Exploring novel HIV-1 reverse transcriptase inhibitors with drug-resistant mutants: A double mutant surprise.

HIV-1 reverse transcriptase (RT) remains a key target for HIV drug development. As successful management of the disease requires lifelong treatment, the emergence of resistance mutations is inevitable, making development of new RT inhibitors, which remain effective against resistant variants crucial. To this end, previous computationally guided drug design efforts have resulted in catechol diether compounds, which inhibit wildtype RT with picomolar affinities and appear to be promising preclinical candidates. To confirm that these compounds remain potent against Y181C, a widespread mutation conferring resistance to first generation inhibitors, they were screened against the HIV-1 N119 clinical isolate, reported as a Y181C single mutant. In comparison to a molecular clone with the same mutation, N119 appears less susceptible to inhibition by our preclinical candidate compounds. A more detailed sequencing effort determined that N119 was misidentified and carries V106A in combination with Y181C. While both indolizine and naphthalene substituted catechol diethers are potent against the classical Y181C single mutant, the addition of V106A confers more resistance against the indolizine derivatives than the naphthalene derivatives. Crystal structures presented in this study highlight key features of the naphthyl group, which allow these compounds to remain potent in the double mutant, including stronger interactions with F227 and less reliance on V106 for stabilization of the ethoxy-uracil ring, which makes critical hydrogen bonds with other residues in the binding pocket.

Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine.

Bipolar disorder's core feature is the pathological disturbances in mood, often accompanied by disrupted thinking and behavior. Its complex and heterogeneous etiology implies that a range of inherited and environmental factors are involved. This heterogeneity and poorly understood neurobiology pose significant challenges to existing drug development paradigms, resulting in scarce treatment options, especially for bipolar depression. Therefore, novel approaches are needed to discover new treatment options. In this review, we first highlight the main molecular mechanisms known to be associated with bipolar depression-mitochondrial dysfunction, inflammation and oxidative stress. We then examine the available literature for the effects of trimetazidine in said alterations. Trimetazidine was identified without a priori hypothesis using a gene-expression signature for the effects of a combination of drugs used to treat bipolar disorder and screening a library of off-patent drugs in cultured human neuronal-like cells. Trimetazidine is used to treat angina pectoris for its cytoprotective and metabolic effects (improved glucose utilization for energy production). The preclinical and clinical literature strongly support trimetazidine's potential to treat bipolar depression, having anti-inflammatory and antioxidant properties while normalizing mitochondrial function only when it is compromised. Further, trimetazidine's demonstrated safety and tolerability provide a strong rationale for clinical trials to test its efficacy to treat bipolar depression that could fast-track its repurposing to address such an unmet need as bipolar depression.

Radial source velocity estimation based on cross-spectrum equalization accumulation compensation in shallow water.

In the former work, the histogram was effectively used to improve the interference immunity of target velocity estimation based on the cross-spectrum. This paper proposes a new method to eliminate the bias introduced by the histogram and to further improve interference immunity. The equalization window is designed to preserve the cross-spectrum peaks while suppressing the interference peaks. All frequency points are compensated and accumulated to improve the interference immunity. Finally, the simulation and sea trial data verify the effectiveness of the proposed method in this paper.

Long-term Cardiovascular Risks of Gonadotropin-releasing Hormone Agonists and Antagonists: A Population-based Cohort Study.

AIMS: Gonadotropin-releasing hormone (GnRH) agonists and antagonists, critical medications for prostate cancer (PCa) treatment, may differ in cardiovascular safety. This prospective cohort study aimed to compare the long-term cardiovascular risks between GnRH agonists and antagonists. MATERIALS AND METHODS: Patients with PCa receiving GnRH agonists or antagonists during 2013-2021 in Hong Kong were identified. Patients with <6 months' prescriptions, who were switching between drugs, had missing baseline prostate-specific antigen level or had a prior stroke or myocardial infarction were excluded. Patients were followed up until September 2021. The primary outcome was major adverse cardiovascular events (MACE) as in the PRONOUNCE trial (MACEPRONOUNCE), i.e. a composite of all-cause mortality, stroke and myocardial infarction. The secondary outcome was MACECVM, i.e. a composite of cardiovascular mortality, stroke and myocardial infarction. Inverse probability treatment weighting was used to balance covariates between groups. The Log-rank test was used to compare the cumulative freedom from the primary outcome between groups. RESULTS: In total, 2479 patients were analysed (162 GnRH antagonist users and 2317 agonist users; median age 75.0 years, interquartile range 68.0-81.6 years). Inverse probability treatment weighting achieved good covariate balance between groups. Over a median follow-up duration of 3.0 years (interquartile range 1.7-5.0 years), 1115 patients (45.0%) had MACEPRONOUNCE and 344 (13.9%) had MACECVM. GnRH agonist users had lower risks of MACEPRONOUNCE (Log-rank P < 0.001) and MACECVM (Log-rank P = 0.027). However, no differences were observed within 1 year of follow-up (MACEPRONOUNCE: Log-rank P = 0.308; MACECVM: Log-rank P = 0.357). Among patients without cardiovascular risk factors at baseline, GnRH agonist users had lower risks of MACEPRONOUNCE (Log-rank P < 0.001) and MACECVM (Log-rank P = 0.001), whereas no differences were observed in those with such risk factor(s) (MACEPRONOUNCE: Log-rank P = 0.569; MACECVM: Log-rank P = 0.615). CONCLUSIONS: GnRH antagonists may be associated with higher long-term, but not short-term, cardiovascular risks than agonists in Asian patients with PCa, particularly in those without known cardiovascular risk factors.

The association of new-onset diabetes with subsequent diagnosis of pancreatic cancer-novel use of a large administrative database.

BACKGROUND: Screening options for pancreatic ductal adenocarcinoma (PDAC) are limited. New-onset type 2 diabetes (NoD) is associated with subsequent diagnosis of PDAC in observational studies and may afford an opportunity for PDAC screening. We evaluated this association using a large administrative database. METHODS: Patients were identified using claims data from the OptumLabs® Data Warehouse. Adult patients with NoD diagnosis were matched 1:3 with patients without NoD using age, sex and chronic obstructive pulmonary disease (COPD) status. The event of PDAC diagnosis was compared between cohorts using the Kaplan-Meier method. Factors associated with PDAC diagnosis were evaluated with Cox's proportional hazards modeling. RESULTS: We identified 640 421 patients with NoD and included 1 921 263 controls. At 3 years, significantly more PDAC events were identified in the NoD group vs control group (579 vs 505; P < 0.001). When controlling for patient factors, NoD was significantly associated with elevated risk of PDAC (HR 3.474, 95% CI 3.082-3.920, P < 0.001). Other factors significantly associated with PDAC diagnosis were increasing age, increasing age among Black patients, and COPD diagnosis (P ≤ 0.05). CONCLUSIONS: NoD was independently associated with subsequent diagnosis of PDAC within 3 years. Future studies should evaluate the feasibility and benefit of PDAC screening in patients with NoD.

The view of Hong Kong parents on secondary use of dried blood spots in newborn screening program.

BACKGROUND: Residual dried blood spots (rDBS) from newborn screening programmes represent a valuable resource for medical research, from basic sciences, through clinical to public health. In Hong Kong, there is no legislation for biobanking. Parents' view on the retention and use of residual newborn blood samples could be cultural-specific and is important to consider for biobanking of rDBS. OBJECTIVE: To study the views and concerns on long-term storage and secondary use of rDBS from newborn screening programmes among Hong Kong Chinese parents. METHODS: A mixed-method approach was used to study the views and concerns on long-term storage and secondary use of rDBS from newborn screening programmes among Hong Kong Chinese parents of children 0-3 years or expecting parents through focus groups (8 groups; 33 participants) and a survey (n = 1012, 85% mothers) designed with insights obtained from the focus groups. We used framework analysis to summarise the themes as supportive factors, concerns and critical arguments for retention and secondary use of rDBS from focus group discussion. We used multiple logistic regression to assess factors associated with support for retention and secondary use of rDBS in the survey. RESULTS: Both in focus groups and survey, majority of parents were not aware of the potential secondary use of rDBS. Overall secondary use of rDBS in medical research was well accepted by a large proportion of Hong Kong parents, even if all potential future research could not be specified in a broad consent. However parents were concerned about potential risks of biobanking rDBS including leaking of data and mis-use of genetic information. Parents wanted to be asked for permission before rDBS are stored and mainly did not accept an "opt-out" approach. The survey showed that parents born in mainland China, compared to Hong Kong born parents, had lower awareness of newborn screening but higher support in biobanking rDBS. Higher education was associated with support in rDBS biobanking only among fathers. CONCLUSION: Long-term storage and secondary use of rDBS from newborn screening for biomedical research and a broad consent for biobanking of rDBS are generally acceptable to Hong Kong parents given their autonomy is respected and their privacy is protected, highlighting the importance of an accountable governance and a transparent access policy for rDBS biobanks.

Common genetic variants do not predict recurrent events in coronary heart disease patients.

BACKGROUND: It is unclear whether genetic variants identified from single nucleotide polymorphisms (SNPs) strongly associated with coronary heart disease (CHD) in genome-wide association studies (GWAS), or a genetic risk score (GRS) derived from them, can help stratify risk of recurrent events in patients with CHD. METHODS: Study subjects were enrolled at the close-out of the LIPID randomised controlled trial of pravastatin vs placebo. Entry to the trial had required a history of acute coronary syndrome 3-36 months previously, and patients were in the trial for a mean of 36 months. Patients who consented to a blood sample were genotyped with a custom designed array chip with SNPs chosen from known CHD-associated loci identified in previous GWAS. We evaluated outcomes in these patients over the following 10 years. RESULTS: Over the 10-year follow-up of the cohort of 4932 patients, 1558 deaths, 898 cardiovascular deaths, 727 CHD deaths and 375 cancer deaths occurred. There were no significant associations between individual SNPs and outcomes before or after adjustment for confounding variables and for multiple testing. A previously validated 27 SNP GRS derived from SNPs with the strongest associations with CHD also did not show any independent association with recurrent major cardiovascular events. CONCLUSIONS: Genetic variants based on individual single nucleotide polymorphisms strongly associated with coronary heart disease in genome wide association studies or an abbreviated genetic risk score derived from them did not help risk profiling in this well-characterised cohort with 10-year follow-up. Other approaches will be needed to incorporate genetic profiling into clinically relevant stratification of long-term risk of recurrent events in CHD patients.

[Investigation of contamination of SARS-CoV-2 in imported frozen seafood from a foreign cargo ship and risk factors for infection in stevedores in Qingdao].

Objective: To investigate the contamination status of SARS-CoV-2 in imported frozen seafood from a Russia cargo ship in Qingdao and to analyze the risk factors for infection in local stevedores. Methods: The method of "two-stage, full coverage and mixed sampling" was used to collect the seafood packaging samples for the nucleic acid detection of SARS-CoV-2 by real-time fluorescent quantitative RT-PCR. A unified questionnaire was designed to investigate 71 stevedores in two shifts through telephone interview. The stevedores were divided into two groups, with 23 in the shit with two infections was group A and 48 in the shift without infection was group B. Software Epi Info7.2 was used to identify the risk factors for SARS-CoV-2 infections in the stevedores. Results: In the frozen seafood from a Russia cargo ship, the total positive rate of SARS-CoV-2 nucleic acid in the frozen seafood was 11.53% (106/919). The positive rate of SARS-CoV-2 nucleic acid in the frozen seafood unloaded by group A (14.29%,70/490) was significantly higher than that in the frozen seafood unloaded by group B (8.39%,36/429)(χ2=7.79,P=0.01) and the viral loads detected in the frozen seafood unloaded by group A were higher than those detected in the frozen seafood unloaded by group B. The scores of personal protection and behaviors in the stevedores in group A were significantly lower than those in group B (P<0.05), and toilet use, smoking and improper hand washing before meals were the risk factors for the infection. Conclusions: The imported frozen seafood was contaminated by SARS-CoV-2 and the contamination distribution was uneven. Supervision and management of personal occupational protection and behaviors of workers engaged in imported frozen food transportation should be strengthened. It is suggested that a closed-loop monitoring and management system for the whole process of "fishing-transport- loading/unloading" should be established by marine fishery authority.

Prevalence and risk factors of peripheral artery disease in a population with chronic kidney disease in Australia: A systematic review and meta-analysis.

There is a lack of clarity and guidance for screening peripheral artery disease (PAD) in persons with chronic kidney disease (CKD) and end stage kidney disease (ESKD) despite this group being at excess risk of cardiovascular disease (CVD). In this current study, we performed a systematic review and meta-analysis to examine the prevalence and risk factors for PAD in persons with CKD in Australian cohorts. We used the inverse variance heterogeneity meta-analysis with double arcsine transformation to summarize the prevalence of PAD (with 95% CIs). Nine studies and 18 reports from the Australia and New Zealand dialysis and transplant registry with 36 cohorts were included in the review. We found a substantially higher PAD prevalence in cohorts based on an ankle-brachial index (ABI) or toe systolic pressure (TBI) than cohorts based on self-reported history. Higher PAD prevalence was observed in ESKD persons than CKD persons without dialysis (PAD diagnosis based on ABI or TBI: 31% in ESKD persons and 23% in CKD persons, PAD diagnosis based on self-reported history: 17% in ESKD persons and 10% in CKD persons). Older age, Caucasian race, cerebrovascular disease and haemodialysis were associated with the presence of PAD in ESKD persons. Our findings indicated a considerable proportion of PAD in CKD and ESKD persons particularly in those with ESKD. To develop and provide an adequate plan to clinically manage CKD patients with PAD, evidence of cost-effectiveness and clinical benefit of early detection of PAD in persons with CKD in Australia is recommended for future studies.

Randomized Trial of 2 Self-Titrated Oral Appliances for Airway Management.

The effectiveness and predictability of 2 different oral appliance (OA) designs to reduce the respiratory event index (REI) in moderate and severe obstructive sleep apnea (OSA) patients requires elucidation. The primary aim of the trial was to determine if 2 widely used midline-traction and bilateral-thrust OA designs differ in effectiveness to reduce the REI within a single test population categorized by OSA severity. Moderate and severe adult OSA patients, who were previously prescribed continuous positive airway pressure therapy (CPAP) but were dissatisfied with it (n = 56), were studied by home-polygraphy in a randomized crossover trial using either midline-traction with restricted mouth opening (MR) or bilateral thrust with opening permitted (BP) design OAs. OAs were used nightly for 4 wk (T2) followed by a 1-wk washout period, then 4 wk (T4) using the alternate OA. REI and oxygen saturation (SaO2) were primary outcomes, while predictability and efficacy comparison of the 2 OAs were secondary outcomes. Thirty-six participants had used MR and BP OAs during both 4-wk study legs. Twenty (55.6%) MR OA-using participants, 25 (69.4%) BP OA-using participants, and 16 (44.4%) participants using both OAs had significant REI reductions. Overall baseline (T0) median REI (interquartile range) of 33.7 (20.7-54.9) was reduced to 18.0 (8.5-19.4) at T2 and to 12.5 (8.2-15.9) at T4 (P < 0.001). Comparison of the 2 sequence groups' (MR-BP and BP-MR) REI showed the median differences between T0 and T2 and T4 were highly significant (P < 0.001). Regression analysis predicted about half of all users will have REIs between 8 and 16 after 2 mo. Baseline overjet measures >2.9 mm predicted greater OA advancement at T4. Mean and minimum SaO2 did not change significantly from T0 to T2 or T4. MR and BP OA designs similarly attenuated REI in moderate and severe OSA individuals who completed the 8-wk study protocol with greater REI reduction in those with severe OSA (ClinicalTrials.gov NCT03219034).

YY1 directly interacts with myocardin to repress the triad myocardin/SRF/CArG box-mediated smooth muscle gene transcription during smooth muscle phenotypic modulation.

Yin Yang 1 (YY1) regulates gene transcription in a variety of biological processes. In this study, we aim to determine the role of YY1 in vascular smooth muscle cell (VSMC) phenotypic modulation both in vivo and in vitro. Here we show that vascular injury in rodent carotid arteries induces YY1 expression along with reduced expression of smooth muscle differentiation markers in the carotids. Consistent with this finding, YY1 expression is induced in differentiated VSMCs in response to serum stimulation. To determine the underlying molecular mechanisms, we found that YY1 suppresses the transcription of CArG box-dependent SMC-specific genes including SM22α, SMα-actin and SMMHC. Interestingly, YY1 suppresses the transcriptional activity of the SM22α promoter by hindering the binding of serum response factor (SRF) to the proximal CArG box. YY1 also suppresses the transcription and the transactivation of myocardin (MYOCD), a master regulator for SMC-specific gene transcription by binding to SRF to form the MYOCD/SRF/CArG box triad (known as the ternary complex). Mechanistically, YY1 directly interacts with MYOCD to competitively displace MYOCD from SRF. This is the first evidence showing that YY1 inhibits SMC differentiation by directly targeting MYOCD. These findings provide new mechanistic insights into the regulatory mechanisms that govern SMC phenotypic modulation in the pathogenesis of vascular diseases.

Adaptive thermogenesis enhances the life-threatening response to heat in mice with an Ryr1 mutation.

Mutations in the skeletal muscle Ca2+ release channel, the type 1 ryanodine receptor (RYR1), cause malignant hyperthermia susceptibility (MHS) and a life-threatening sensitivity to heat, which is most severe in children. Mice with an MHS-associated mutation in Ryr1 (Y524S, YS) display lethal muscle contractures in response to heat. Here we show that the heat response in the YS mice is exacerbated by brown fat adaptive thermogenesis. In addition, the YS mice have more brown adipose tissue thermogenic capacity than their littermate controls. Blood lactate levels are elevated in both heat-sensitive MHS patients with RYR1 mutations and YS mice due to Ca2+ driven increases in muscle metabolism. Lactate increases brown adipogenesis in both mouse and human brown preadipocytes. This study suggests that simple lifestyle modifications such as avoiding extreme temperatures and maintaining thermoneutrality could decrease the risk of life-threatening responses to heat and exercise in individuals with RYR1 pathogenic variants.

Absorption and interaction mechanisms of uranium & cadmium in purple sweet potato(Ipomoea batatas L.).

The purpose of this study was to reveal the absorption and interaction mechanisms of uranium (U) & cadmium (Cd) in corps. Purple sweet potato (Ipomoea batatas L.) was selected as the experimental material. The absorption behavior of U and Cd in this crop and the effects on mineral nutrition were analyzed in a pot experiment. The interactions between U and Cd in purple sweet potato were analyzed using UPLC-MS metabolome analysis. The pot experiment confirmed that the root tuber of the purple sweet potato had accumulated U (1.68-5.16 mg kg-1) and Cd (0.78-2.02 mg kg-1) and would pose a health risk if consumed. Both U and Cd significantly interfered with the mineral nutrient of the roots. Metabolomics revealed that a total of 4865 metabolites were identified in roots. 643 (419 up; 224 down), 526 (332 up; 194 down) and 634 (428 up; 214 down) different metabolites (DEMs) were identified in the U, Cd, and U + Cd exposure groups. Metabolic pathway analysis showed that U and Cd induced the expression of plant hormones (the first messengers) and cyclic nucleotides (cAMP and cGMP, second messengers) in cells and regulated the primary/secondary metabolism of roots to induce resistance to U and Cd toxicity.

Mesenchymal stem cell exosomes in bone regenerative strategies-a systematic review of preclinical studies.

The ability of bone for regeneration has long been recognized. However, once beyond a critical size, spontaneous regeneration of bone is limited. Several studies have focused on enhancing bone regeneration by applying mesenchymal stromal/stem cells (MSCs) in the treatment strategies. Despite the therapeutic efficacy of MSCs in bone regeneration, cell-based therapies are impeded by several challenges in maintaining the optimal cell potency and viability during expansion, storage, and final delivery to patients. Recently, there has been a paradigm shift in therapeutic mechanism of MSCs in tissue repair from one based on cellular differentiation and replacement to one based on secretion and paracrine signaling. Among the broad spectrum of trophic factors, extracellular vesicles â€‹particularly the exosomes have been reported to be therapeutically efficacious in several injury/disease indications, including bone defects and diseases. The current systematic review aims to summarize the results of the existing animal studies which were conducted to evaluate the therapeutic efficacy of MSC exosomes for bone regeneration. Following the Preferred Reporting Items for Systematic Reviews and Meta-analysis â€‹guidelines, the PubMed and The Cochrane Library database were searched for relevant controlled preclinical animal studies. A total of 23 studies were identified, with the total sample size being 690 rats or mice and 38 rabbits. Generally, MSC exosomes were found to be efficacious for bone regeneration in animal models of bone defects and diseases such as osteonecrosis and osteoporosis. In these studies, MSC exosomes promoted new bone formation with supporting vasculature â€‹and displayed improved morphological, biomechanical, and histological outcomes, coupled with positive effects on cell survival, proliferation, and migration, osteogenesis, and angiogenesis. Unclear-to-low risk in bias and incomplete reporting in the primary studies highlighted the need for standardization in outcome measurements and reporting. Further studies in large animal models to establish the safety and efficacy would provide useful information on guiding the design of clinical trials.

Asbestos-related diseases.

Knowledge of asbestos-related diseases has been accumulating for over one hundred years as the industrial value of asbestos was recognised for the strength of its fibres and their resistance to destruction, resulting in increasing production and use until the multiple health effects have become apparent. Deposition in the lung parenchyma results in an inflammatory/progressively fibrotic response, with impaired gas exchange and reduced lung compliance ('asbestosis'), causing progressive dyspnoea and respiratory failure for which only palliation is indicated, although anti-fibrotic agents used for idiopathic usual interstitial pneumonitis remain to be evaluated. Benign pleural effusion, diffuse pleural fibrosis (occasionally with associated rolled atelectasis) and pleural plaques are the non-malignant pleural diseases that result from fibres reaching the pleura. But the main issues that led to the ban on asbestos in industry are those of malignancy: lung cancer, malignant mesothelioma (MM) of the pleura and MM of the peritoneum. Bronchogenic carcinoma risk from asbestos exposure is dose-dependent and multiplies the risk attributable to tobacco smoking. The principles of treatment are as for all cases of lung cancer. Low-dose computed tomography screening of exposed people can detect early-stage, non-small cell cancers, with improved survival. The amphibole varieties of asbestos are much more potent causes of MM than chrysotile, and the risk increases exponentially for 40-50 years following first exposure. As MM is non-resectable and poorly responsive to chemotherapy and radiotherapy, curative treatment is not possible and screening not justified.

[Clinical and pathological analysis of 64 patients with primary neoplasms of the lacrimal drainage system].

Objective: To analyze the pathological classification and age distribution of primary neoplasms of the lacrimal drainage system. Methods: Retrospective case series study. A total of 64 patients (65 eyes) were diagnosed with primary neoplasms of the lacrimal drainage system and received surgery at Tianjin Eye Hospital from January 2006 to December 2016. All the clinical data of the patients were analyzed, including gender, diseased eye, age, clinical manifestations, composition of benign and malignant masses, and prognosis. The histopathological composition and age distribution of patients with primary lacrimal mass, lacrimal duct mass and lacrimal sac mass were analyzed according to the different diseased sites. Results: Twenty-three patients (24 eyes) were male, and 41 patients (41 eyes) were female. The right eye was involved in 36 patients, the left eye in 27 patients, and both eyes in one patient. The age at diagnosis ranged from 12 to 78 years old [mean, (46±4) years]. The course of disease was (13.1±4.2) months, ranging from 1 month to 7 years. The chief complaint was tear discharge in 43 patients, tumor in 19 patients, and abscess discharge in 2 patients. There were 29 patients with angular displacement and 21 patients with swelling pain. There were 51 patients with benign lesions, 4 with borderline lesions, and 9 with malignantlesions. These neoplasms consisted of primary peripunctal neoplasms in 17 patients, primary canalicular neoplasms in 2 patients, and primary lacrimal sac neoplasms in 45 patients. All primary peripunctal neoplasms (17 cases) were benign, among which nevi (10 cases) occupied the first place. All primary canalicular neoplasms (2 cases) were benign, there were 1 case of epidermoid cysts and 1 case of degenerative disease. Among the primary benign lacrimal sac masses (32 cases), mucous epithelial cysts (9 cases), dermoid cysts (6 cases), and epidermoid cysts (6 cases) occupied the first three places. Among the primary borderlin lacrimal sac masses (4 cases), there were 2 cases of giant cell tumor of soft tissue, 1 case of solitary fibrous tumor, and 1 case of inflammatory myofibroblastic tumor. The primary malignant mass of lacrimal sac (9 cases) was dominated by squamous cell carcinoma (3 cases). In terms of age distribution, the patients with primary peripunctal mass were mainly in the group of 40-59 years old (14 cases). The primary benign mass of lacrimal sac mainly occurred in the group of less than 40 years old (15 cases) and the group of 40-59 years old (11 cases). The patients with primary lacrimal sac borderline and malignant masses were all in the groups of over 40 years old. A total of 49 patients were followed up for 27 months to 16 years. The average follow-up time was (57.2±3.8) months. Lacrimal sac transitional cell carcinoma relapsed 7 months after surgery in one patient, and lacrimal sac melanoma relapsed 1 year after surgery in one patient. The patients did not relapse in 24 months and 38 months after surgery respectively. There were no recurrence of other cases. Conclusions: Primary peripunctal neoplasms are mostly characterized with benign lesions, among which nevi are most common. Mucous epithelial cysts, epidermoid cysts, and dermoid cysts are the major benign lacrimal sac neoplasms. Squamous cell carcinomas are the most common malignant lacrimal sac neoplasms. The malignant tumor of lacrimal sac often occurs in the middle-aged and elderly patients. (Chin J Ophthalmol, 2020, 56: 364-369).

Dissociated roles of dorsal and ventral hippocampus in recall and extinction of conditioned fear in male and female juvenile rats.

Reduction of conditioned fear expression by extinction underlies cue exposure therapies that treat anxiety disorders. Extinction is context-specific. Renewal, for example, is the relapse of extinguished fear when subjects are tested in a different context to extinction. This context-specificity is developmentally regulated and sex-dependent, with renewal being observed in postnatal day (P) 18 female, but not in male, rats. Given the hippocampus (HPC) is critical for context-specific extinction in adult rodents, we investigated dorsal or ventral hippocampus (dHPC or vHPC) involvement in context-specific extinction in P18 male and female rats. We microinfused muscimol (GABAA agonist) to inactivate either structure before extinction, then tested rats for renewal the next day. Regardless of sex, dHPC inactivation accelerated extinction acquisition, while vHPC inactivation reduced fear expression during extinction and impaired extinction recall. Consistent with previous findings, renewal was observed in females but not in males. Surprisingly, inactivation of dHPC or vHPC had no effects on renewal in either sex, indicating that the hippocampus does not play a critical role in context-dependent extinction learning in juvenile rats. These findings are the first to demonstrate dissociated roles of dHPC and vHPC in conditioned fear expression and extinction in juvenile rats. In addition, context-specific extinction shown by juvenile females, but not males, likely is not due to potential sex differences in hippocampus involvement in extinction of conditioned fear in developing rats.