Descending perineal syndrome cure by deep transversus perinei ligament repair: surgical options.

Descending perineal syndrome (DPS) was described by Parks et al. as descent of the anus on straining, typically 3-4 cm below a line drawn from the coccyx to the lower end of the. DPS is associated with obstructed defecation, with increased bulging of the perineum with straining, although perineal descent can also be seen at rest. In their review, Chaudhry and Tarnay stated: "It is controversial whether surgical management is even an option for patients with DPS". The deep transversus perinei (DTP) ligaments are the suspensory ligaments of the perineal body (PB). DTP are approximately 4 cm long. They attach behind the upper 2/3 and lower 1/3 of the descending ramus. If, at childbirth, the PB is overstretched and displaced laterally and inferiorly, the DTP lengthens. DPS is described as descent of the anus on straining, typically 3-4 cm below a line drawn from the coccyx to the lower end of the symphysis. DPS is associated with obstructed and often, assisted defecation, with increased bulging of the perineum with straining descent of the anus on straining. The surgical methodology begins as a standard PB repair which dissects the rectum from the vagina and PB and approximates the displaced components of the PB. We added an additional step: identifying the DTPs, shortening and reinforcing them with the Tissue Fixation System (TFS) minisling or No. 2 polyester sutures. High cure rates for obstructed defecation were achieved with the TFS minisling, and initial results using No. 2 polyester sutures are favourable. The key messages from both operations is DPS is caused by stretching and elongation of DPS ligaments, and these are surgically repairable.

Structural, functional, and dysfunctional pelvic anatomy.

The structural basis of the Integral Theory is holistic. Four main pelvic muscles interact holistically with five main pelvic ligaments to maintain pelvic organ structure and function. The vagina is structurally weak. The support it provides to the bladder base is contingent on being stretched by opposite pelvic muscle forces, much like a trampoline. Its main role is to transmit muscle forces to facilitate continence, evacuation and control of urgency. Therefore, as an organ that cannot regenerate, the vagina should be conserved, and not excised. The ligaments provide the main structural support for the organs and are the most vulnerable part of the anatomical system to injury because their structural collagen is depolymerized prior to labour, and stretched during labour. Further ligament weakening occurs after menopause due to collagen breakdown. Hence, collagen loss is the main cause of organ prolapse and lower urinary tract symptoms (LUTS). The strengthening of damaged ligaments, whether surgically or non-surgically, can improve or cure symptoms and prolapse. Because collagen loss in ligaments is a principal cause of dysfunction in older women, collagen-creating techniques are advised: precisely inserted tapes to create neoligaments, or wide-bore No. 2 or No. 3 polyester ligament sutures instead of dissolvable sutures.

Principles of surgery according to the Integral Theory Paradigm (ITP).

A core concept of the Integral Theory System is that "ligaments are for structure; vagina is for function". The vagina and uterus should be conserved. Because the vagina is an organ, its collagen and elastin, which are so necessary for its function, cannot regenerate once they are removed. Removing the uterus involves severing the descending uterine artery, which is the principal blood supply of the proximal part of the uterosacral ligaments (USLs), and so may cause atrophy, which can cause future incontinence problems because of collagen loss after menopause. The diagnostic algorithm guides which of the five pelvic ligaments need repair. Native ligament plication can be adequate for prolapse/symptom cure, but only in premenopausal women. Postmenopausal women are usually collagen deficient and require collagen-creating tapes or wide-bore polyester sutures to restore structural collagen in the ligaments. Of extreme importance, vaginal tissue excision should be avoided, as consequent scarring may cause "tethered vagina syndrome" (TVS). TVS can cause massive uncontrolled urine loss because the scar tissue in the bladder neck area of the vagina can link the more powerful posterior muscles to the anterior, so the posterior urethra wall is forcibly pulled open, when given the signal to close. Instead of vaginal excision, a "concertina" suture technique re-assigns and shrinks excess vaginal tissue to normal anatomy by 6 weeks. In conclusion, the five key surgical principles of the Integral Theory System are: ligaments are for structure, vagina is for function; structure (prolapse) and function (symptoms) are related; repair the structure and you will restore the function; avoid vaginal excision and hysterectomy; create new collagen to reinforce the damaged ligaments.

Type-I-interferon-responsive microglia shape cortical development and behavior.

Microglia are brain-resident macrophages that shape neural circuit development and are implicated in neurodevelopmental diseases. Multiple microglial transcriptional states have been defined, but their functional significance is unclear. Here, we identify a type I interferon (IFN-I)-responsive microglial state in the developing somatosensory cortex (postnatal day 5) that is actively engulfing whole neurons. This population expands during cortical remodeling induced by partial whisker deprivation. Global or microglial-specific loss of the IFN-I receptor resulted in microglia with phagolysosomal dysfunction and an accumulation of neurons with nuclear DNA damage. IFN-I gain of function increased neuronal engulfment by microglia in both mouse and zebrafish and restricted the accumulation of DNA-damaged neurons. Finally, IFN-I deficiency resulted in excess cortical excitatory neurons and tactile hypersensitivity. These data define a role for neuron-engulfing microglia during a critical window of brain development and reveal homeostatic functions of a canonical antiviral signaling pathway in the brain.

Single amino acid mutation of nectin-1 provides remarkable resistance against lethal pseudorabies virus infection in mice.

An approach to genetically engineered resistance to pseudorabies virus (PRV) infection was examined by using a mouse model with defined point mutation in primary receptor for alphaherpesviruses, nectin-1, by the CRISPR/Cas9 system. It has become clear that phenylalanine at position 129 of nectin-1 is important for binding to viral glycoprotein D (gD), and mutation of phenylalanine 129 to alanine (F129A) prevents nectin-1 binding to gD and virus entry in vitro. Here, to assess the antiviral potential of the single amino acid mutation of nectin-1, F129A, in vivo, we generated genome-edited mutant mouse lines; F129A and 135 knockout (KO). The latter, 135 KO used as a nectin-1 knockout line for comparison, expresses a carboxy-terminal deleted polypeptide consisting of 135 amino acids without phenylalanine 129. In the challenge with 10 LD50 PRV via intranasal route, perfect protection of disease onset was induced by expression of the mutation of nectin-1, F129A (survival rate: 100% in F129A and 135 KO versus 0% in wild type mice). Neither viral DNA/antigens nor pathological changes were detected in F129A, suggesting that viral entry was prevented at the primary site in natural infection. In the challenge with 50 LD50 PRV, lower but still strong protective effect against disease onset was observed (survival rate: 57% in F129A and 75% in 135 KO versus 0% in wild type mice). The present results indicate that single amino acid mutation of nectin-1 F129A provides significant resistance against lethal pseudorabies.

Astrocytic ß-catenin signaling via TCF7L2 regulates synapse development and social behavior.

The Wnt/ß-catenin pathway contains multiple high-confidence risk genes that are linked to neurodevelopmental disorders, including autism spectrum disorder. However, its ubiquitous roles across brain cell types and developmental stages have made it challenging to define its impact on neural circuit development and behavior. Here, we show that TCF7L2, which is a key transcriptional effector of the Wnt/ß-catenin pathway, plays a cell-autonomous role in postnatal astrocyte maturation and impacts adult social behavior. TCF7L2 was the dominant Wnt effector that was expressed in both mouse and human astrocytes, with a peak during astrocyte maturation. The conditional knockout of Tcf7l2 in postnatal astrocytes led to an enlargement of astrocytes with defective tiling and gap junction coupling. These mice also exhibited an increase in the number of cortical excitatory and inhibitory synapses and a marked increase in social interaction by adulthood. These data reveal an astrocytic role for developmental Wnt/ß-catenin signaling in restricting excitatory synapse numbers and regulating adult social behavior.

Incidence of and risk factors for suspected COVID-19 reinfection in Kyoto City: a population-based epidemiological study.

To determine the clinical characteristics of and risk factors for suspected reinfection with coronavirus 2019 (COVID-19). This was a retrospective cohort study using population-based notification records of residents in Kyoto City (1.4 M) with laboratory-confirmed COVID-19 infection between 1 March 2020 and 15 April 2022. Reinfection was defined by two or more positive COVID-19 test results ≧ 90 days apart. Demographic characteristics, the route and timing of infection and history of vaccination were analysed to identify risk factors for reinfection. Among the cohort of 107,475 patients, reinfection was identified in 0.66% (n = 709). The age group with the highest reinfection rate was 18-39 years (1.06%), followed by 40-59 years (0.58%). Compared to the medical and nursing professionals, individuals who worked in the construction and manufacturing industry (odds ratio [OR]: 2.86; 95% confidence interval [CI]: 1.66-4.92) and hospitality industry (OR: 2.05; 95% CI: 1.28-.31) were more likely to be reinfected. Symptomatic cases at initial infection, receiving more than 2 doses of vaccination and risk factors for severe infection at initial infection were protective factors against reinfection. Of the reinfected individuals, the reinfection route was unknown in 65%. Reinfection with COVID-19 is uncommon, with suspected reinfections more likely in adults, those with high exposure and unvaccinated individuals; the reinfection route was unknown in the majority of cases. This study confirmed the need to continue with self-protection efforts and to implement vaccination programs in high-risk populations.

Microglial pattern recognition via IL-33 promotes synaptic refinement in developing corticothalamic circuits in mice.

Microglia are critical regulators of brain development that engulf synaptic proteins during postnatal synapse remodeling. However, the mechanisms through which microglia sense the brain environment are not well defined. Here, we characterized the regulatory program downstream of interleukin-33 (IL-33), a cytokine that promotes microglial synapse remodeling. Exposing the developing brain to a supraphysiological dose of IL-33 altered the microglial enhancer landscape and increased binding of stimulus-dependent transcription factors including AP-1/FOS. This induced a gene expression program enriched for the expression of pattern recognition receptors, including the scavenger receptor MARCO. CNS-specific deletion of IL-33 led to increased excitatory/inhibitory synaptic balance, spontaneous absence-like epileptiform activity in juvenile mice, and increased seizure susceptibility in response to chemoconvulsants. We found that MARCO promoted synapse engulfment, and Marco-deficient animals had excess thalamic excitatory synapses and increased seizure susceptibility. Taken together, these data define coordinated epigenetic and functional changes in microglia and uncover pattern recognition receptors as potential regulators of postnatal synaptic refinement.

Type I interferon responsive microglia shape cortical development and behavior.

Microglia are brain resident phagocytes that can engulf synaptic components and extracellular matrix as well as whole neurons. However, whether there are unique molecular mechanisms that regulate these distinct phagocytic states is unknown. Here we define a molecularly distinct microglial subset whose function is to engulf neurons in the developing brain. We transcriptomically identified a cluster of Type I interferon (IFN-I) responsive microglia that expanded 20-fold in the postnatal day 5 somatosensory cortex after partial whisker deprivation, a stressor that accelerates neural circuit remodeling. In situ, IFN-I responsive microglia were highly phagocytic and actively engulfed whole neurons. Conditional deletion of IFN-I signaling (Ifnar1fl/fl) in microglia but not neurons resulted in dysmorphic microglia with stalled phagocytosis and an accumulation of neurons with double strand DNA breaks, a marker of cell stress. Conversely, exogenous IFN-I was sufficient to drive neuronal engulfment by microglia and restrict the accumulation of damaged neurons. IFN-I deficient mice had excess excitatory neurons in the developing somatosensory cortex as well as tactile hypersensitivity to whisker stimulation. These data define a molecular mechanism through which microglia engulf neurons during a critical window of brain development. More broadly, they reveal key homeostatic roles of a canonical antiviral signaling pathway in brain development.

Transmissibility of SARS-CoV-2 B.1.1.214 and Alpha Variants during 4 COVID-19 Waves, Kyoto, Japan, January 2020-June 2021.

Household transmission is a primary source of SARS-CoV-2 spread. We used COVID-19 epidemiologic investigation data and viral genome analysis data collected in the city of Kyoto, Japan, during January 2020-June 2021 to evaluate the effects of different settings and viral strains on SARS-CoV-2 transmission. Epidemiologic investigations of 5,061 COVID-19 cases found that the most common category for close contact was within households (35.3%); this category also had the highest reverse transcription PCR positivity. The prevalent viral lineage shifted from B.1.1.214 in the third wave to the Alpha variant in the fourth wave. The proportion of secondary cases associated with households also increased from the third to fourth waves (27% vs. 29%). Among 564 contacts from 206 households, Alpha variant was significantly associated with household transmission (odds ratio 1.52, 95% CI 1.06-2.18) compared with B.1.1.214. Public health interventions targeting household contacts and specific variants could help control SARS-CoV-2 transmission.

Pathogenicity of Bordetella bronchiseptica isolated from apparently healthy rabbits in guinea pig, rat, and mouse.

Bordetella bronchiseptica (B. bronchiseptica) is associated with respiratory tract infections in laboratory animals. In our laboratory animal facility, B. bronchiseptica was isolated from 21 of 27 apparently healthy rabbits obtained from a breeding farm contaminated with B. bronchiseptica. Restriction fragment length polymorphism (RFLP) analysis showed that the flagellin genotype of isolates from the laboratory animal facility and breeding farm was type A, which is seen relatively frequently in rabbits in Europe. To examine its pathogenicity, guinea pigs, rats, and mice were inoculated intranasally with a representative strain isolated in the laboratory animal facility. Following inoculation of 107 colony forming unit (cfu), severe inflammation was observed in the lungs of guinea pig and mice, although the inflammation was less severe in rats. The strain was recovered from the trachea and lungs of these species after inoculation with lower dose such as 103 or 104 cfu. These results suggest that the isolated strain causes respiratory tract infection in guinea pigs, rats, and mice, and that its pathogenicity higher in mice than in rats. This study extends our knowledge of interpreting the microbiologic status of laboratory animals, which will contribute to the development of reliable and reproducible animal experiments.

Lung cancer screening by single-shot dual-energy subtraction using flat-panel detector.

PURPOSE: The purpose of this study was to evaluate the usefulness of single-shot dual-energy subtraction (DES) method using a flat-panel detector for lung cancer screening MATERIALS AND METHODS: The subjects were 13,315 residents (5801 males and 7514 females) aged 50 years or older (50-97 years, with an intermediate value of 68 years) who underwent lung cancer screening for a period of 1 year and 6 months from January 2019 to June 2020. We investigated whether the number of lung cancers detected, the detection rate, and the rate of required scrutiny changed, when DES images were added to the judgment based on conventional chest radiography. RESULTS: When DES images were added, the number and percentage of cancer detection increased from 16 (0.12%) to 23 (0.17%) (P < 0.05). Five of the newly detected 7 lung cancers were in the early stages of resectable cancer. The rate of participants requiring scrutiny increased slightly from 1.1 to 1.3%. CONCLUSION: DES method improved the detection of lung cancer in screening. The increase in the percentage of participants requiring scrutiny was negligible.

Synthesis and Characterization of Radiogallium-Labeled Cationic Amphiphilic Peptides as Tumor Imaging Agents.

SVS-1 is a cationic amphiphilic peptide (CAP) that exhibits a preferential cytotoxicity towards cancer cells over normal cells. In this study, we developed radiogallium-labeled SVS-1 (67Ga-NOTA-KV6), as well as two SVS-1 derivatives, with the repeating KV residues replaced by RV or HV (67Ga-NOTA-RV6 and 67Ga-NOTA-HV6). All three peptides showed high accumulation in epidermoid carcinoma KB cells (53-143% uptake/mg protein). Though 67Ga-NOTA-RV6 showed the highest uptake among the three CAPs, its uptake in 3T3-L1 fibroblasts was just as high, indicating a low selectivity. In contrast, the uptake of 67Ga-NOTA-KV6 and 67Ga-NOTA-HV6 into 3T3-L1 cells was significantly lower than that in KB cells. An endocytosis inhibition study suggested that the three 67Ga-NOTA-CAPs follow distinct pathways for internalization. In the biodistribution study, the tumor uptakes were found to be 4.46%, 4.76%, and 3.18% injected dose/g of tissue (% ID/g) for 67Ga-NOTA-KV6, 67Ga-NOTA-RV6, and 67Ga-NOTA-HV6, respectively, 30 min after administration. Though the radioactivity of these peptides in tumor tissue decreased gradually, 67Ga-NOTA-KV6, 67Ga-NOTA-RV6, and 67Ga-NOTA-HV6 reached high tumor/blood ratios (7.7, 8.0, and 3.8, respectively) and tumor/muscle ratios (5.0, 3.3, and 4.0, respectively) 120 min after administration. 67Ga-NOTA-HV6 showed a lower tumor uptake than the two other tracers, but it exhibited very low levels of uptake into peripheral organs. Overall, the replacement of lysine in SVS-1 with other basic amino acids significantly influenced its binding and internalization into cancer cells, as well as its in vivo pharmacokinetic profile. The high accessibility of these peptides to tumors and their ability to target the surface membranes of cancer cells make radiolabeled CAPs excellent candidates for use in tumor theranostics.

Tissue Fixation System ligament repair cures major pelvic organ prolapse in ageing women with minimal complications - a 10-year Japanese experience in 960 women.

INTRODUCTION: Japan's ageing crisis has brought major prolapse and incontinence problems. We hypothesized the problem was collagen leaching out of ligaments which support organs and could be corrected by the TFS (Tissue Fixation System) minisling which uses 7 mm wide tapes to create new collagen for ligament reinforcement.We analysed our 10-year experience (2009-2019) with TFS minisling prolapse repair with regard to one main question: "Is this technology of benefit to the ageing Japanese population?". MATERIAL AND METHODS: Retrospective analysis from two tertiary referral units; 3100 tapes were implanted (variously) into cardinal, uterosacral, arcus tendineus fascia pelvis (ATFP), perineal body ligaments of 960 Japanese women (mean age 69.6 years), to repair POPQ 3rd or 4th degree prolapse (918/960), 50% under local anesthesia/sedation, remainder general/spinal anesthesia. RESULTS: Patient discharge within 24 hours indicated minimal intra-operative problems. Prolapse cure at 12 months reached 90%. Complications requiring intervention were infected rectal perforation by tape, 3 delayed ileus complications. Eroded tapes (2.4-3.5%) were trimmed in the clinic. De novo long-term pain and major urine loss were virtually absent. CONCLUSIONS: The TFS system works by restoring ligament support (pubourethral, ATFP, cardinal, uterosacral, perineal body), differently from mesh sheets which work by blocking organ descent, which can lead to fibrosis of the vagina, and may cause chronic pain and massive incontinence. We had no such problems, because tapes have small volume, are applied transversely, with little vaginal contact. Specific ligament reinforcement with collagenopoietic tapes seems to be an important new direction for aged women with major prolapse, with high cure rate, acceptable complications, low erosions and virtually no long-term pain.

Treatment Outcome of the Combination Therapy of High-dose rate Intracavitary Brachytherapy and Intensity-modulated Radiation Therapy With Central-shielding for Cervical Cancer.

BACKGROUND/AIM: This study aimed to evaluate the clinical outcome of intensity-modulated radiation therapy (IMRT) and high-dose-rate intracavitary brachytherapy (HDR-ICBT) in uterine cervical cancer (UCC). IMRT consisted of whole-pelvic radiation therapy (WPRT) and sequential WPRT with central-shielding (WPRT-CS). PATIENTS AND METHODS: Thirty UCC patients treated with IMRT using TomoTherapy, were retrospectively analyzed. RESULTS: The median dose of WPRT and WPRT-CS was 36 and 14.4 Gy and the median total dose of these was 50 Gy in 25 fractions (Fr). Median HDR-ICBT dose/Fr to Point A was 25 Gy/5 Fr. Median 2 Gy per fraction-equivalent dose (EQD2) of combined WPRT and HDR-ICBT to Point A (α/ß=10) was 71.0 Gy. The 3-year local control, disease-free survival, and overall survival rates were 89.9%, 83.3%, and 86.3%. CONCLUSION: IMRT of WPRT and WPRT-CS given in combination with HDR-ICBT was a feasible therapy resulting in good disease control and tolerance in patients with UCC.

Microglial Remodeling of the Extracellular Matrix Promotes Synapse Plasticity.

Synapse remodeling is essential to encode experiences into neuronal circuits. Here, we define a molecular interaction between neurons and microglia that drives experience-dependent synapse remodeling in the hippocampus. We find that the cytokine interleukin-33 (IL-33) is expressed by adult hippocampal neurons in an experience-dependent manner and defines a neuronal subset primed for synaptic plasticity. Loss of neuronal IL-33 or the microglial IL-33 receptor leads to impaired spine plasticity, reduced newborn neuron integration, and diminished precision of remote fear memories. Memory precision and neuronal IL-33 are decreased in aged mice, and IL-33 gain of function mitigates age-related decreases in spine plasticity. We find that neuronal IL-33 instructs microglial engulfment of the extracellular matrix (ECM) and that its loss leads to impaired ECM engulfment and a concomitant accumulation of ECM proteins in contact with synapses. These data define a cellular mechanism through which microglia regulate experience-dependent synapse remodeling and promote memory consolidation.

Neonatal outcomes of two-step delivery in low-risk pregnancy: A prospective observational study.

AIM: Extraction of the fetal body is typically performed immediately after delivery of the head in Western obstetric care. Reports justifying immediate extraction are few. Two-step delivery entails waiting for the next uterine contraction after delivery of the head. The present study evaluates neonatal asphyxia and respiratory impairment in two-step delivery using the head-to-body delivery interval. METHODS: This prospective observational study performed at a single birth clinic used the data of 262 low-risk pregnant women with two-step delivery. We measured the time interval of head-to-body delivery and correlation analysis and simple linear regression analysis between the head-to-body delivery interval and umbilical artery pH. The women were divided into two groups according to the head-to-body delivery interval: ≤60 or >60 s. The prevalence of neonatal asphyxia and neonatal respiratory impairment was compared between the groups. RESULTS: The mean head-to-body delivery interval was 88.9 ± 71.3 s. The umbilical artery pH tended to decrease with increasing head-to-body delivery interval; however, there was almost no correlation and the decline of pH was only 0.010 for every additional minute. Low Apgar score incidence at 5 min did not differ significantly between the groups. No cases of shoulder dystocia were reported, and tachypnea at 4 h after birth occurred in 3% of the births. CONCLUSIONS: A longer head-to-body delivery interval is not associated with negative outcomes in two-step delivery. We believe that two-step delivery could have some superior outcomes compared with one-step delivery outcomes, particularly as to improving fetal circulation and preventing shoulder dystocia.

Anxiety or Nervousness Disturbs the Progress of Birth Based on Human Behavioral Evolutionary Biology.

In general, anxiety or nervousness in pregnant women increases the risk of dystocia. Pregnant women are easily susceptible to anxiousness or nervousness. To support a safe and healthy birthing process, childbirth educators, other health-care professionals, and pregnant women require an in-depth understanding about the disruptive effects of anxiety or nervousness on birth progress. Anxiety and nervousness are difficult to quantify and may be influenced by culture. Therefore, reports comparing anxiety or nervousness with dystocia must include various biases. It is difficult to find this issue by medical research. Here, we discuss links between anxiety or nervousness and disturbance in the progress of birth based on the adaptive standpoint of human behavioral evolutionary biology.

Cure of Underactive and Overactive Bladder Symptoms in Women by 1,671 Apical Sling Operations Gives Fresh Insights into Pathogenesis and Need for Definition Change.

INTRODUCTION: To check evidence that symptoms identical with those constituting "underactive bladder" (UAB) and "overactive bladder" (OAB) are caused by apical prolapse and cured by repair thereof. MATERIAL AND METHODS: After repair of apical prolapse by mesh tape reinforcement of lax uterosacral ligaments (USL) data form 1,671 women were retrospectively examined to determine the presence of OAB and UAB symptoms and to check, how many were cured surgically. Thereby 3 different techniques were performed: elevate (n = 277), "Posterior IVS" (n = 1,049), and TFS cardinal (CL)/USL (n = 345). RESULTS: Symptoms identical with those comprising UAB and OAB were cured in up to 80% of cases following surgical repair of the CL/USL complex. CONCLUSIONS: These symptoms may be consistent with symptoms of the posterior fornix syndrome, which comprises 4 main symptoms: micturition difficulties, urge/frequency, nocturia, chronic pelvic pain, all consequent on USL laxity. Surgical cure of OAB and UAB is inconsistent with existing definitions, which imply pathogenesis of the detrusor muscle itself. A reconsideration and reformulation of existing definitions may be required. Altering UAB definition to "bladder emptying difficulties" and return to former definitions for OAB such as "detrusor" or "bladder instability" may help to restore compatibility with surgical cure of these conditions.