Tick-Borne Rickettsiosis and Tsutsugamushi Disease Recorded in 313.

Tsutsugamushi disease was first described in China by Hong Ge in 313. In his book Zhouhou Beiji Fang, three eschar-associated febrile diseases were described: Shashidu, Zhongxidu, and Shegongdu. Shashidu was identified as being identical to tsutsugamushi disease in Japan: it occurred in riverside areas, exhibited an eschar, and was transmitted by tiny red "sand lice". The nature of Zhongxidu remains unknown, but we propose that it is another type of Orientia tsutsugamushi infection: it occurred in mountainous areas, an eschar was observed, and the causative vector was not identified. Moreover, Zhongxidu would have predated Shashidu by five centuries; thus, the first documentation of tsutsugamushi disease would date back 2.2 millennia. O. tsutsugamushi infection without eschar has not been identified in ancient Chinese literature and may be included in Shanghan. Several ancient Chinese books describe that Shegongdu occurs following a Shegong bite. Shegong is described as a bug resembling a cockroach or cicada with a crossbow-like structure, possibly the hypostome and unfolded palps of tick, in its mouth. Thus, Shegong refers to an engorged tick and Shegongdu is a tick-borne rickettsiosis. However, due to a lack of entomological knowledge, these findings have not been recognized for the past 1.7 millennia.

Early outcomes of single-port robotic left lateral sectionectomy in patients with hepatic tumor.

Purpose: Laparoscopic left lateral sectionectomy (L-LLS) stands as a cornerstone procedure in hepatobiliary minimal surgery, frequently employed for various benign and malignant liver lesions. This study aimed to analyze the peri- and postoperative surgical outcomes of single-port robotic left lateral sectionectomy (SPR-LLS) vs. those of L-LLS in patients with hepatic tumors. Methods: From January 2020 through June 2023, 12 patients underwent SPR-LLS. During the same period, 30 L-LLS procedures were performed. In total, 12 patients in the robotic group and 24 patients in the laparoscopic group were matched. Results: When the SPR-LLS and L-LLS groups were compared, the operation time was longer in the SPR-LLS group with less blood loss and shorter hospital stay. Postoperative complications were observed in 3 patients in the L-LLS group (12.5%) and 1 patient in the SPR-LLS group (8.3%). Conclusion: SPR-LLS using the da Vinci SP system was comparable to laparoscopic LLS in terms of surgical outcomes. SPR-LLS was associated with lower blood loss and less postoperative length of stay compared to L-LLS. These findings suggest that left lateral sectionectomy is technically feasible and safe with the da Vinci SP system in select patients.

Adult re-expression of IRSp53 rescues NMDA receptor function and social behavior in IRSp53-mutant mice.

IRSp53 (or BAIAP2) is an abundant excitatory postsynaptic scaffolding/adaptor protein that is involved in actin regulation and has been implicated in autism spectrum disorders, schizophrenia, and attention-deficit/hyperactivity disorder. IRSp53 deletion in mice leads to enhanced NMDA receptor (NMDAR) function and social deficits that are responsive to NMDAR inhibition. However, it remains unclear whether IRSp53 re-expression in the adult IRSp53-mutant mouse brain after the completion of brain development could reverse these synaptic and behavioral dysfunctions. Here we employed a brain-blood barrier (BBB)-penetrant adeno-associated virus (AAV) known as PHP.eB to drive adult IRSp53 re-expression in IRSp53-mutant mice. The adult IRSp53 re-expression normalized social deficits without affecting hyperactivity or anxiety-like behavior. In addition, adult IRSp53 re-expression normalized NMDAR-mediated excitatory synaptic transmission in the medial prefrontal cortex. Our results suggest that adult IRSp53 re-expression can normalize synaptic and behavioral deficits in IRSp53-mutant mice and that BBB-penetrant adult gene re-expression has therapeutic potential.

Buerger's Disease May be a Chronic Rickettsial Infection with Superimposed Thrombosis: Literature Review and Efficacy of Doxycycline in Three Patients.

Buerger's disease (BD) is a chronic inflammatory vasculitis of unknown etiology. The infectious etiology of BD was proposed by Buerger in 1914. Furthermore, there are scattered reports insisting that BD may be related to rickettsial infection, first asserted by Goodman since 1916, followed by Giroud and other French investigators from the 1940s through the 1960s, Nicolau in the 1960s, Bartolo (1980s), and Fazeli (2010s). However, their causal relationship has hardly been accepted because rickettsial infections are known to be acute febrile, vector-borne illnesses, whereas BD is a chronic afebrile illness. In this article we review the relevant literature on the chronic nature of Rickettsia and Orientia infections and on the rickettsial etiology of BD. Excellent initial responses to doxycycline in three patients with BD are briefly described. Based on these findings, we hypothesize that BD patients acquired a rickettsial infection far before the onset of BD. Over years, the infected area expands to become a segment of the infected vessel. Subsequently, thrombus develops on the luminal surface of the infected endothelial cells, which produces the vascular obstructive manifestations of BD. Collectively, it is postulated that BD is a chronic infection with a member of the family Rickettsiaceae with superimposed thrombosis.

Preoperative carbohydrate antigen 19-9 and standard uptake value of positron emission tomography-computed tomography as prognostic markers in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: Among various prognostic factors of pancreatic cancer, preoperative clinical information is obtained by imaging modality. This study aimed to evaluate clinical usefulness of preoperative carbohydrate antigen and preoperative standard uptake value in 18F-fluorodeoxyglucose positron emission tomography as predictive biological markers for resectable pancreatic ductal adenocarcinoma. METHODS: A total of 189 patients with PDAC who underwent preoperative PET-computed tomography were evaluated. Patients underwent neoadjuvant chemotherapy, and R2 resection was excluded. The correlation between SUVmax and clinicopathologic parameters was analyzed. The C-tree statistical method was used to estimate cutoff values of logCA19-9 and SUVmax for survival rate. A multivariate analysis was conducted to identify prognostic factors for overall survival. RESULTS: The median duration of OS was 26 months, and the 5-year survival rate was 22.4%. The optimal cutoff values for CA19-9 level was 150 U/mL and SUVmax was 5.5. When subjects were divided into three groups according to the combination of CA19-9 level and SUVmax from C-tree (high-risk group, CA19-9 > 150 U/mL and SUVmax > 5.5; intermediate-risk group, CA19-9 ≤ 150 U/mL and SUVmax > 5.5 or CA19-9 > 150 U/mL and SUVmax ≤ 5.5; and low-risk group, CA19-9 ≤ 150 U/mL and SUVmax ≤ 5.5), there was a significant 5YSR difference (5.6%, 24.3%, and 36.5%, P < .001). The multivariate analysis revealed high SUVmax, high preoperative CA19-9 level, venous invasion, and adjuvant chemotherapy were prognostic factors of OS. CONCLUSIONS: CA19-9 and SUVmax are strong prognostic biological factors in resectable PDAC. Moreover, patients with high CA19-9 level and SUVmax are not indicated for upfront surgery.

Clinical characteristics of patients with malignancy and long-term outcomes of surgical treatment of patients with choledochal cyst.

PURPOSE: There are few reports of postoperative long-term malignant risk or postoperative sequelae after surgery for choledochal cysts (CCs). This study aimed to analyze the clinical characteristics of patients with malignancy and the long-term results of operated CC. METHODS: The patients who underwent surgical treatments for CC between 2003 and 2020 at Seoul National University Hospital were enrolled. Clinicopathologic factors and pre-/postoperative computed tomography or magnetic resonance imaging were reviewed. RESULTS: Of the 153 patients, Todani classification Ic (36.6%), C-P type (43.8%) anomalous pancreaticobiliary duct union were the most common type respectively. Fourteen patients (9.2%) had biliary tract cancer and a comparison of patients with and without malignancy showed that the diameter of cyst was significantly lower in malignant patients and malignancy was observed to be significantly higher in P-C type. The incidence of long-term complications was 9.8%, and the median time interval was 30 months. The 2 most common complications were cholangitis and stricture (60.0%). There was one case of new cancer near the intrapancreatic remnant bile duct. CONCLUSION: Of the resected CCs, 9.2% had a combined malignancy on the biliary tracts. Long-term complications such as cholangitis, anastomotic stricture, and new cancers may occur. Therefore, continuous surveillance is required.

Association of vitreous vitamin C depletion with diabetic macular ischemia in proliferative diabetic retinopathy.

PURPOSE: Vitreous vitamin C, as an anti-oxidant, is responsible for regulating oxygen tension and oxidative stress in the eye. Oxidative stress and retinal ischemia are implicated in the development of proliferative diabetic retinopathy (PDR). In this study, we aimed to determine whether vitreous level of vitamin C is compromised in patients with PDR and to investigate the association of diabetic macular ischemia and vitamin C. METHODS: This prospective study enrolled forty patients who underwent pars plana vitrectomy for the treatment of PDR (PDR group, n = 20) and idiopathic epiretinal membrane (control group, n = 20). Serum, aqueous humor, and the vitreous were collected for the analysis of vitamin C level by HPLC. Diabetic macular ischemia (DMI) in PDR group was evaluated with fluorescein angiography (FA). RESULTS: PDR patients (60.4 ± 2.1 y) were younger than non-diabetic control patients (67.4 ± 1.2 y). Serum, aqueous, and vitreous levels of vitamin C in PDR were 38.7%, 22.5%, and 11.1% of non-diabetic control group, respectively. All PDR patients had DMI (grade 1: 25%, grade 2: 30%, grade 3: 30%, grade 4: 15%). DMI grade was inversely correlated with the level of vitreous vitamin C (r = -0.546, P = 0.019), not with HbA1C, serum, or aqueous vitamin C level. In addition, the level of vitreous vitamin C (4.5 ± 2.6 µg/ml) in high DMI group (Gr 3 &4) was lower than that (31.0 ± 9.1 µg/ml) in low DMI group (Gr 1&2) (P = 0.015). CONCLUSIONS: Vitreous level of vitamin C in PDR patients showed a tenfold decrease, which was associated with the degree of macular ischemia. This suggests that vitreous vitamin C depletion may cause macula ischemia in PDR patients.

Sexually dimorphic behavior, neuronal activity, and gene expression in Chd8-mutant mice.

Autism spectrum disorders (ASDs) are four times more common in males than in females, but the underlying mechanisms are poorly understood. We characterized sexually dimorphic changes in mice carrying a heterozygous mutation in Chd8 (Chd8+/N2373K) that was first identified in human CHD8 (Asn2373LysfsX2), a strong ASD-risk gene that encodes a chromatin remodeler. Notably, although male mutant mice displayed a range of abnormal behaviors during pup, juvenile, and adult stages, including enhanced mother-seeking ultrasonic vocalization, enhanced attachment to reunited mothers, and isolation-induced self-grooming, their female counterparts do not. This behavioral divergence was associated with sexually dimorphic changes in neuronal activity, synaptic transmission, and transcriptomic profiles. Specifically, female mice displayed suppressed baseline neuronal excitation, enhanced inhibitory synaptic transmission and neuronal firing, and increased expression of genes associated with extracellular vesicles and the extracellular matrix. Our results suggest that a human CHD8 mutation leads to sexually dimorphic changes ranging from transcription to behavior in mice.

NGL-2 Deletion Leads to Autistic-like Behaviors Responsive to NMDAR Modulation.

Netrin-G ligand 2 (NGL-2)/LRRC4, implicated in autism spectrum disorders and schizophrenia, is a leucine-rich repeat-containing postsynaptic adhesion molecule that interacts intracellularly with the excitatory postsynaptic scaffolding protein PSD-95 and trans-synaptically with the presynaptic adhesion molecule netrin-G2. Functionally, NGL-2 regulates excitatory synapse development and synaptic transmission. However, whether it regulates synaptic plasticity and disease-related specific behaviors is not known. Here, we report that mice lacking NGL-2 (Lrrc4-/- mice) show suppressed N-Methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity in the hippocampus. NGL-2 associates with NMDARs through both PSD-95-dependent and -independent mechanisms. Moreover, Lrrc4-/- mice display mild social interaction deficits and repetitive behaviors that are rapidly improved by pharmacological NMDAR activation. These results suggest that NGL-2 promotes synaptic stabilization of NMDARs, regulates NMDAR-dependent synaptic plasticity, and prevents autistic-like behaviors from developing in mice, supporting the hypothesis that NMDAR dysfunction contributes to autism spectrum disorders.

Characterization of Clinical Isolates of Bartonella henselae Strains, South Korea.

Bartonella henselae, a gram-negative bacterium, is a common causative agent of zoonotic infections. We report 5 culture-proven cases of B. henselae infection in South Korea. By alignment of the 16S rRNA sequences and multilocus sequencing typing analysis, we identified all isolates as B. henselae Houston-1 strain, which belongs to sequence type 1.

Serologic Study of Bartonella henselae in Patients with Acute Undifferentiated Febrile Illness in Korea.

BACKGROUND: Bartonella infection is an emerging cause of acute febrile illness; however, its significance has not been thoroughly investigated. We studied the antibody specific to Bartonella henselae in patients with various febrile diseases in Korea. MATERIALS AND METHODS: A total of 177 patients with acute febrile illness who were managed at the Inha University Hospital from February 2012 to January 2013 were evaluated with an in-house immunofluorescent antibody test to detect B. henselae immunoglobulin G (IgG) antibody. The clinical features of the patients included fever of undetermined origin (n = 88 patients), lymphadenopathy (n = 28), febrile rash (n = 17), respiratory infection (n = 12), aseptic meningitis (n = 7), intra-abdominal infection (n = 5), arthritis (n = 4), and other conditions (n = 16). We reviewed the medical records of these patients and collected demographic data, clinical features, and their histories of animal exposure. RESULTS: Among the 177 patients with acute febrile illness, 23.7% (42/177) had elevated levels of IgG antibodies to B. henselae (≥1:160). Of these seropositive patients, 32.4% (12/37) had contact with animals and had developed arthralgia (29.5%), headache (25%), or lymphadenopathy (15.9%). Seven (16.7%) of the 42 patients had higher IgG titers (≥1:640). Among them, four patients presented fourfold increase/decrease of IgG in convalescent serum. According to the clinical diagnosis, the antibody positivity rates were as follows: 24/88 with undifferentiated fever, 8/28 with lymphadenopathy, 4/17 with febrile rash, 2/12 with respiratory infection, 2/7 with aseptic meningitis, and 2/16 with other illnesses. CONCLUSIONS: There was high prevalence of B. henselae in patients with undifferentiated fever in Korea, for which further research is needed.

Longevity of antibody and T-cell responses against outer membrane antigens of Orientia tsutsugamushi in scrub typhus patients.

Scrub typhus, caused by Orientia tsutsugamushi infection, has been a serious public health issue in the Asia-Pacific region, with rising incidence and sporadic outbreaks. However, human protective immunity against specific antigens has been poorly characterized for this bacterium. In addition, immunity produced in early vaccine trials or even after natural infections, did not last long and had poor cross-reactivity among various genotypes. Here, we systematically investigated the kinetics and magnitude of specific adaptive immunity against two membrane antigens, 56 kDa type-specific antigen (TSA56) and surface cell antigen A (ScaA), that are involved in bacterial adhesion and invasion of the host in 64 recovered scrub typhus patients. Antibody responses to the bacterial antigens in patients were generally short-lived and waned to baseline levels 2 years after recovery. The anti-TSA56 IgG responses were predominantly composed of the IgG1 and IgG3 subclasses and persisted for up to 1 year after recovery, whereas IgG specific to ScaA primarily consisted of more transient IgG1, with limited responses by other subclasses. Cellular immunity, including CD4 and CD8 T-cells specific to membrane antigens, also rapidly declined from 1 year after infection, as measured by enzyme-linked immunospot (ELISPOT) assays and flow cytometry. The short longevity of antigen-specific adaptive immunity might be attributable to limited memory responses, as observed in earlier vaccine studies using whole bacterial antigens. Finally, we identified HLA-A*0201-restricted and highly conserved CD8 T-cell epitopes in the TSA56 antigen, which may be valuable tools for assessing cellular immunity against O. tsutsugamushi and developing an effective scrub typhus vaccine.

The seroprevalence of Bartonella henselae in healthy adults in Korea.

BACKGROUND/AIMS: Cat-scratch disease (CSD), caused by Bartonella henselae is one of the most common zoonosis. However, only several cases of B. henselae infection have been reported in Korea. This study investigated the seroprevalence of B. henselae in healthy adults and related risk factors. METHODS: Serum samples from 300 healthy participants were analyzed using an immunoglobulin G immunof luorescence assay (IFA) for B. henselae isolated in Korea. Surveys on the risk factors for B. henselae infection were conducted simultaneously. RESULTS: Of the participants, 47.7% and 15.0% raised dogs and cats, respectively. The overall seroprevalence of B. henselae was 15.0% (IFA titer ≥ 1:64). Participants who had raised cats showed 22.2% seropositivity against B. henselae, and those with no experience with cats showed 13.7% seroprevalence (p = 0.17). Participants who had cats as pets or been scratched by cats, showed 9.8% seropositivity against B. henselae (IFA titer ≥ 1:256). However, those who had not raised or been scratched by a cat showed 2.0% seropositivity (p = 0.015). CONCLUSIONS: In Korea, the seroprevalence of B. henselae is higher than expected, suggesting that Bartonella infection due to B. henselae is not uncommon. Cats are proposed to play a more important role than dogs in transmission of CSD.

Diversification of Orientia tsutsugamushi genotypes by intragenic recombination and their potential expansion in endemic areas.

BACKGROUND: Scrub typhus is a mite-borne febrile disease caused by O. tsutsugamushi infection. Recently, emergence of scrub typhus has attracted considerable attention in several endemic countries in Asia and the western Pacific. In addition, the antigenic diversity of the intracellular pathogen has been a serious obstacle for developing effective diagnostics and vaccine. METHODOLOGY/PRINCIPAL FINDINGS: To understand the evolutionary pathway of genotypic diversification of O. tsutsugamushi and the environmental factors associated with the epidemiological features of scrub typhus, we analyzed sequence data, including spatiotemporal information, of the tsa56 gene encoding a major outer membrane protein responsible for antigenic variation. A total of 324 tsa56 sequences covering more than 85% of its open reading frame were analyzed and classified into 17 genotypes based on phylogenetic relationship. Extensive sequence analysis of tsa56 genes using diverse informatics tools revealed multiple intragenic recombination events, as well as a substantially higher mutation rate than other house-keeping genes. This suggests that genetic diversification occurred via frequent point mutations and subsequent genetic recombination. Interestingly, more diverse bacterial genotypes and dominant vector species prevail in Taiwan compared to other endemic regions. Furthermore, the co-presence of identical and sub-identical clones of tsa56 gene in geographically distant areas implies potential spread of O. tsutsugamushi genotypes. CONCLUSIONS/SIGNIFICANCE: Fluctuation and diversification of vector species harboring O. tsutsugamushi in local endemic areas may facilitate genetic recombination among diverse genotypes. Therefore, careful monitoring of dominant vector species, as well as the prevalence of O. tsutsugamushi genotypes may be advisable to enable proper anticipation of epidemiological changes of scrub typhus.

Generation of protective immunity against Orientia tsutsugamushi infection by immunization with a zinc oxide nanoparticle combined with ScaA antigen.

BACKGROUND: Zinc oxide nanoparticle (ZNP) has been applied in various biomedical fields. Here, we investigated the usage of ZNP as an antigen carrier for vaccine development by combining a high affinity peptide to ZNP. RESULTS: A novel zinc oxide-binding peptide (ZBP), FPYPGGDA, with high affinity to ZNP (K a  = 2.26 × 106 M-1) was isolated from a random peptide library and fused with a bacterial antigen, ScaA of Orientia tsutsugamushi, the causative agent of scrub typhus. The ZNP/ZBP-ScaA complex was efficiently phagocytosed by a dendritic cell line, DC2.4, in vitro and significantly enhanced anti-ScaA antibody responses in vivo compared to control groups. In addition, immunization with the ZNP/ZBP-ScaA complex promoted the generation of IFN-γ-secreting T cells in an antigen-dependent manner. Finally, we observed that ZNP/ZBP-ScaA immunization provided protective immunity against lethal challenge of O. tsutsugamushi, indicating that ZNP can be used as a potent adjuvant when complexed with ZBP-conjugated antigen. CONCLUSIONS: ZNPs possess good adjuvant potential as a vaccine carrier when combined with an antigen having a high affinity to ZNP. When complexed with ZBP-ScaA antigen, ZNPs could induce strong antibody responses as well as protective immunity against lethal challenges of O. tsutsugamushi. Therefore, application of ZNPs combined with a specific soluble antigen could be a promising strategy as a novel vaccine carrier system.

A Case of Scrub Typhus Complicated by Adult Respiratory Distress Syndrome and Successful Management with Extracorporeal Membrane Oxygenation.

A 67-year-old woman was diagnosed as having scrub typhus with pneumonitis. On admission, she was started on a combination therapy with levofloxacin and doxycycline. However, the patient developed severe acute respiratory distress syndrome (ARDS) on the 2nd day, and as a result, she underwent extracorporeal membrane oxygenation (ECMO). She was weaned from ECMO on the 10th day, as her respiratory status gradually improved. She was discharged without sequelae on the 23rd day. The outcome suggests that the use of ECMO should be considered for patients with ARDS induced from scrub typhus.

Bartonella henselae infection presenting with a picture of adult-onset Still's disease.

We report a patient with a clinical picture of suggestive for adult-onset Still's Disease (ASOD) due to Bartonella infection. A 42-year-old immunocompetent man was admitted with fever, rash, arthralgia and sore throat. As his clinical picture suggested ASOD except unusual skin manifestation, we treated him on steroid and ibuprofen. His fever and constitutional symptoms responded immediately within 24hrs of commencing therapy, yet rash and leukocytosis remained. Meanwhile, Bartonella infection was proved by culture of bone marrow. Minocyclin treatment started combined with hydroxychloroquine sulfate and the patient discharged with overall improvement.

IRSp53/BAIAP2 in dendritic spine development, NMDA receptor regulation, and psychiatric disorders.

IRSp53 (also known as BAIAP2) is a multi-domain scaffolding and adaptor protein that has been implicated in the regulation of membrane and actin dynamics at subcellular structures, including filopodia and lamellipodia. Accumulating evidence indicates that IRSp53 is an abundant component of the postsynaptic density at excitatory synapses and an important regulator of actin-rich dendritic spines. In addition, IRSp53 has been implicated in diverse psychiatric disorders, including autism spectrum disorders, schizophrenia, and attention deficit/hyperactivity disorder. Mice lacking IRSp53 display enhanced NMDA (N-methyl-d-aspartate) receptor function accompanied by social and cognitive deficits, which are reversed by pharmacological suppression of NMDA receptor function. These results suggest the hypothesis that defective actin/membrane modulation in IRSp53-deficient dendritic spines may lead to social and cognitive deficits through NMDA receptor dysfunction. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'.

Identification of Outer Membrane Vesicles Derived from Orientia tsutsugamushi.

Orientia tsutsugamushi, a causative pathogen of Scrub typhus, is a gram-negative intracellular bacterium. Outer membrane vesicles (OMVs) are produced from the membrane of bacteria and play many roles related to the survival of the pathogen. However, there have been no reports confirming whether O. tsutsugamushi indeed produce OMVs. O. tsutsugamushi boryong was cultured in ECV-304 cells for the purification of OMVs. Western blot analysis and immunoenrichment using anti-O. tsutsugamushi monoclonal antibody and electron microscopy were employed for identification and characterization of OMVs. We confirm the presence of OMVs derived from O. tsutsugamushi, and also found that those OMVs contain a major surface antigen of 56-kDa protein and variant immunogenic antigens.

Suppression of NMDA receptor function in mice prenatally exposed to valproic acid improves social deficits and repetitive behaviors.

Animals prenatally exposed to valproic acid (VPA), an antiepileptic agent, have been used as a model for autism spectrum disorders (ASDs). Previous studies have identified enhanced NMDA receptor (NMDAR) function in the brain of VPA rats, and demonstrated that pharmacological suppression of NMDAR function normalizes social deficits in these animals. However, whether repetitive behavior, another key feature of ASDs, can be rescued by NMDAR inhibition remains unknown. We report here that memantine, an NMDAR antagonist, administered to VPA mice rescues both social deficits and repetitive behaviors such as self-grooming and jumping. These results suggest that suppression of elevated NMDAR function in VPA animals normalizes repetitive behaviors in addition to social deficits.