Peripheral Neuropathy and Decreased Locomotion of a RAB40B Mutation in Human and Model Animals

Rab40 proteins are an atypical subgroup of Rab GTPases containing a unique suppressor of the cytokine signaling (SOCS) domain that is recruited to assemble the CRL5 E3 ligase complex for proteolytic regulation in various biological processes. A nonsense mutation deleting the C-terminal SOCS box in the RAB40B gene was identified in a family with axonal peripheral neuropathy (Charcot-Marie-Tooth disease type 2), and pathogenicity of the mutation was assessed in model organisms of zebrafish and Drosophila. Compared to control fish, zebrafish larvae transformed by the human mutant hRAB40B-Y83X showed a defective swimming pattern of stalling with restricted localization and slower motility. We were consistently able to observe reduced labeling of synaptic markers along neuromuscular junctions of the transformed larvae. In addition to the neurodevelopmental phenotypes, compared to normal hRAB40B expression, we further examined ectopic expression of hRAB40B-Y83X in Drosophila to show a progressive decline of locomotion ability. Decreased ability of locomotion by ubiquitous expression of the human mutation was reproduced not with GAL4 drivers for neuron-specific expression but only when a pan-glial GAL4 driver was applied. Using the ectopic expression model of Drosophila, we identified a genetic interaction in which Cul5 down regulation exacerbated the defective motor performance, showing a consistent loss of SOCS box of the pathogenic RAB40B. Taken together, we could assess the possible gain-of-function of the human RAB40B mutation by comparing behavioral phenotypes in animal models; our results suggest that the mutant phenotypes may be associated with CRL5-mediated proteolytic regulation.

Empathy With Patients and Post-Traumatic Stress Response in Verbally Abused Healthcare Workers

Objective@#The current study examined the differential empathic capacity, post-traumatic symptoms, and coping strategies in healthcare workers (HCWs) according to the exposure of verbal or physical workplace violence (WPV). @*Methods@#Using online survey, a total of 422 HCWs employed at a training general hospital of South Korea participated and completed self-reporting questionnaires including the WPV questionnaire with coping strategy, the Jefferson Scale of Physician Empathy. @*Results@#Those who experienced either only verbal violence or both physical and verbal violence had lower Jefferson Scale of Physician Empathy scores (p<0.05). Posttraumatic stress symptom severity was higher among people who experienced verbal violence than physical violence. HCWs’ exposure to verbal violence was associated with severe posttraumatic symptoms and a low level of empathy with patients (p<0.05). More than half of the victims of verbal violence responded that they did not take any action, receive organizational protection, or peer support, while most physically-abused HCWs received institutional intervention or help from others. @*Conclusion@#Our findings highlight the critical importance of reducing verbal violence, which may represent a larger psychological burden compared to physical violence, by actively implementing effective strategies and policies at the institutional level.

Different Influence of Negative and Positive Spillover between Work and Life on Depression in a Longitudinal Study

Background@#This study investigated the longitudinal associations between the degrees of positive and negative spillover in work–life balance (WLB) at baseline and reports of depressive mood at a 2-year follow-up in Korean women employees. @*Methods@#We used a panel study design data of 1386 women employees who participated in the Korean Longitudinal Survey of Women and Families in both 2014 and 2016. Depressive mood was measured using the “10-item Center for Epidemiologic Studies Depression Scale.” Associations between the positive and negative spillover in WLB at baseline and reports of new incidence of depressive mood at 2-year follow-up were explored using a multivariate logistic regression model. @*Results@#Negative spillover in WLB at baseline showed a significant linear association with reports of depressive mood at 2-yearfollow-up after adjusting for age, education level, marital status, number of children, and positive spillover (P = 0.014). The highest scoring group in negative spillover (fourth quartile) showed a significant higher odds ratio of 1.95 compared with the lowest scoring group (first quartile; P = 0.036). @*Conclusion@#Positive spillover in WLB showed a U-shaped association with depression. The degrees of positive and negative spillover in WLB among Korean women employees at baseline were associated with new incidence of depressive mood within 2 years. To prevent depression of female workers, more discrete and differentiated policies on how to maintain healthy WLB are required.

Clinical and Neuroimaging Features in Charcot-Marie-Tooth Patients with GDAP1 Mutations

Background@#and Purpose Mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) are known to cause Charcot-Marie-Tooth disease (CMT). These mutations are very rare in most countries, but not in certain Mediterranean countries. The purpose of this study was to identify the clinical and neuroimaging characteristics of Korean CMT patients with GDAP1 mutations. @*Methods@#Gene sequencing was applied to 1,143 families in whom CMT had been diagnosed from 2005 to 2020. PMP22 duplication was found in 344 families, and whole-exome sequencing was performed in 699 patients. Magnetic resonance imaging (MRI) were obtained using either a 1.5-T or 3.0-T MRI system. @*Results@#We found ten patients from eight families with GDAP1 mutations: five with autosomal dominant (AD) CMT type 2K (three families with p.R120W and two families with p.Q218E) and three with autosomal recessive (AR) intermediate CMT type A (two families with homozygous p.H256R and one family with p.P111H and p.V219G mutations). The frequency was about 1.0% exclusive of the PMP22 duplication, which is similar to that in other Asian countries. There were clinical differences among AD GDAP1 patients according to mutation sites. Surprisingly, fat infiltrations evident in lower-limb MRI differed between AD and AR patients. The posterior-compartment muscles in the calf were affected early and predominantly in AD patients, whereas AR patients showed fat infiltration predominantly in the anterolateral-compartment muscles. @*Conclusions@#This is the first cohort report on Korean patients with GDAP1 mutations. The patients with AD and AR inheritance routes exhibited different clinical and neuroimaging features in the lower extremities. We believe that these results will help to expand the knowledge of the clinical, genetic, and neuroimaging features of CMT.

Empathy With Patients and Post-Traumatic Stress Response in Verbally Abused Healthcare Workers

Objective@#The current study examined the differential empathic capacity, post-traumatic symptoms, and coping strategies in healthcare workers (HCWs) according to the exposure of verbal or physical workplace violence (WPV). @*Methods@#Using online survey, a total of 422 HCWs employed at a training general hospital of South Korea participated and completed self-reporting questionnaires including the WPV questionnaire with coping strategy, the Jefferson Scale of Physician Empathy. @*Results@#Those who experienced either only verbal violence or both physical and verbal violence had lower Jefferson Scale of Physician Empathy scores (p<0.05). Posttraumatic stress symptom severity was higher among people who experienced verbal violence than physical violence. HCWs’ exposure to verbal violence was associated with severe posttraumatic symptoms and a low level of empathy with patients (p<0.05). More than half of the victims of verbal violence responded that they did not take any action, receive organizational protection, or peer support, while most physically-abused HCWs received institutional intervention or help from others. @*Conclusion@#Our findings highlight the critical importance of reducing verbal violence, which may represent a larger psychological burden compared to physical violence, by actively implementing effective strategies and policies at the institutional level.

Different Influence of Negative and Positive Spillover between Work and Life on Depression in a Longitudinal Study

Background@#This study investigated the longitudinal associations between the degrees of positive and negative spillover in work–life balance (WLB) at baseline and reports of depressive mood at a 2-year follow-up in Korean women employees. @*Methods@#We used a panel study design data of 1386 women employees who participated in the Korean Longitudinal Survey of Women and Families in both 2014 and 2016. Depressive mood was measured using the “10-item Center for Epidemiologic Studies Depression Scale.” Associations between the positive and negative spillover in WLB at baseline and reports of new incidence of depressive mood at 2-year follow-up were explored using a multivariate logistic regression model. @*Results@#Negative spillover in WLB at baseline showed a significant linear association with reports of depressive mood at 2-yearfollow-up after adjusting for age, education level, marital status, number of children, and positive spillover (P = 0.014). The highest scoring group in negative spillover (fourth quartile) showed a significant higher odds ratio of 1.95 compared with the lowest scoring group (first quartile; P = 0.036). @*Conclusion@#Positive spillover in WLB showed a U-shaped association with depression. The degrees of positive and negative spillover in WLB among Korean women employees at baseline were associated with new incidence of depressive mood within 2 years. To prevent depression of female workers, more discrete and differentiated policies on how to maintain healthy WLB are required.

Identification of causative mutations in patients with Leigh syndrome and MERRF by mitochondrial DNA-targeted next-generation sequencing

PURPOSE: Mitochondrial diseases are clinically and genetically heterogeneous disorders, which make their exact diagnosis and classification difficult. The purpose of this study was to identify pathogenic mitochondrial DNA (mtDNA) mutations in 2 Korean families with myoclonic epilepsy with ragged-red fibers (MERRF) and Leigh syndrome, respectively. MATERIALS AND METHODS: Whole mtDNAs were sequenced by the method of mtDNA-targeted next-generation sequencing (NGS). RESULTS: Two causative mtDNA mutations were identified from the NGS data. An m.8344A>G mutation in the tRNA-Lys gene (MT-TK ) was detected in a MERRF patient (family ID: MT132), and an m.9176T>C (p.Leu217Pro) mutation in the mitochondrial ATP6 gene (MT-ATP6) was detected in a Leigh syndrome patient (family ID: MT130). Both mutations, which have been reported several times before in affected individuals, were not found in the control samples. CONCLUSION: This study suggests that mtDNA-targeted NGS will be helpful for the molecular diagnosis of genetically heterogeneous mitochondrial diseases with complex phenotypes.

Novel Compound Heterozygous Nonsense PRX Mutations in a Korean Dejerine-Sottas Neuropathy Family

BACKGROUND: Mutations in the gene encoding periaxin (PRX) are known to cause autosomal recessive Dejerine-Sottas neuropathy (DSN) or Charcot-Marie-Tooth disease type 4F. However, there have been no reports describing Korean patients with these mutations. CASE REPORT: We examined a Korean DSN patient with an early-onset, slowly progressive, demyelinating neuropathy with prominent sensory involvement. Whole-exome sequencing and subsequent capillary sequencing revealed novel compound heterozygous nonsense mutations (p.R392X and p.R679X) in PRX. One mutation was transmitted from each of the patient's parents. No unaffected family member had both mutations, and the mutations were not found in healthy controls. CONCLUSIONS: We believe that these novel compound heterozygous nonsense mutations are the underlying cause of DSN. The clinical, electrophysiologic, and pathologic phenotypes in this family were similar to those described previously for patients with PRX mutations. We have identified the first PRX mutation in a Korean patient with DSN.

Exome Sequencing Reveals a Novel PRPS1 Mutation in a Family with CMTX5 without Optic Atrophy

BACKGROUND: X-linked Charcot-Marie-Tooth disease type 5 (CMTX5) is caused by mutations in the gene encoding phosphoribosyl pyrophosphate synthetase I (PRPS1). There has been only one case report of CMTX5 patients. The aim of this study was to identify the causative gene in a family with CMTX with peripheral neuropathy and deafness. CASE REPORT: A Korean family with X-linked recessive CMT was enrolled. The age at the onset of hearing loss of the male proband was 5 months, and that of steppage gait was 6 years; he underwent cochlear surgery at the age of 12 years. In contrast to what was reported for the first patients with CMTX5, this patient did not exhibit optic atrophy. Furthermore, there was no cognitive impairment, respiratory dysfunction, or visual disturbance. Assessment of his family history revealed two male relatives with very similar clinical manifestations. Electrophysiological evaluations disclosed sensorineural hearing loss and peripheral neuropathy. Whole-exome sequencing identified a novel p.Ala121Gly (c.362C>G) PRPS1 mutation as the underlying genetic cause of the clinical phenotype. CONCLUSIONS: A novel mutation of PRPS1 was identified in a CMTX5 family in which the proband had a phenotype of peripheral neuropathy with early-onset hearing loss, but no optic atrophy. The findings of this study will expand the clinical spectrum of X-linked recessive CMT and will be useful for the molecular diagnosis of clinically heterogeneous peripheral neuropathies.

Pregnancy Outcome of Cervical Incompetence in Twin Versus Singleton Pregnancies / 대한주산의학회잡지

OBJECTIVE: The aim of this study was to compare the incidence and clinical features of cervical incompetence between singleton and twin pregnancies in women with newly diagnosed cervical incompetence. METHODS: We retrospectively reviewed the medical records of 64 women who were diagnosed with cervical incompetence for the first time during pregnancy and delivered between 1994 and 2004. Cervical incompetence was defined by the presence of painless cervical dilatation during mid-trimester with either bulging amniotic membranes through the external cervical os or shortened cervical length (<2 cm) with funneling on transvaginal ultrasound. RESULTS: The incidence of cervical incompetence which was diagnosed for the first time during pregnancy was 0.16% (54/33, 176) in singleton pregnancies and 1.23% (10/813) in twin pregnancies. Multiparity or a history of preterm delivery was more common in the singleton compared to the twin pregnancies. The median gestational age at diagnosis was similar in the two groups. In the patients who had undergone emergent cerclage, twin pregnancies had more advanced cervical dilatation [median (range); 3.0 (2.0~5.0) vs. 2.0 (1.0~4.0) cm, p<0.05] and effacement [median (range); 75 (50~100) vs. 50 (10~100) %, p<0.05] compared to the singleton pregnancies. After emergent cerclage, gestational age at delivery was earlier in the twin pregnancies [median (range); 24.8 (23.1~30.6) vs. 35.3 (16.4~41.1) weeks, p<0.05] than in the singleton pregnancies. CONCLUSION: The incidence of cervical incompetence in twin pregnancies was seven times greater than in singleton pregnancies. Although the onset of cervical incompetence was not different in the groups, prolongation of pregnancy, after emergent cerclage, was less likely in the twin pregnancies compared to singleton pregnancies, due to a more advanced cervical change at the time of diagnosis.

Comparison of pregnancy outcomes based on chorionicity between spontaneous and in vitro fertilization twins / 대한산부인과학회지

OBJECTIVE: To compare the pregnancy outcomes of in vitro fertilization (IVF) twins with those of spontaneous twins based on their chorionicities. METHODS: We performed a retrospective analysis of 598 twin pregnancies beyond 24 weeks of gestation delivered from October 1994 to December 2003. Subjects were grouped into the spontaneous group (n=392) and the IVF group (n=206) and then subgrouped into dichorionic (n=193, spontaneous vs. n=156, IVF) and monochorionic (n=154, spontaneous vs. n=34, IVF) subgroups. First, the obstetric and perinatal outcomes were compared between the spontaneous group and the IVF group regardless of their chorionicity. Second, the same outcome variables were compared between the spontaneous and the IVF group with same chorionicity. RESULTS: There was a significant increase in the incidence of preterm deliveries before 37 weeks of gestation in IVF twins (74.5% spontaneous vs. 82.5% IVF, p=0.031). However, the gestational age at delivery was not significantly different (34.5+/-2.86 weeks vs. 34.2+/-0.28 weeks). Antepartum admission was also significantly increased in IVF group (4.6% vs. 9.2%, p<0.001). We were unable to observe any significant difference in perinatal outcomes between the two groups other than increased in utero fetal demise in utero in the IVF group (0.3% vs. 1.5%, p<0.05). When we reanalyzed pregnancy outcomes based on chorionicity, there were more frequent admission to neonatal intensive care unit (42.7% vs. 52.6%, p<0.05) and necrotizing enterocolitis (0.5% vs. 3.5%, p<0.05) in dichorionic twins of the IVF group. In monochorionic twins, the incidence of placenta previa was increased in the IVF twin group (0% vs. 11.8%, p<0.001). CONCLUSION: In the IVF twins, the incidence of placenta previa was increased in monochrionic twins and the incidence of neonatal intensive care unit admission and necrotizing enterocolitis were also increased in dichorionic twins.

A comparison of laparoscopically-assisted radical vaginal hysterectomy and radical abdominal hysterectomy in the treatment of cervical cancer / 부인종양

OBJECTIVE: The aim of this study was to compare peri-operative morbidity and safety of patients treated by laparoscopically-assisted radical vaginal hysterectomy (LARVH)with laparoscopic pelvic lymphadenectomy (LPL)and radical abdominal hysterectomy (RAH)with pelvic lymph node dissection (PLND) in early stage of cervical cancer. METHODS: Since September 2004,all patients with FIGO stage Ia-IIa cervical cancer undergoing radical surgery by members of our division have been entered into a prospective database. Two surgeons at our center have performed LARVH by Schneider method on all surgically appropriate patients. RESULTS: Between September 2004 and May 2005, 26 patients were performed LARVH with LPL,30 patients were performed RAH with PLND. There were no differences in estimated blood loss, the number of lymph nodes, duration of hospital stay and postoperative complications.But operative time was significantly prolonged in LARVH group. Intraoperative complications in the LARVH with LPL group included: bladder injuries(2), shift to laparotomy due to ureter injury(1). There was one case of vesicovaginal fistula in the RAH group. CONCLUSION: LARVH with LPL in early stage of cervical cancer is a safe and technically effective alternative to RAH. Despite the inherent limitations of LARVH with LPL and its associated learning curve, the procedure conveys many advantages over the open laparotomy technics in terms of postoperative wound pain and recovery. However further study is needed to evaluate long-term recurrence rate and survival rate.