Expanding the clinical history associated with syndromic Klippel-Feil: A unique case of comorbidity with medulloblastoma

Klippel-Feil syndrome (KFS) is an exceedingly rare constitutional disorder in which a paucity of knowledge exists about the disease and its associated morbidity and mortality. We present a 4-year-old male with KFS, who notably was also diagnosed with large-cell anaplastic medulloblastoma. We evaluated the genetic basis of co-occurring KFS and medulloblastoma and the role of MYO18B as related to medulloblastoma. Constitutional and somatic variant and copy number analyses were performed from DNA-based exome studies, along with RNA-sequencing of tumor tissue, to elucidate the genetic etiology of the co-existing disease states. We identified novel constitutional compound heterozygous frameshift variants (NM_032608.5: p.Leu2257SerfsTer16 and p.Arg2220SerfsTer74) each encoding a premature stop of translation in MYO18B, consistent with a diagnosis of KFS. We did not identify any somatic variants of known relevance or disease-relevant therapeutic targets in the tumor. The somatic copy number profile was suggestive of Group 3γ medulloblastoma. Relative to pediatric brain tumors, medulloblastoma, particularly, Group 3, had increased gene expression of MYO18B. In summary, coexisting constitutional and somatic diagnoses in this patient enabled the elucidation of the genetic etiology of KFS and provided support for the role of MYO18B in tumor suppression.     

Mutations in GDF6 are associated with vertebral segmentation defects in Klippel-Feil syndrome

Klippel-Feil syndrome (KFS) is a congenital disorder of spinal segmentation distinguished by the bony fusion of anterior/cervical vertebrae. Scoliosis, mirror movements, otolaryngological, kidney, ocular, cranial, limb, and/or digit anomalies are often associated. Here we report mutations at the GDF6 gene locus in familial and sporadic cases of KFS including the recurrent missense mutation of an extremely conserved residue c.866T>C (p.Leu289Pro) in association with mirror movements and an inversion breakpoint downstream of the gene in association with carpal, tarsal, and vertebral fusions. GDF6 is expressed at the boundaries of the developing carpals, tarsals, and vertebrae and within the adult vertebral disc. GDF6 knockout mice are best distinguished by fusion of carpals and tarsals and GDF6 knockdown in Xenopus results in a high incidence of anterior axial defects consistent with a role for GDF6 in the etiology, diversity, and variability of KFS.     

Performance status and comorbidity predict transplant-related mortality after allogeneic hematopoietic cell transplantation.

Comorbidity measurements have recently been used to improve estimation of tolerance to allogeneic hematopoietic cell transplantation (HCT). We sought to determine the independent effect of comorbidity and performance status on HCT outcome and to devise a simple risk classification system for transplant-related mortality. We analyzed 105 consecutively enrolled patients who underwent HCT and received reduced intensity conditioning with fludarabine, melphalan, and alemtuzumab. Comorbid conditions were tabulated using 2 scales, the Charlson Comorbidity Index (CCI) and the Kaplan-Feinstein Scale (KFS). Comorbid conditions were found in 47% of patients by the KFS and in 27% by the CCI (P < .001). Using the Eastern Cooperative Oncology Group Performance Status (PS) scale, 34% had a PS score >0 (range, 0-2). A simple scale combining the KFS and PS enabled separation of high- from low-risk patients, with 6-month cumulative incidences 50% and 15%, respectively for transplant-related mortality (P = .001) and enhanced prognostic power over the CCI alone (P = .018). Prospective studies evaluating more comprehensive functional and comorbidity measurements are warranted.     

Muscle strength and soft tissue composition as measured by dual energy x-ray absorptiometry in women aged 18–87 years

Dual energy x-ray absorptiometry (DEXA) offers the possibility of assessing regional soft tissue composition, i.e. lean mass (LM) and fat mass : LM may be considered a measure of muscle mass. We examined age-related differences in LM, percentage fat (%fat) and muscle strength in 100 healthy non-athletic women aged 18–87 years. Relationships between muscle strength and leg LM in 20 elite female weight lifters and in 18 inactive women with previous hip fractures were also studied. The LM and %fat of the whole body, trunk, arms and legs were derived from a whole body DEXA scan. Isokinetic knee extensor strength (KES) and flexor strength (KFS) at 30°?·?s^–1 were assessed using an isokinetic dynamometer. The women aged 71–87 years had 35% lower KES and KFS than the women aged 18–40 years (P P r _partial?=??0.74, P r _partial?=?0.65, P r?=??0.70, P P P 相似文献   

Cultured mucosal cell sheet with a double layer of keratinocytes and fibroblasts on a collagen membrane

The aim of this study was to develop a novel cultured mucosal membrane that was facile to prepare and easy to handle, and that could be applied to mucosal defects in the oral cavity. Human oral keratinocytes and fibroblasts were prepared from the oral mucosa. We made the following two types of cultured mucosal cell sheets: a monolayer sheet of keratinocytes cultured on a collagen membrane (K-S) and a double-layered sheet of keratinocytes and fibroblasts on a collagen membrane (KF-S). A collagen membrane was used as a control. Each type of sheet was transplanted onto dorsal skin defects of nude mice. The wound area was measured for the assessment of wound contraction and a specimen was harvested for histologic evaluation 1 week and 4 weeks after grafting. Wound contraction was minimal with KF-S grafts. Although histologic examination showed normal differentiation of the epithelium in all graft types, the involucrin expression pattern of KFS was most similar to that of normal epithelium. These results indicate that a double-layered sheet of keratinocytes and fibroblasts cultured on a collagen membrane may facilitate epithelial healing and prevent wound contraction.     

Comparison of the clinical and patient-reported outcomes between medial stabilized and posterior stabilized total knee arthroplasty: A systematic review and meta-analysis

BackgroundTotal knee arthroplasty (TKA) is effective in relieving pain and improving function in patients with end-stage knee osteoarthritis. Both medial stabilized total knee arthroplasty (MS-TKA) and posterior stabilized total knee arthroplasty (PS-TKA) can achieve satisfactory clinical results, but comparisons between MS-TKA and PS-TKA have yielded contradictory conclusions. This systematic review and meta-analysis were performed to investigate the differences in clinical and patient-reported outcomes (PROMs) between MS-TKA and PS-TKA.MethodsIn December 2020, systematic searches of the following databases were undertaken: Pubmed, Embase, Cochrane Library, Clinical Trials.gov. Studies with PROMs comparing MS-TKA to PS-TKA were included. Meta-analysis was conducted for range of motion (ROM), Knee Society Score (KSS), Knee Society Functional Score (KFS), Forgotten Joint Score (FJS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Oxford Knee Score (OKS).ResultsThere were 17 studies included in this review, 13 studies used for quantitative analysis, and 4 studies used for qualitative synthesis. Meta-analysis concluded that the WOMAC mean difference (MD) for MS-TKA was 1.55 higher than for PS-TKA (MD = −1.55; 95 %CI = −2.45 to −0.64, P = 0.0008); however, this difference was less than the minimum clinically important difference (MCID) value of 15. Assessment using the OKS determined that the MD for PS-TKA was 0.58 higher than for MS-TKA (MD = 0.58; 95 %CI = 0.25 to 0.91, P = 0.0006); again, this MD was less than the MCID value of 5. There were no significant differences between MS-TKA and PS-TKA when assessed by ROM (P = 0.23), KSS (P = 0.13), KFS (P = 0.61), or FJS (P = 0.22).ConclusionDerived from numerous sources, utilizing a multitude of validated functional and patient-reported outcome assessment tools, there was no clinically evident advantage of MS-TKA compared to PS-TKA.RegistrationThe registration number on PROSPERO is CRD42021228555.     

Activity in vitro of twelve antibiotics against clinical isolates of extended-spectrum beta-lactamase producing Escherichia coli

Twelve beta-lactam and non-beta-lactam antibiotics were evaluated against 115 clinical isolates of extended-spectrum beta-lactamase-producing (ESBLs) Escherichia coli using a broth microdilution test in accordance with the CLSI guidelines. Susceptibility was 100% with imipenem, ertapenem and amikacin, 95.7% with piperacillin-tazobactam, 91.3% with cefoxitin, 87% with tobramycin, 81.7% with amoxicillin-clavulanate, 80% with cefepime, 67.8% with ceftazidime, 27.8% with ciprofloxacin, 27% with levofloxacin and 13% with ceftriaxone. Ertapenem was the antibiotic with the lowest minimum inhibitory concentrations (MICs) for all isolates. There were no clinically relevant differences in the activity of the antibiotics in the presence of CTX-M-9 or SHV enzymes.     

血清CA153、CEA和TPA联检在术前乳腺肿瘤鉴别诊断中的价值

目的:本文探讨血清CA153、CEA和TPA联检在术前乳腺肿瘤鉴别诊断中价值,以期为乳腺癌患者即时手术提供帮助.方法:采用放射免疫分析,检测乳腺肿瘤患者和健康人群血清CA153、CEA和TPA含量.结果:在CA153、CEA和TPA血清学检测中,术前乳腺癌组与乳腺良性肿瘤和健康人群组表达水平存在明显差异.术前乳腺癌组阳性率:CA153为63.8%,CEA为22.4%,TPA为62.1%;术前乳腺癌组联检阳性率:CA153和CEA为69.8%,CA153和TPA为87.1%,三者联检为90.5%;术前乳腺癌组检测特异性:CA153为77.9%,CA153和CEA联检为77.9%,CA153和TPA联检为71.9%,三者联检为73.4%.结论:当CA153、CEA和TPA三者联检时,术前乳腺癌组诊断阳性率显著提高,阳性组特异性无明显下降,值得临床推广应用.     

阿苯达唑及黄芪对肝吸虫病大鼠红细胞免疫功能的影响

目的 观察药物阿苯达唑联合中药黄芪对肝吸虫感染大鼠的治疗效果并探讨其作用机制。方法 取健康成年Wistar大鼠32只,随机分为对照组、感染组、阿苯达唑治疗组和阿苯达唑联合黄芪治疗组,每组8只大鼠。对肝吸虫病大鼠感染及治疗前后红细胞C3b受体花环率（RBC-C3bRR）,红细胞免疫复合物花环率（RBC-ICR）,血清红细胞免疫促进因子（RFER）和红细胞免疫抑制因子（RFIR）活性进行检测。结果 大鼠感染肝吸虫后RBC-C3bRR和RFER水平下降,RBC-ICR和RFIR水平升高,与正常对照组比较,差异有统计学意义。经阿苯达唑及黄芪治疗后,肝吸虫病大鼠RBC-C3bRR和RFER水平升高,RBC-ICR和RFIR水平下降,与感染组比较差异有统计学意义;与阿苯达唑单独治疗组比较,阿苯达唑联合黄芪治疗肝吸虫病的效果更显著。结论 红细胞免疫功能在肝吸虫病大鼠致病过程中具有重要的作用,药物阿苯达唑和黄芪对肝吸虫病大鼠具有较好的疗效,中药黄芪对红细胞免疫具有调节作用。     

Antinuclear Antibodies and Anti-DNA Antibodies in Scleroderma

Antinuclear antibodies (ANA), including anti-DNA antibodies, and rheumatoid factors (RAT, Waaler-Rose) were determined prospectively during a 3-year period in 40 patients with localized scleroderma (LS) compared with 77 patients with generalized scleroderma (GS). ANA were increased in 26% of patients with LS, and in 47% with GS, anti-DNA antibodies in 23% of patients with LS, and in 34% with GS. Thus, the anti-DNA antibody level was lower compared with the known level in systemic lupus erythematosus. Rheumatoid factors were present in 6-7% of patients with LS, and in 14-15% of patients with GS. Increased antinuclear antibodies were not associated with any specific type of localized scleroderma, nor with internal disorders, and no case of clinical overlap to discoid or systemic lupus erythematosus was observed. However, six patients with localized scleroderma and complaints of arthralgia all presented increased antibodies, and one patient showed overlap to rheumatoid arthritis. It is suggested that increased ANA and anti-DNA antibodies in localized scleroderma, associated with joint manifestations, represents a systemic component in this type of scleroderma, with activation of the immune system and similarities with generalized collagen diseases.     

Stronger nasal responsiveness to cold air in individuals with rhinitis and asthma, compared with rhinitis alone

BACKGROUND: We have previously proposed that, compared with rhinitis alone, the constellation of upper and lower airway allergic disease is a manifestation of a more severe form of a syndrome affecting the entire airway. If this is correct, not only the lower, but also the upper airways of patients with asthma and rhinitis should demonstrate more abnormalities compared with patients with rhinitis alone, including higher sensitivity to irritant factors. Objective To test the hypothesis that, a previously well-studied natural nasal stimulus, cold, dry air (CDA), produces a stronger response in subjects with allergic rhinitis (AR) and asthma compared with subjects with AR alone. METHODS: We performed nasal provocation with CDA on 24 individuals with asthma and rhinitis and 17 with rhinitis alone. Prior to and after the challenge, nasal symptoms were recorded using visual analogue scales and nasal lavages were performed to determine histamine and lysozyme levels. RESULTS: The two groups reacted differently to CDA: after the challenge, patients with rhinitis and asthma reported significantly higher scores for nasal congestion, rhinorrhea and lacrimation. Also in this group, significant increases in histamine and in lysozyme levels in nasal lavage fluids were induced by CDA. In subjects with rhinitis alone, CDA failed to increase histamine or lysozyme levels above baseline. The CDA-induced change from baseline in histamine was significantly higher in the patients with rhinitis and asthma, compared with the rhinitis-only group. CONCLUSION: Patients with AR and asthma have stronger nasal responsiveness to CDA compared with patients with rhinitis alone. This observation is consistent with the notion that compared with rhinitis alone, the presence of asthma and rhinitis signifies a higher degree of functional abnormality of the entire airway.     

伴抑郁症状的精神分裂症临床分析

目的 了解精神分裂症的抑郁症状临床特征。方法 对76例件抑郁症状的精神分裂症,140例不伴抑郁症状的精神分裂症进行临床对照分析。结果 抑郁症状在精神分裂症中颇为普遍,抑郁症状与精神病性症状关系密切,抑郁症状与复发率、住院时间、自杀有关;与性别、年龄、精神疾病总痛程比较,差异均无显著性;加用与不加用抗抑郁剂比较,在治疗起效时间、症状改善时间方面的差异均有非常显著性(P<0.01)。结论 对伴抑郁症状的精神分裂患者治疗上加用抗抑郁剂是缩短疗程的有效途径。     

肾组织中perlecan的表达及其与蛋白尿的关系

目的 观察基膜蛋白多糖（perlecan）在不同病理改变儿童原发性肾病综合征及阿霉素肾病大鼠的肾组织中表达变化,探讨其参与蛋白尿发生的机制。方法 应用免疫组化法检测阿霉素肾病大鼠在阿霉素注射后第7、14、28天时肾组织perlecan的表达变化,并与24h尿蛋白进行相关分析。在69例不同病理类型原发性肾病综合征和血尿患儿的肾组织,应用免疫组化法检测perlecan表达,并分别与尿蛋白肌酐比值及电镜下平均足突宽度（FPW）进行相关分析。结果 在阿霉素肾病大鼠中随着蛋白尿的加重,perlecan在肾小球内染色强度明显减低,且与24h尿蛋白呈显著负相关（P〈0．01）。Perlecan在正常肾组织中沿肾小球血管襻及肾小管基膜分布。肾小球perlecan的表达在MCD、FSGS中分别较正常对照或TBMN显著减低,而在MN中沿增宽的GBM分布,表达显著升高。在IgA肾病中,肾小球内可见perlecan沿血管襻及系膜区分布,蛋白尿组的肾小球中perlecan表达量较单纯血尿组显著减低（P〈0．05）。MCD肾小球中perlecan免疫组化指数与尿蛋白肌酐比值呈负相关,与FPW无显著相关。结论 Perlecan在肾小球内表达减低与阿霉素肾病大鼠及不同病理类型的儿童原发性肾病综合征的蛋白尿的发生有关。     

Comparative study of pituitary and bacteria-derived human growth hormone by monoclonal antibodies

We have established hybridoma lines which secrete mouse monoclonal antibodies (Mabs) to human pituitary growth hormone, hGH. Using indirect competitive ELISA and indirect passive hemagglutination inhibition twelve different Mabs were characterized with regard to cross-reactivity with the hGH-related hormones, human chorionic somatomammotropin, hCS, and human prolactin, hPRL. The reactivity of these Mabs with pituitary hGH was compared to that with either bacterially-produced methionyl-hGH or to that of reduced and S-carboxymethylated hGH, which has an altered conformation. None of the Mabs reacted with hPRL. Four did not react with hCS whereas the others showed varying degree of cross-reactivity with hCS. All Mabs reacted more weakly with reduced and S-carboxymethylated hGH than with the native form of the hormone, which was not seen with conventional rabbit antisera to hGH. Thus in the case of hGH the Mabs are superior to conventional antisera in revealing small conformational differences. However the pituitary and bacterially-derived methionyl-hGH were indistinguishable as determined by the 12 Mabs.     

Low plasma level of adiponectin is associated with stavudine treatment and lipodystrophy in HIV-infected patients

This study tested the hypothesis that in patients with HIV-associated lipodystrophy, adiponectin levels were related to insulin resistance, TNF-alpha and IL-6 and treatment with nucleoside analogues. HIV seropositive men undergoing highly active antiretroviral treatment were enrolled into three predetermined clinical groups: lipodystrophy with central fat accumulation (n = 12); lipodystrophy without central fat accumulation (n = 15); no lipodystrophy (n = 15). HIV-negative healthy men served as controls (n = 12). Both lipodystrophic groups had a low percentage of limb fat compared to the two control groups. Patients with lipodystrophy with fat accumulation had increased truncal fat compared with controls. Levels of adiponectin did not correlate with either TNF-alpha or IL-6. Low levels of adiponectin were found in both lipodystrophic groups and were associated with current or previous treatment with stavudine. Furthermore, the adiponectin level correlated with the percentage of limb fat. Patients with lipodystrophy with fat accumulation were more insulin resistant, measured by HOMA-IR, compared with controls. However, HOMA-IR did no correlate to adiponectin or other cytokines. In conclusion, the finding of no difference between the two lipodystrophic groups with regard to adiponectin, indicates that low levels of adiponectin reflects fat atrophy, whereas the insulin resistance was best explained by increased truncal fat mass.     

α-干扰素中和抗体对慢性乙肝患者干扰素抗病毒疗效的影响

目的 研究慢性乙型肝炎患者α-干扰素(IFN-α)中和抗体(NA)产生的情况,并探讨其对IFN抗病毒疗效的影响.方法 采用抗病毒中和生物测定法检测了48例慢性乙型肝炎患者IFN-α治疗前、治疗后3-6个月血清中NA产生的情况;同时,也检测了10名健康人血清中NA.结果 慢性乙型肝炎患者IFN-α治疗前和健康人血清中均无NA产生.48例患者IFN-α治疗6个月后,完全应答有15例,部分应答23例,无应答10例;IFN-α治疗后3个月和6个月时血清中NA阳转率分别为25%和37.5%(P>0.05).治疗后3个月时完全应答组和部分应答组NA阳转率均显著高于无应答组;同时,治疗后6个月时完全应答组NA阳转率较无应答组也显著升高.结论 IFN-α治疗后机体可产生NA;NA的产生可影响IFN-α抗病毒疗效,尤其是IFN-α治疗后早期(3个月)即产生了NA.     

阿霉素诱导下多发性骨髓瘤细胞中自噬和氧化应激的相互作用

 目的: 探讨阿霉素(doxorubicin,DOX)诱导对多发性骨髓瘤细胞系RPMI-8226细胞内自噬和活性氧簇(reactive oxidative species,ROS)生成的影响及其相互作用关系。方法: 不同浓度阿霉素诱导RPMI-8226细胞24 h,采用Western blot技术检测细胞内beclin 1、LC3等自噬相关蛋白的表达水平。采用DCFH-DA荧光染色法检测RPMI-8226细胞内ROS的水平,荧光显微镜采集图像。采用氧自由基清除剂N-乙酰半胱氨酸(N-acetyl-L-cysteine,NAC)及tempol处理RPMI-8226细胞后,通过Western blot技术检测阿霉素诱导下细胞内beclin 1、LC3等蛋白的表达水平。采用自噬抑制剂3-甲基腺嘌呤(3-methyladenine,3-MA)处理PRMI-8226细胞后,检测阿霉素诱导下细胞内ROS和凋亡的表达水平。结果: RPMI-8226细胞内beclin 1和LC3Ⅱ/LC3Ⅰ表达水平呈阿霉素剂量依赖性增加,当阿霉素诱导浓度达2 mg/L时,与对照组比较显著增加(P<0.05)。采用2 mg/L阿霉素处理RPMI-8226细胞,通过荧光显微镜观察,ROS水平较对照组明显增加。氧自由基清除剂NAC和tempol处理RPMI-8226细胞后,beclin 1和LC3Ⅱ/Ⅰ的表达水平较阿霉素处理组下降。采用自噬抑制剂3-MA处理细胞后,RPMI-8226细胞内ROS和凋亡的水平较阿霉素处理组及对照组增加。结论: 阿霉素能增加RPMI-8226细胞内自噬和ROS的生成,抑制自噬能增加阿霉素诱导下ROS和凋亡的水平,抑制ROS后能减少阿霉素诱导下多发性骨髓瘤细胞中的自噬。     

Constitutive deficiency in DNA mismatch repair

Mutations in the DNA mismatch repair (MMR) genes are associated with the inheritance of hereditary non-polyposis colorectal cancer, also known as Lynch syndrome, a cancer syndrome with an average age at onset of 44. Individuals presenting with colorectal cancer are diagnosed with Lynch I, whereas individuals who present with extra-colonic tumors (such as endometrial, stomach, etc.) are identified as patients with Lynch syndrome II. Recently, 30 families have been reported with inheritance of biallelic mutations in the MMR genes. Here we summarize the phenotype of individuals with inheritance of homozygous or compound heterozygous mutations in the MMR genes that result in a complete lack of protein or greatly compromised protein function. In contrast to individuals with Lynch syndrome I and II, individuals with no MMR function present with childhood onset of hematological and brain malignancies, whereas residual MMR function can also result in gastrointestinal cancers and an age of onset in the second to fourth decade. Individuals with biallelic MMR mutations often present with café-au-lait spots, regardless of the level of MMR function remaining. Thus, the inheritance of two MMR gene mutations is a separate entity from Lynch I or II or the subtypes Turcot and Muir-Torre.     

乳酸杆菌和低聚异麦芽糖对抗生素相关腹泻大鼠肠粘膜SlgA的影响

目的：研究抗生素相关腹泻(Antibiotic-associated diarrhea，AAD)大鼠肠粘膜分泌型免疫球蛋白A(SIgA)的含量变化，探讨乳酸杆菌和低聚异麦芽糖复合配方(合生元)对肠粘膜SIgA水平的调节作用。方法：以盐酸林可霉素复制AAD模型，治疗组采用不同剂量的合生元灌胃。分别在实验第6d、第9d、第13d进行肠道菌群分析和肠粘膜SIgA水平检测(放射免疫分析)。结果：AAD大鼠肠道菌群失调，肠粘膜组织中SIgA水平下降；不同剂量的合生元均能调节肠道菌群失调、促进肠粘膜SIgA水平的分泌。结论：乳酸杆菌和低聚异麦芽糖组成的合生元配方可提高AAD大鼠肠粘膜SIgA的分泌，提高肠道相关淋巴组织免疫功能，对AAD肠粘膜免疫屏障具有保护作用。