Acupotomy alleviates knee osteoarthritis in rabbit by regulating chondrocyte mitophagy Pink1-Parkin pathway.

OBJECTIVE: To investigate the effect of acupotomy, on mitophagy and the Pink1-Parkin pathway in chondrocytes from rabbits with knee osteoarthritis (KOA). METHODS: A KOA model was established via the modified Videman method. Rabbits were randomly divided into a control group (CON), KOA group and KOA + acupotomy group (Acu). Rabbits in the acupotomy group were subjected to acupotomy for 4 weeks after model establishment. The behavior of the rabbits before and after intervention was recorded. Cartilage degeneration was evaluated by optical microscopy and fluorescence microscopy. The level of mitophagy was evaluated by transmission electron microscopy, immunofluorescence and enzyme-linked immunosorbent assay (ELISA). The expression of phosphatase and tensin homolog (PTEN)-induced kinase 1 (Pink1)-Parkin mitophagy pathway components was evaluated by immunofluorescence, Western blotting and real-time polymerase chain reaction. RESULTS: In rabbits with KOA, joint pain, mobility disorders and cartilage degeneration were observed, the Mankin score was increased, collagen type Ⅱ (Col-Ⅱ) expression was significantly decreased, mitophagy was inhibited, mitochondrial function was impaired, and factors associated with the Pink1-Parkin pathway were inhibited. Acupotomy regulated the expression of Pink1-Parkin pathway-related proteins, the mitophagy-related protein microtubule-associated protein-1 light chain-3, the translocase of the outer membrane, and the inner mitochondrial membrane 23; increased the colocalization of mitochondria and autophagosomes; promoted the removal of damaged mitochondria; restored mitochondrial adenosine-triphosphate (ATP) production; and alleviated cartilage degeneration in rabbits with KOA. CONCLUSIONS: Acupotomy played a role in alleviating KOA in rabbits by activating mitophagy in chondrocytes via the regulation of proteins that are related to the Pink1-Parkin pathway.

Steps to Improve Precision Medicine in Epilepsy.

Precision medicine is an old concept, but it is not widely applied across human health conditions as yet. Numerous attempts have been made to apply precision medicine in epilepsy, this has been based on a better understanding of aetiological mechanisms and deconstructing disease into multiple biological subsets. The scope of precision medicine is to provide effective strategies for treating individual patients with specific agent(s) that are likely to work best based on the causal biological make-up. We provide an overview of the main applications of precision medicine in epilepsy, including the current limitations and pitfalls, and propose potential strategies for implementation and to achieve a higher rate of success in patient care. Such strategies include establishing a definition of precision medicine and its outcomes; learning from past experiences, from failures and from other fields (e.g. oncology); using appropriate precision medicine strategies (e.g. drug repurposing versus traditional drug discovery process); and using adequate methods to assess efficacy (e.g. randomised controlled trials versus alternative trial designs). Although the progress of diagnostic techniques now allows comprehensive characterisation of each individual epilepsy condition from a molecular, biological, structural and clinical perspective, there remain challenges in the integration of individual data in clinical practice to achieve effective applications of precision medicine in this domain.

Targeting the renin angiotensin system for respiratory diseases.

Renin-angiotensin system (RAS) plays an indispensable role in regulating blood pressure through its effects on fluid and electrolyte balance. As an aside, cumulative evidence from experimental to clinical studies supports the notion that dysregulation of RAS contributes to the pro-inflammatory, pro-oxidative, and pro-fibrotic processes that occur in pulmonary diseases like asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and acute lung injury (ALI). Pharmacological intervention of the various RAS components can be a novel therapeutic strategy for the treatment of these respiratory diseases. In this chapter, we first give a recent update on the RAS, and then compile, review, and analyse recent reports on targeting RAS components as treatments for respiratory diseases. Inhibition of the pro-inflammatory renin, angiotensin-converting enzyme (ACE), angiotensin (Ang) II, and Ang II type 1 receptor (AT1R) axis, and activation of the protective ACE2, AT2R, Ang (1-7), and Mas receptor axis have demonstrated varying degrees of efficacies in experimental respiratory disease models or in human trials. The newly identified alamandine/Mas-related G-protein-coupled receptor member D pathway has shown some therapeutic promise as well. However, our understanding of the RAS ligand-and-receptor interactions is still inconclusive, and the modes of action and signaling cascade mediating the newly identified RAS receptors remain to be better characterized. Clinical data are obviously lacking behind the promising pre-clinical findings of certain well-established molecules targeting at different pathways of the RAS in respiratory diseases. Translational human studies should be the focus for RAS drug development in lung diseases in the next decade.

Myxoid glioneuronal tumor: Histopathologic, neuroradiologic, and molecular features in a single center series.

BACKGROUND: Myxoid glioneuronal tumor (MGT) is a benign glioneuronal neoplasm recently introduced in the World Health Organization (WHO) classification of the central nervous system (CNS) tumors. MGTs are typically located in the septum pellucidum, foramen of Monro or periventricular white matter of the lateral ventricle. They were previously diagnosed as dysembryoplastic neuroepithelial tumors (DNT), showing histological features almost indistinguishable from classical cortical DNT. Despite that, MGTs have been associated with a specific dinucleotide substitution at codon 385 in the platelet-derived growth factor receptor alpha (PDGFRA) gene, replacing a lysine residue with either leucine or isoleucine (p. LysK385Leu/Iso). This genetic variation has never been described in any other CNS tumor. MATERIALS AND METHODS: Thirty-one consecutive tumors, previously diagnosed as DNTs at the Meyer Children's Hospital IRCCS between January 2010 and June 2021 were collected for a comprehensive study of their clinical, imaging, pathological features, and molecular profile. RESULTS: In six out of the thirty-one tumors we had previously diagnosed as DNTs, we identified the recurrent dinucleotide mutation in the PDGFRA. All six tumors were typically located within the periventricular white matter of the lateral ventricle and in the septum pellucidum. We then renamed these lesions as MGT, according to the latest WHO CNS classification. In all patients we observed an indolent clinical course, without recurrence. CONCLUSION: MGT represent a rare but distinct group of neoplasm with a typical molecular profiling, a characteristic localization, and a relative indolent clinical course.

A peculiar family with recurrent self-limited epileptic syndrome and associated developmental disorders in six girls.

We describe a complex family with two couples (two sisters who married two brothers) with consistent social and neuropsychiatric problems, originally from Sardinia. Each couple had three daughters, which shared electroclinical epileptic syndrome and developmental disorders. All patients suffered from mild to moderate intellectual disability, speech difficulties and behavioural disorders. Four out of six patients had epilepsy onset between 3 and 4 years of age. The epileptic history almost reflected the typical clinical course of a self-Limited Focal Epilepsy of Childhood. However, our patients don't have the complete features characteristic of one of the four specific self-Limited Focal Epilepsies of Childhood; a progressive evolution into a Developmental and/or Epileptic Encephalopathy with spike-wave activation in sleep was observed in the two older sister of the first family, which developed more severe developmental disorder too. In the other epileptic patients, improvement of EEG pattern was not coincident with an improvement of the developmental disorders. Brain MRI, performed in three patients, showed normal findings. Genetic analysis carried out so far (SNP-array, study of Runs of homozygosity, FMR1 triplet-repeat primer-PCR assay, Next Generation Sequencing based gene panel for epilepsy and neurodevelopmental disorders and Exome Sequencing), did not provide useful elements for an aetiological diagnosis.

Clinical efficacy of autogenous dentin grafts with guided bone regeneration for horizontal ridge augmentation: a prospective observational study.

The aim of this study was to evaluate the efficacy of autogenous dentin grafts with guided bone regeneration (GBR) for horizontal ridge augmentation. Nineteen patients with dentition and bone defects in whom tooth/teeth extraction was indicated were recruited. Autogenous teeth were prepared, fixed on the buccal sides of the defects, and covered with bone powder and resorbable membranes before implantation. The horizontal bone mass at 0 mm (W1), 3 mm (W2), and 6 mm (W3) from the alveolar crest was recorded using cone beam computed tomography, before, immediately after, and 6 months after dentin grafting. All adverse effects were recorded. The implant stability quotient (ISQ) was measured 6 months after implantation. Twenty-eight implants were placed 6 months after dentin grafting. At this time point, the bone mass was 4.72 ± 0.72 mm (W1), 7.35 ± 1.57 mm (W2), and 8.96 ± 2.38 mm (W3), which was significantly different from that before the surgery (P < 0.05). The bone gain was 2.50 ± 0.72 mm (W1), 4.10 ± 1.42 mm (W2), and 4.56 ± 2.09 mm (W3). No soft tissue dehiscence or infection was observed. Overall, 26.3% of the patients experienced severe pain after dentin grafting. The ISQ was 78.31 ± 6.64 at 6 months after implantation. Autogenous tooth roots with GBR might be effective for horizontal ridge augmentation. This technique could be an alternative to augmentation using autogenous bone grafts.

[Peking Union Medical College Hospital and Its Training of Pharmaceutical Staff in the Republican Period].

Several training programs for the pharmacy staff in the Pharmacy Department of Beijing Union Medical College Hospital were implemented over 1910's to 1942, such as apprenticeships, prior courses on pharmaceutical sciences,vocational training, study overseas, and developing the Beiping Pharmacy Evening School in collaboration with the North China Pharmaceutical Society around the 1930's. These programs explored training models for the hospital, developed practical talent with competence ensuring the needs and requirements within the hospital, established practical education on pharmacy in Beiping and therefore contributed to promoting future pharmaceutical training systems in China.

Hepatitis B virus infection status is not associated with poor prognosis in classical Hodgkin lymphoma patients.

Few studies focused on the relationship between hepatitis B virus (HBV) infection and classical Hodgkin lymphoma (cHL). This study was to evaluate the impact of HBV infection on the treatment outcome and survival of cHL patients. Clinical data of 352 cHL patients treated with ABVD regimen (doxorubicin, bleomycin, vincristine and dacarbazine) between January 2002 and January 2018 were retrospectively collected. According to HBV infection status, the patients were divided into three groups: with HBV infection [hepatitis B surface antigen (HBsAg)-positive], with past HBV infection [HBsAg-negative but anti-hepatitis B core antigen (anti-HBc)-positive], and without HBV infection (HBsAg-negative and anti-HBc-negative). The incidence of HBV infection and past HBV infection in cHL patients were 7.4% (26/352) and 16.5% (58/352), respectively. The median age of patients without HBV infection was lower than those in other two groups (p<0.001). The complete remission rates after first-line therapy were different among 3 groups (65.4% for the group with HBV infection, 87.9% for the group with past HBV infection, and 76.1% for the group without HBV infection, respectively, p=0.049). After a median follow-up of 34.6 months, the 3-year progression-free survival rates for the three groups were 69%, 74% and 80%, respectively (p=0.566) and the 3-year overall survival rates were 72%, 91% and 87%, respectively (p=0.096). No HBV reactivation was observed during chemotherapy among 3 groups, but 1 patient in the group with HBV infection experienced delayed HBV reactivation when prophylactic entecavir was discontinued 12 months after the last cycle of chemotherapy. HBV infection status did not affect the clinical outcome and prognosis of cHL patients, especially in the era of prophylactic antiviral therapy.

[The prognosis value of comprehensive geriatric assessment in elder patients with acute myeloid leukemia in a single center].

Objective: To evaluate the prognostic significance of comprehensive geriatric assessment (CGA) in Chinese elderly acute myeloid leukemia (AML) patients. Methods: 73 AML patients over the age of 60 were enrolled. CGA stratification included the following 3 instrument assessment: activity of daily living (ADL) ; instrumental activity of daily living (IADL) ; comorbidity score according to the Modified cumulative illness rating score for geriatrics (MCIRS-G) . According to CGA and age, the enrolled patients were grouped into 'fit', 'unfit' and 'frail' categories. Results: The median age of 73 elderly AML patients were 75 years old. According to CGA, 37 (50.1%) patients were classified as 'fit', 14 (19.2%) as 'unfit', and 22 (30.7%) as 'frail'. 33 (89.2%) patients in fit group received induction chemotherapy, or demethylation treatment, as 8 (57.9%) in unfit, 10 (45.5%) in frail. The overall response rate was 68.7%、62.5%, 75.0% in fit, unfit, and frail group, respectively (χ(2)=0.615, P=0.769) .The early mortality (8 weeks) in three groups were different: 5.4%, 7.1%, 27.3%, respectively (P<0.05) . The 1-year overall survival in the 'fit', 'unfit' and 'frail' groups was 64.9%, 28.6% and 22.7%, respectively (P<0.05) . The CGA score, age, ECOG score, WHO classification (2016) were the prognostic factors of AML patients. Conclusion: CGA can be used to determine the prognosis of elderly AML patients.

The prognostic significance of macroscopic serosal change in subserosal invasion (stage T3) gastric cancer.

BACKGROUND: For patients with gastric cancer intraoperative macroscopic serosal change is not always consistent with pathological T stage. We investigated whether macroscopic serosal change is associated with unfavourable prognosis of patients with gastric cancer. METHODS: We reviewed 856 patients with stage T3 gastric cancer who underwent curative gastrectomy in our institution. All patients were classified as serosa negative and serosa positive according to the macroscopic serosal change during the operation. The prognostic difference between two groups was compared and clinicopathologic features were analysed. RESULTS: The percentage of macroscopic serosal change accounted for 55.7% of all patients. Compared with normal serosal surface, the patients with macroscopic serosal change had larger tumour size, more extensive stomach involvement and more advanced stage N. The prognosis of stage T3 with macroscopic serosal change was significantly poorer than that of those with normal serosal surface, especially for those with stages T3N0 and T3N1. Multivariate analysis identified macroscopic serosal change as an independent factor associated with unfavourable prognosis of stage T3 cancer. CONCLUSION: Although the depth of tumour invasion mainly depends on pathological evaluation after surgery, the prognostic significance of intraoperative macroscopic serosal change should not be ignored for those patients with subserosal invasion.

[A comparative study of comprehensive geriatric assessment in elder patients with non-Hodgkin's lymphoma].

Objective: To measure the comprehensive geriatric assessment (CGA) in elder non-Hodgkin's Lymphoma (NHL) patients in a cross-sectional study; to compare the differences between Eastern Cooperative Oncology Group (ECOG)-performance status (PS) and CGA. Methods: CGA stratification included the following 3 instrument assessments: activity of daily living (ADL);instrumental activity of daily living (IADL);comorbidity score according to the modified cumulative illness rating score for geriatrics (MCIRS-G). According to CGA and age, NHL patients, aged ≥60 years, were classified as"fit","unfit"and"frail"groups. ECOG-PS was evaluated and compared with CGA. Results: According to CGA, 51.6% senior NHL patients (33 cases) were classified as"fit", 12.5%(8 cases) as"unfit"and 35.9%(23 cases) as"frail". Several comorbidities were observed in majority patients, such as cardiovascular disease, diabetes mellitus and hypertension. In the"younger aged"patients between 60 to 64ys, 25%(3/12) was considered as"frail". However, this proportion increased to 42.9%(6/14) in patients older than 80ys. Moreover, impaired CGA was observed in 38.9%(21/54) of ECOG-PS ≤1 patient. Conclusions: Impaired CGA is as common as approximately half in elderly NHL patients and more than one third even in ECOG-PS ≤1 patients. ECOG-PS may underestimate the impaired fitness function in elder NHL patients.

Aggravated nausea and vomiting induced by fat emulsion for hyperemesis gravidarum: A case report.

WHAT IS KNOWN AND OBJECTIVE: Total parental nutrition (TPN) for hyperemesis gravidarum (HG) is generally effective and well-tolerated. We report a case of aggravated nausea and vomiting caused by fat emulsion. CASE DESCRIPTION: A 40-year-old pregnant woman through IVF was admitted to the hospital at 11-week gestation and diagnosed with HG. During TPN treatment, the patient suffered from aggravated nausea and vomiting. We identified fat emulsion as the most likely culprit using challenge, dechallenge and rechallenge. WHAT IS NEW AND CONCLUSION: This is the first report of fat emulsion aggravating nausea and vomiting in such situation.

Discrete breathers in a mass-in-mass chain with Hertzian local resonators.

We report on the existence of discrete breathers in a one-dimensional, mass-in-mass chain with linear intersite coupling and nonlinear, precompressed Hertzian local resonators, which is motivated by recent studies of the dynamics of microspheres adhered to elastic substrates. After predicting theoretically the existence of discrete breathers in the continuum and anticontinuum limits of intersite coupling, we use numerical continuation to compute a family of breathers interpolating between the two regimes in a finite chain, where the displacement profiles of the breathers are localized around one lattice site. We then analyze the frequency-amplitude dependence of the breathers by performing numerical continuation on a linear eigenmode (vanishing amplitude) solution of the system near the upper band gap edge. Finally, we use direct numerical integration of the equations of motion to demonstrate the formation and evolution of the identified localized modes in energy-conserving and dissipative scenarios, including within settings that may be relevant to future experimental studies.

Expression divergence of FRUITFULL homeologs enhanced pod shatter resistance in Brassica napus.

To improve pod shatter resistance in the important oilseed crop Brassica napus, the phenotypic diversity of B. napus was tested using 80 B. napus varieties for pod shatter resistance by a random impact test. Among these varieties, R1-1 was identified as resistant, while R2, 8908B was susceptible to shatter. To understand the molecular basis for this phenotypic difference based on the candidate gene approach, B. napus FRUITFULL (FUL) homologs were identified and characterized. Two FUL loci in the A and C genomes of B. napus were identified. In the susceptible variety, both BnaA.FUL and BnaC.FUL were expressed in the same tissues. However, the expression level of BnaC.FUL differed in varieties with different pod shatter resistance. In the most resistant variety, R1-1, only BnaA.FUL was expressed, while BnaC.FUL was silenced. Therefore, the functional divergence and differing expression of BnaX.FUL homeologs may significantly affect phenotypic variation, which is an important consequence of allopolyploid evolution. This expression level divergence may be useful for selecting pod shatter resistant lines through marker-assisted selection in B. napus-breeding programs.

Focal dysplasia of the cerebral cortex and infantile spasms associated with somatic 1q21.1-q44 duplication including the AKT3 gene.

Somatic and germline duplications or activating mutations of AKT3 have been reported in patients with hemimegalencephaly and megalencephaly. We performed array comparative genomic hybridization on brain tissue and blood in 16 consecutive patients with symptomatic epilepsy due to focal or multilobar malformations of cortical development who underwent surgical treatment of epilepsy. One patient with infantile spasms and a dysplastic left frontal lobe harboured a somatic trisomy of the 1q21.1-q44 chromosomal region, encompassing the AKT3 gene, in the dysplastic brain tissue but not in blood and saliva. Histopathology revealed severe cortical dyslamination, a thin cortex in the premotor area with microgyri and microsulci, immature neurons with disoriented dendrites and areas of cortical heterotopia in the sub-cortical white matter. These cytoarchitectural changes are close to those defining type Ib focal cortical dysplasia. Immunohistochemistry in brain specimens showed hyperactivation of the PI3K/AKT/mTOR pathway. These findings indicate that AKT3 upregulation may cause focal malformations of cortical development. There appears to be an etiologic continuum between hemimegalencephaly and focal cortical dysplastic lesions. The extent of brain malformations due to AKT3 upregulation may be related to the embryonic stage when the post-zygotic gene alteration occurs.

Bilateral cavitations of ganglionic eminence: a fetal MR imaging sign of halted brain development.

SUMMARY: Ganglionic eminence is the main transitory proliferative structure of the ventral telencephalon in human fetal brain and it contributes for at least 35% to the population of cortical interneurons; however data on the human GE anomalies are scarce. We report 5 fetal MR imaging observations with bilateral symmetric cavitations in their GE regions resembling an inverted open C shape and separating the GE itself form the deeper parenchyma. Imaging, neuropathology, and follow-up features suggested a malformative origin. All cases had in common characteristics of lissencephaly with agenesis or severe hypoplasia of corpus callosum of probable different genetic basis. From our preliminary observation, it seems that GE cavitations are part of conditions which are also accompanied by severe cerebral structure derangement.

First detection of multiple knockdown resistance (kdr)-like mutations in voltage-gated sodium channel using three new genotyping methods in Anopheles sinensis from Guangxi Province, China.

To investigate knockdown resistance (kdr)-like mutations associated with pyrethroid resistance in Anopheles sinensis (Wiedemann, 1828), from Guangxi province, southwest China, a segment of a sodium channel gene was sequenced and genotyped using three new genotyping assays. Direct sequencing revealed the presence of TTG-to-TCG and TG-to-TTT mutations at allele position L1014, which led to L1014S and L1014F substitutions in a few individual and two novel substitutions of N1013S and L1014W in two DNA templates. A low frequency of the kdr allele mostly in the heterozygous state of L1014S and L1014F was observed in this mosquito population. In this study, the genotyping of An. sinensis using three polymerase chain reaction-based methods generated consistent results, which agreed with the results of DNA sequencing. In total, 52 mosquitoes were genotyped using a direct sequencing assay. The number of mosquitoes and their genotypes were as follows: L/L = 24, L/S = 19, L/F = 8, and F/W = 1. The allelic frequency of L1014, 1014S, and 1014F were 72, 18, and 9%, respectively.

FLNA genomic rearrangements cause periventricular nodular heterotopia.

OBJECTIVE: To identify copy number variant (CNV) causes of periventricular nodular heterotopia (PNH) in patients for whom FLNA sequencing is negative. METHODS: Screening of 35 patients from 33 pedigrees on an Affymetrix 6.0 microarray led to the identification of one individual bearing a CNV that disrupted FLNA. FLNA-disrupting CNVs were also isolated in 2 other individuals by multiplex ligation probe amplification. These 3 cases were further characterized by high-resolution oligo array comparative genomic hybridization (CGH), and the precise junctional breakpoints of the rearrangements were identified by PCR amplification and sequencing. RESULTS: We report 3 cases of PNH caused by nonrecurrent genomic rearrangements that disrupt one copy of FLNA. The first individual carried a 113-kb deletion that removes all but the first exon of FLNA. A second patient harbored a complex rearrangement including a deletion of the 3' end of FLNA accompanied by a partial duplication event. A third patient bore a 39-kb deletion encompassing all of FLNA and the neighboring gene EMD. High-resolution oligo array CGH of the FLNA locus suggests distinct molecular mechanisms for each of these rearrangements, and implicates nearby low copy repeats in their pathogenesis. CONCLUSIONS: These results demonstrate that FLNA is prone to pathogenic rearrangements, and highlight the importance of screening for CNVs in individuals with PNH lacking FLNA point mutations.

Protocadherin 19 mutations in girls with infantile-onset epilepsy.

OBJECTIVE: To explore the causative role of PCDH19 gene (Xq22) in female patients with epilepsy. METHODS: We studied a cohort of 117 female patients with febrile seizures (FS) and a wide spectrum of epilepsy phenotypes including focal and generalized forms with either sporadic or familial distribution. RESULTS: PCDH19 screening showed point mutations in 13 probands (11%). Mean age at seizure onset was 8.5 months; 8 patients (62%) presented with FS, 4 (33%) with cluster of focal seizures, and 1 with de novo status epilepticus (SE). Subsequent seizure types included afebrile tonic-clonic, febrile, and afebrile SE, absences, myoclonic, and focal seizures. Seven patients (54%) had a clinical diagnosis consistent with Dravet syndrome (DS); 6 (46%) had focal epilepsy. In most patients, seizures were particularly frequent at onset, manifesting in clusters and becoming less frequent with age. Mental retardation was present in 11 patients, ranging from mild (7; 64%) to moderate (1; 9%) to severe (3; 27%). Five patients (38%) had autistic features in association to mental retardation. Mutations were missense (6), truncating (2), frameshift (3), and splicing (2). Eleven were new mutations. Mutations were inherited in 3 probands (25%): 2 from apparently unaffected fathers and 1 from a mother who had had generalized epilepsy. CONCLUSIONS: PCDH19 is emerging as a major gene for infantile-onset familial or sporadic epilepsy in female patients with or without mental retardation. In our cohort, epileptic encephalopathy with DS-like features and focal epilepsy of variable severity were the associated phenotypes and were equally represented.