线异常和并指（趾）畸形为胎儿典型超声表现。产前超声发现胎儿头颅畸形、面容特殊应注意观察有无肢体畸形并连续追踪观察至产后。产前超声诊断Apert综合征对孕妇遗传咨询和胎儿出生后手术治疗有重要指导作用。     

Increased calvaria cell differentiation and bone matrix formation induced by fibroblast growth factor receptor 2 mutations in Apert syndrome.

Apert syndrome, associated with fibroblast growth factor receptor (FGFR) 2 mutations, is characterized by premature fusion of cranial sutures. We analyzed proliferation and differentiation of calvaria cells derived from Apert infants and fetuses with FGFR-2 mutations. Histological analysis revealed premature ossification, increased extent of subperiosteal bone formation, and alkaline phosphatase- positive preosteoblastic cells in Apert fetal calvaria compared with age-matched controls. Preosteoblastic calvaria cells isolated from Apert infants and fetuses showed normal cell growth in basal conditions or in response to exogenous FGF-2. In contrast, the number of alkaline phosphatase- positive calvaria cells was fourfold higher than normal in mutant fetal calvaria cells with the most frequent Apert FGFR-2 mutation (Ser252Trp), suggesting increased maturation rate of cells in the osteoblastic lineage. Biochemical and Northern blot analyses also showed that the expression of alkaline phosphatase and type 1 collagen were 2-10-fold greater than normal in mutant fetal calvaria cells. The in vitro production of mineralized matrix formed by immortalized mutant fetal calvaria cells cultured in aggregates was also increased markedly compared with control immortalized fetal calvaria cells. The results show that Apert FGFR-2 mutations lead to an increase in the number of precursor cells that enter the osteogenic pathway, leading ultimately to increased subperiosteal bone matrix formation and premature calvaria ossification during fetal development, which establishes a connection between the altered genotype and cellular phenotype in Apert syndromic craniosynostosis.     

Metopic suture in fetuses with Apert syndrome at 22-27 weeks of gestation.

OBJECTIVES: To examine the possible association of skull deformity and the development of the cranial sutures in fetuses with Apert syndrome. METHODS: Three-dimensional (3D) ultrasound was used to examine the metopic and coronal sutures in seven fetuses with Apert syndrome at 22-27 weeks of gestation. The gap between the frontal bones in the transverse plane of the head at the level of the cavum septi pellucidi was measured and compared to findings in 120 anatomically normal fetuses undergoing routine ultrasound examination at 16-32 weeks. RESULTS: In the normal group, the gap between the frontal bones in the metopic suture at the level of the cavum septi pellucidi, decreased significantly with gestation from a mean of 2.2 mm (5th and 95th centiles: 1.5 mm and 2.9 mm) at 16 weeks to 0.9 mm (5th and 95th centiles: 0.3 mm and 1.6 mm) at 32 weeks. In the seven cases with Apert syndrome, two-dimensional ultrasound examination demonstrated the characteristic features of frontal bossing, depressed nasal bridge and bilateral syndactyly. On 3D examination there was complete closure of the coronal suture and a wide gap in the metopic suture (15-23 mm). CONCLUSION: In normal fetuses, cranial bones are believed to grow in response to the centrifugal pressure from the expanding brain and proximity of the dura to the suture is critical in maintaining its patency. In Apert syndrome, the frontal bossing may be a mere consequence of a genetically predetermined premature closure of the coronal suture. Alternatively, there is a genetically predetermined deformation of the brain, which in turn, through differential stretch of the dura in the temporal and frontal regions, causes premature closure of the coronal suture and impaired closure of the metopic suture.     

Second-trimester molecular prenatal diagnosis of sporadic Apert syndrome following suspicious ultrasound findings.

Apert syndrome, an autosomal dominant disorder characterized by craniosynostosis, mid-facial malformations, symmetric bony syndactyly of hands and feet, and varying degrees of mental retardation, is most frequently caused by a de novo mutation. Two missense mutations in the fibroblast growth factor receptor 2 (FGFR2) gene have been found to account for the disorder in approximately 98% of affected patients. Seven cases of prenatal ultrasound diagnosis have been reported. Although one earlier diagnosis has been made in a familial case, sporadic cases have not been definitively diagnosed until the third trimester when craniosynostosis is usually detected. We report a second-trimester molecular diagnosis of a sporadic case, based on the ultrasound observation of fetal 'mitten hands' and craniosynostosis. We discuss the approach to such ultrasound features, given the current availability of molecular diagnosis for Apert syndrome.     

Mutation analysis of Crouzon syndrome in Taiwanese patients

Crouzon syndrome is an autosomal-dominant disorder that causes premature fusion of the cranial suture. Crouzon, Pfeiffer, and Apert syndromes are caused by mutations in the extracellular, third immunoglobulin-like domain, and adjacent linker regions (exons IIIa and IIIc) of the fibroblast growth factor receptor 2 (FGFR2) gene. We screened 12 Crouzon syndrome patients for mutations in exons IIIa and IIIc of the FGFR2 gene by polymerase chain reaction (PCR) and direct sequencing. Mutations were detected in nine of 12 patients at amino acid positions 278, 281, 289, 342, and 354. More than half of the studied Crouzon patients carried a mutation resulting in either the loss or gain of a cysteine residue. A novel missense Ser354Phe substitution at exon IIIc of the human FGFR2 gene was found. According to our results, sequencing analysis of IgIII domain of the FGFR2 gene can lead to a genetic diagnosis of Crouzon syndrome.     

Effects of lisinopril, atenolol, and isosorbide 5-mononitrate on angina pectoris and QT dispersion in patients with syndrome X: An open-label, randomized, crossover study

Background: The triad of angina pectoris, a positive exercise electrocardiographic test, and a normal coronary angiogram is described as syndrome X. Because the definite underlying pathophysiologic mechanism of syndrome X is not fully understood, there is no consensus about its treatment. It has been suggested that the prolonged QT interval observed in patients with syndrome X is due to autonomic nervous system dysfunction.Objective: The purpose of this study was to investigate the effects of treatment with lisinopril, atenolol, and isosorbide 5-mononitrate on angina pectoris and QT dispersion in patients with syndrome X.Methods: Adult patients with syndrome X and a control group of healthy subjects were included in this open-label, crossover study. After a 30-day washout period, patients with syndrome X were randomized into 3 different groups and were sequentially given, in a crossover study design, the angiotensin-converting enzyme inhibitor lisinopril (10 mg/d), the beta-blocker atenolol (50 mg/d), and isosorbide 5-mononitrate (60 mg/d) for 30 days each. Treatment periods were separated by a 10-day washout period. At the end of each 30-day period, QT dispersion (defined as maximal QT interval minus minimal QT interval) was measured on 12-lead electrocardiography, and patients' diary records were assessed to calculate the number of angina attacks and use of sublingual nitrates. Only an electrocardiographic analysis for QT dispersion was performed for the control group; no medication was given. This group was included in our study to test the validity of our method of determining QT dispersion.Results: A total of 21 patients (18 women and 3 men; mean age, 49.5 ± 10.4 years) and 18 control subjects (13 women and 5 men; mean age, 47.6 ± 9.8 years) were enrolled in the study. QT dispersion was found to be significantly increased in patients with syndrome X compared with the control group (102.0 ± 50.9 milliseconds vs 38.9 ± 18.5 milliseconds, P < 0.01). QT dispersions were 103.2 ± 42.1 milliseconds, 72.4 ± 35.0 milliseconds, and 80.7 ± 25.4 milliseconds after treatment with lisinopril, atenolol, and isosorbide 5-mononitrate, respectively. QT dispersion was reduced significantly versus baseline only after treatment with atenolol. The number of anginal episodes and sublingual nitrate consumption decreased significantly during the atenolol and lisinopril treatment periods.Conclusions: Our data suggest that increased sympathetic activation may be the underlying pathophysiologic mechanism of syndrome X and that atenolol appeared to be more effective than lisinopril or isosorbide 5-mononitrate for its treatment.     

滑膜炎、痤疮、脓疱病、骨肥厚、骨炎综合征99mTc-MDP全身骨显像分析

目的 探讨^99mTc-MDP全身骨显像诊断滑膜炎、痤疮、脓疱病、骨肥厚、骨炎(SAPHO)综合征的临床价值。方法 回顾性分析12例SAPHO综合征患者的骨显像特点。与X线平片、CT及MRI比较,分析骨显像对SAPHO综合征诊断的价值。结果 12例患者中均见前胸壁骨质受累,典型"牛头"征改变的仅25.00%(3/12),其余表现为不完全"牛头"征或单侧"牛角"征。脊柱受累6例,4例累及椎体,其中3例累及邻近多个椎体;2例累及椎间小关节,呈比邻分布。3例骨显像所见病灶在X线平片上未见异常,而在其他影像学检查均有异常改变。结论 典型"牛头"征或不完全"牛头"征、"牛角"征是SAPHO综合征在骨显像中的特征性表现,有利于早期诊断本病及评价病情。     

Pyogenic arthritis,pyoderma gangrenosum,and acne syndrome in a Chinese family: A case report and review of literature

BACKGROUNDPyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is a rare autosomal dominant genetic disease characterized by severe autoimmune inflammation, caused by mutations in the PSTPIP1 gene. Due to PAPA heterogeneous clinical manifestation, misdiagnosis or delayed diagnoses are difficult to avoid. With the use of whole-exome sequencing, we identified a missense mutation in the PSTPIP1 gene in a Chinese family. To the best of our knowledge, this is the first case of PAPA reported in China.CASE SUMMARYA 9-year-old boy suffered from recurrent aseptic pyogenic arthritis triggered by minor trauma or few obvious predisposing causes for more than 3 years. Pyogenic arthritis occurred every 3-5 mo, affecting his knees, elbows, and ankle joints. Treatments, such as glucocorticoids, antibiotics, even surgeries could alleviate joints pain and swelling to some extent but could not inhibit the recurrence of arthritis. Similar symptoms were present in his younger brother but not in his parents. According to the whole-exome sequencing, a missense mutation in exon 11 of the PSTPIP1 gene (c.748G>C; p.E250Q) was detected in the boy, his younger brother and his father. Taking into account the similar phenotypic features with PAPA syndrome reported previously, we confirmed a diagnosis of PAPA syndrome for the family.CONCLUSIONIn this case, a missense mutation (c.748G>C; p.E250Q) in PSTPIP1 gene was identified in a Chinese family with PAPA syndrome. Previous studies emphasize the fact that PAPA syndrome is hard to diagnose just through the clinical manifestations owing to its heterogeneous expression. Genetic testing is an effectual auxiliary diagnostic method, especially in the early stages of pyogenic arthritis. Only if we have a deep understanding and rich experience of this rare disease can we make a prompt diagnosis, develop the best clinical treatment plan, and give good fertility guidance.     

The relationship between rearfoot, tibial and hip kinematics in individuals with patellofemoral pain syndrome

Background

Excessive rearfoot eversion is thought to be a risk factor for patellofemoral pain syndrome development, based on theoretical rationale linking it to greater tibial internal rotation and hip adduction. This study aimed to establish the relationship of rearfoot eversion with tibial internal rotation and hip adduction during walking in individuals with and without patellofemoral pain syndrome.

Methods

Twenty-six individuals with patellofemoral pain syndrome and 20 controls (18–35 years) participated. Each underwent instrumented three-dimensional motion analysis during over-ground walking. Pearson's correlation coefficients (r) were calculated to establish the relationship of rearfoot eversion with tibial internal rotation and hip adduction (peak and range of motion).

Findings

Greater peak rearfoot eversion was associated with greater peak tibial internal rotation in the patellofemoral pain syndrome group (r = 0.394, P = 0.046). Greater rearfoot eversion range of motion was associated with greater hip adduction range of motion in the patellofemoral pain syndrome (r = 0.573, P = 0.002) and control (r = 0.460, P = 0.041) groups; and greater peak hip adduction in the control group (r = 0.477, P = 0.033).

Interpretation

Associations between greater rearfoot eversion and greater hip adduction indicate that interventions targeted at the foot or hip in individuals with patellofemoral pain syndrome may have similar overall effects on lower limb motion and clinical outcomes. The relationship between rearfoot eversion and tibial internal rotation identified in the patellofemoral pain syndrome group may be related to aetiology. However, additional prospective research is needed to confirm this.     

Integrated strategy for fast and automated molecular characterization of genes involved in craniosynostosis

BACKGROUND: Craniosynostosis, the premature fusion of 1 or more sutures of the skull, is a common congenital defect, with a prevalence of 1 in 2500 live births. Untreated progressive craniosynostosis leads to inhibition of brain growth and increased intracranial and intraorbital pressure. The heterogeneity of clinical phenotypes and the overlap of the various associated syndromes render the correct diagnosis of the different craniosynostoses particularly difficult. METHODS: To identify 10 common mutations in the genes for fibroblast growth factor receptors 2 and 3 (FGFR2 and FGFR3), we developed a microelectronic microchip assay that exploited the PCR multiplexing format and coupled it with serial addressing and probe hybridization on the same pad. For the molecular characterization of patients who tested negative in the microchip screening, we also developed conditions for denaturing HPLC (DHPLC) analysis of the most mutated regions of FGFR2 and FGFR3 and the entire coding region of the TWIST1 gene. RESULTS: In our cohort of 159 patients with various craniosynostosis syndromes, mutations were found in 100% of patients with Apert syndrome, 83.3% with Pfeiffer syndrome, 72.7% with Crouzon syndrome, 50.0% with Saethre-Chotzen syndrome, 27.7% with plagiocephaly, 31.8% with brachicephaly, 20% of complex cases, and 6.9% of mixed cases. No mutations were found in syndromic cases. CONCLUSIONS: The combined microchip-DHPLC strategy allows rapid and specific molecular diagnosis of craniosynostosis and is an effective tool for the medical and surgical management of these common congenital anomalies in a newborn or an infant with a developmental defect of the cranial vault.     

Metabolic Syndrome and Diabetes, Alone and in Combination, as Predictors of Cardiovascular Disease Mortality Among Men

OBJECTIVE

To examine cardiovascular disease (CVD) mortality risk in men with diabetes only, metabolic syndrome only, and concurrent metabolic syndrome and diabetes.

RESEARCH DESIGN AND METHODS

We examined CVD mortality risk by metabolic syndrome and diabetes status in men from the Aerobics Center Longitudinal Study (ACLS) (mean ± SD age 45.1 ± 10.2 years). Participants were categorized as having neither diabetes nor metabolic syndrome (n = 23,770), metabolic syndrome only (n = 8,780), diabetes only (n = 532), or both (n = 1,097). The duration of follow-up was 14.6 ± 7.0 years with a total of 483,079 person-years of exposure and 1,085 CVD deaths.

RESULTS

Age-, examination year–, and smoking-adjusted CVD death rates (per 1,000 man-years) in men with neither metabolic syndrome nor diabetes, metabolic syndrome only, diabetes only, and both were 1.9, 3.3, 5.5, and 6.5, respectively. CVD mortality was higher in men with metabolic syndrome only (hazard ratio 1.8 [95% CI 1.5–2.0]), diabetes only (2.9 [2.1–4.0]), and both (3.4 [2.8–4.2]) compared with men with neither. The presence of metabolic syndrome was not associated (1.2 [0.8–1.7]) with higher CVD mortality risk in individuals with diabetes. In contrast, the presence of diabetes substantially increased (2.1 [1.7–2.6]) CVD mortality risk in individuals with metabolic syndrome.

CONCLUSIONS

The presence of diabetes was associated with a threefold higher CVD mortality risk, and metabolic syndrome status did not modify this risk. Our findings support the fact that physicians should be aggressive in using CVD risk–reducing therapies in all diabetic patients regardless of metabolic syndrome status.Approximately 7.8% of the U.S. population has diabetes, and it is estimated that the number of adults with diabetes will increase to 48.3 million by 2050 in the U.S. and to 300 million worldwide in the year 2025, representing a 122% rise compared with 1995 (1–3). The public health importance is great, considering that individuals with diabetes have more than twice the risk for premature death, heart disease, and stroke compared with individuals without diabetes (1). Although clinical definitions differ slightly, metabolic syndrome is generally characterized as a clustering of abnormal levels of blood lipids (low HDL and high triglycerides), impaired fasting glucose, elevated blood pressure, and excess abdominal obesity (4–7). Approximately 25% of Americans and >50% of those aged >50 years meet the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III definition of metabolic syndrome (8). Similar to individuals with diabetes, individuals with metabolic syndrome have an increased risk for premature death, heart disease, and stroke (9–12).Metabolic syndrome and diabetes share many common characteristics, so it is not surprising that 65–85% of individuals with diabetes also have metabolic syndrome (13–15). However, relativity few studies have examined the effect of the combination of metabolic syndrome and diabetes on cardiovascular disease (CVD) risk (11,13,14). A cross-sectional study using National Health and Nutrition Examination Survey data reported that the prevalence of coronary heart disease (CHD) among individuals with diabetes and without metabolic syndrome was similar to that in those without diabetes or metabolic syndrome (7.5 vs. 8.7%, respectively) (14). However, individuals with concurrent diabetes and metabolic syndrome had a substantially greater prevalence (19.2%) compared with these groups. This finding suggests that in individuals with diabetes there is an increased risk for CHD only when metabolic syndrome also is present. Similarly, in a prospective study Hunt et al. (16) reported that within individuals with diabetes, those with metabolic syndrome have an increased risk for CVD mortality, whereas individuals with diabetes but not metabolic syndrome do not. However, this study was relatively small (n = 2,815) with only 117 CVD deaths. Finally, the UK Prospective Diabetes Study (UKPDS) reported that in individuals with type 2 diabetes, the presence of metabolic syndrome (NCEP) increased the risk of CVD events (17). However, it was noted from a clinical perspective that the presence of metabolic syndrome in individuals with diabetes provided little information for detecting who has an increased risk of CVD.Given the high prevalence of both metabolic syndrome and diabetes, it is of great clinical and public health importance that we develop a better understanding of the interactions of diabetes and metabolic syndrome on the risk of CVD. The primary aim of the current investigation is to examine the risk of CVD mortality in individuals with metabolic syndrome only, diabetes only, and concurrent metabolic syndrome and diabetes in a large prospective study population.     

Posterior reversible leukoencephalopathy syndrome presenting in a post-partum, 25-year-old-female with concomitant subarachnoid hemorrhage

Hinchey et al., first described that posterior reversible leukoencephalopathy syndrome has having a unique neuroradiographical finding of vasogenic edema and clinical symptoms including headache, altered mental status, seizure and visual disturbances in 1996. We present a rare case of posterior reversible leukoencephalopathy syndrome in a 2-week, post-partum G2P2A0 (normal spontaneous vaginal delivery at forty-weeks, without complications) 25-year-old-female with subarachnoid hemorrhage.     

Serum zinc and alpha2-macroglobulin concentration in myocardial infarction, decubitus ulcer, multiple myeloma, prostatic carcinoma, Down's syndrome and nephrotic syndrome

α₂-Macroglobulin has been suggested as a transport protein for zinc and other trace metals. To elucidate the implications of this relationship, serum zinc and α₂-macroglobulin levels were measured in 20 control people and in 75 patients with various conditions that frequently alter serum zinc levels.Serum α₂-macroglobulin was found elevated in myocardial infarction (P < 0.01), prostatic carcinoma, (P < 0.01) and nephrotic syndrome (P < 0.001). In myocardial infarction, serum zinc was initially depressed and returned gradually to normality; in contrast, the elevated a 2-macroglobulin level persisted. Thus, α₂-macroglobulin responds more slowly than zinc to the healing of the infarct. Additionally the elevated (α₂-macroglobulin level may prove of diagnostic significance in myocardial disease.Although there was no significant correlation between zinc and α₂-macroglobulin levels in most states studied, very high α₂-macroglobulin levels in the nephrotic syndrome were accompanied by very low serum zinc levels. Thus, certain extreme elevations in α₂-macroglobulin levels may be associated with changes in metal metabolism that are not apparent when lesser protein alterations occur.A rapid technique of radial immunodiffusion, employing cellulose acetate proved reliable in the measurement of α₂-macroglobulin. Equivalence was attained and precipitation zone migration ceased within 48 h of sample application.     

Safe,Efficient, and Reproducible Gene Therapy of the Brain in the Dog Models of Sanfilippo and Hurler Syndromes

Recent trials in patients with neurodegenerative diseases documented the safety of gene therapy based on adeno-associated virus (AAV) vectors deposited into the brain. Inborn errors of the metabolism are the most frequent causes of neurodegeneration in pre-adulthood. In Sanfilippo syndrome, a lysosomal storage disease in which heparan sulfate oligosaccharides accumulate, the onset of clinical manifestation is before 5 years. Studies in the mouse model showed that gene therapy providing the missing enzyme α-N-acetyl-glucosaminidase to brain cells prevents neurodegeneration and improves behavior. We now document safety and efficacy in affected dogs. Animals received eight deposits of a serotype 5 AAV vector, including vector prepared in insect Sf9 cells. As shown previously in dogs with the closely related Hurler syndrome, immunosuppression was necessary to prevent neuroinflammation and elimination of transduced cells. In immunosuppressed dogs, vector was efficiently delivered throughout the brain, induced α-N-acetyl-glucosaminidase production, cleared stored compounds and storage lesions. The suitability of the procedure for clinical application was further assessed in Hurler dogs, providing information on reproducibility, tolerance, appropriate vector type and dosage, and optimal age for treatment in a total number of 25 treated dogs. Results strongly support projects of human trials aimed at assessing this treatment in Sanfilippo syndrome.     

Sedentary Behavior,Cardiorespiratory Fitness,Physical Activity,and Cardiometabolic Risk in Men: The Cooper Center Longitudinal Study

ObjectiveTo examine the association between sedentary behavior and cardiometabolic risk, while taking into account cardiorespiratory fitness (fitness) and physical activity.Participants and MethodsWe examined the association of sedentary behavior, physical activity, and fitness (exposure variables) to cardiometabolic biomarkers and metabolic syndrome (outcome measures) among a historic cohort (January 2, 1981, through October 16, 2012) of men. First, we estimated the association (cross-sectionally and longitudinally) of sedentary behavior along with physical activity and fitness to lipids and lipoproteins, glucose, blood pressure, and markers of adiposity, including body mass index, waist circumference, and body fat percentage. We then prospectively examined the effects of baseline sedentary time on the incidence of metabolic syndrome, while adjusting for physical activity, fitness, and other covariates in multivariate models.ResultsMultivariate analysis of baseline data revealed that in comparison with the reference group (≤9 h/wk of sedentary time), more sedentary behavior was significantly associated with a higher triglyceride level, a higher triglycerides–high-density lipoprotein cholesterol ratio, and a higher body mass index, waist circumference, and body fat percentage (P<.05 for trend), after adjusting for physical activity and covariates. When adjusting for fitness and covariates, prolonged sedentary time was only associated with a higher triglyceride–high-density lipoprotein cholesterol ratio (P=.02 for trend). Sedentary time was not associated with the incidence of metabolic syndrome in multivariate models. Longitudinal analyses revealed that a 1–metabolic equivalent increase in fitness was significantly (P<.05) associated with almost all biomarkers when adjusting for sedentary behavior, with little moderation observed.ConclusionThe association between prolonged sedentary time and cardiometabolic biomarkers is markedly less pronounced when taking fitness into account. Further exploration of the effects of sedentary behavior on cardiometabolic risk is warranted in cohorts with available fitness data. Furthermore, our findings underscore the need to encourage achieving higher fitness levels through meeting physical activity guidelines to decrease disease risk factors.     

Association of Smoking Status, Weight Change, and Incident Metabolic Syndrome in Men: A 3-Year Follow-Up Study

OBJECTIVE

We investigated the incidence of the metabolic syndrome and assessed the effect of smoking status and weight change on incident metabolic syndrome.

RESEARCH DESIGN AND METHODS

This study included 4,542 men without metabolic syndrome at baseline who were followed for an average of 3 years. Subjects were divided into four categories according to smoking status at baseline and at the 3-year follow-up.

RESULTS

The overall incidence of metabolic syndrome was 10.6%: 8.0% in nonsmokers, 7.1% in new smokers, 17.1% in ex-smokers, and 13.9% in sustained smokers (P < 0.001). In a multivariate regression model, ex-smokers had significantly increased odds for incident metabolic syndrome with a mean 1.45 (95% CI 1.06–1.98) compared with sustained smokers. This was no longer significant after including weight change.

CONCLUSIONS

Smoking cessation within 3 years may be a higher risk factor for incident metabolic syndrome than sustained smoking, indicating that weight control in ex-smokers is critical to attenuate the additional risk for incident metabolic syndrome.As the number of smokers who quit cigarette smoking is increasing, recent research has focused on the impact of prior smoking on cardiometabolic disorders. Several epidemiological studies have reported that smoking cessation is associated with an increased prevalence of the metabolic syndrome (1,2) compared with that of nonsmokers. However, the studies were cross-sectional and could not exactly evaluate the effects of smoking status on the risk of incident metabolic syndrome. The aim of the present study was to investigate the 3-year incidence of metabolic syndrome in men who did not have metabolic syndrome at baseline and to assess the effect of smoking status and weight change on the risk of incident metabolic syndrome.     

Effects of yoga exercise on maximum oxygen uptake,cortisol level,and creatine kinase myocardial bond activity in female patients with skeletal muscle pain syndrome

[Purpose] This study analyzed the effects of yoga exercise on maximum oxygen uptake, cortisol level, and creatine kinase myocardial bond activity in female patients with skeletal muscle pain syndrome. [Subjects] The subjects were 24 female patients with skeletal muscle pain syndrome. [Methods] The subjects were divided into 2 groups: a yoga exercise group (n = 12) and a non-exercise control group (n = 12). Body composition, maximum oxygen uptake, cortisol level, and creatine kinase myocardial bond activity were measured before and after a 12-week yoga exercise program. [Results] After the 12-week yoga exercise program, the exercise group exhibited slightly higher maximum oxygen uptake and creatine kinase myocardial bond activity than the control group, but the differences were not statistically significant. In addition, the exercise group exhibited a significant decrease in cortisol level. [Conclusion] Regular and continuous aerobic exercise such as yoga improves body composition, maximum oxygen uptake, cortisol level, and creatine kinase myocardial bond activity in female patients with skeletal muscle pain syndrome.Key words: VO₂max, Cortisol, Creatine kinase myocardial bond