Chyluria secondary to disseminated tuberculosis in a 13-year-old female child: A case report.

We report the case of chyluria secondary to disseminated tuberculosis in a 13-year-old female child who presented with passage of white colored urine since 5 months, progressive weight loss for 3 months, abdominal distension for 2 months, generalized swelling of body for 15 days, and pain in abdomen for 10 days. Child had good recovery following treatment with antitubercular drugs. Though chyluria is uncommon in children, tuberculosis could be considered as a differential, after ruling out filariasis.

Dilemma in diagnosing incomplete Kawasaki disease in a resource limited setting.

Introduction and importance: Kawasaki disease (KD) is an acute febrile systemic vasculitis that predominantly affects small to medium sized vessels and mostly occurs in children below 5 years of age. The morbidity and mortality mostly occur due to cardiac involvement. Case presentation: The authors present a case of a 5-year-old male child from hilly region of Nepal who presented with fever for 7 days along with strawberry tongue and non-exudative conjunctivitis without rashes, extremity changes or lymphadenopathy. A suspicion of incomplete KD (IKD) was made. The notable investigation findings were increased erythrocyte sedimentation rate, C-reactive protein, leucocyte count and platelets. Echocardiography showed normal findings. Based on the clinical features and supplemental laboratory findings, a diagnosis of IKD was made. The patient improved after intravenous immunoglobulin and Aspirin. Clinical discussion: The main learning objective that the authors get from this case is the challenges in the diagnosis of IKD in the resource limited setting like Nepal. Whether or not to start intravenous immunoglobulin is a dilemma for the physician in most of the cases of suspected IKD, due to the high cost and poor availability of intravenous immunoglobulin in this setting. Hence, the use of inflammatory markers, supplemental laboratory findings together with the few diagnostic criteria met by the patient helps in making a diagnosis and institute timely treatment with intravenous immunoglobulin and aspirin. Conclusion: Diagnosis of KD in difficult in resource limited setting.

A tale of two receptors: simultaneous targeting of NMDARs and 5-HT 4 Rs exerts additive effects against stress.

BACKGROUND: Serotonin (5-HT) receptors and N -methyl-D-aspartate receptors (NMDARs) have both been implicated in the pathophysiology of depression and anxiety disorders. Here, we evaluated whether targeting both receptors through combined dosing of ( R , S )-ketamine, an NMDAR antagonist, and prucalopride, a serotonin type IV receptor (5-HT 4 R) agonist, would have additive effects, resulting in reductions in stress-induced fear, behavioral despair, and hyponeophagia. METHODS: A single injection of saline (Sal), ( R , S )-ketamine (K), prucalopride (P), or a combined dose of ( R , S )-ketamine and prucalopride (K+P) was administered before or after contextual fear conditioning (CFC) stress in both sexes. Drug efficacy was assayed using the forced swim test (FST), elevated plus maze (EPM), open field (OF), marble burying (MB), and novelty-suppressed feeding (NSF). Patch clamp electrophysiology was used to measure the effects of combined drug on neural activity in hippocampal CA3. c-fos and parvalbumin (PV) expression in the hippocampus (HPC) and medial prefrontal cortex (mPFC) was examined using immunohistochemistry and network analysis. RESULTS: We found that a combination of K+P, given before or after stress, exerted additive effects, compared to either drug alone, in reducing a variety of stress-induced behaviors in both sexes. Combined K+P administration significantly altered c-fos and PV expression and network activity in the HPC and mPFC. CONCLUSIONS: Our results indicate that combined K+P has additive benefits for combating stress-induced pathophysiology, both at the behavioral and neural level. Our findings provide preliminary evidence that future clinical studies using this combined treatment strategy may prove advantageous in protecting against a broader range of stress-induced psychiatric disorders.

A case report of infanticide in rural Nepal: Sociocultural perspectives and forensic considerations.

This case highlights the complex interplay of mental health, stigma, and lack of contraceptive access underlying tragic instances of infanticide. Comprehensive medicolegal investigation paired with cross-sector efforts to expand reproductive services and transform cultural attitudes is crucial to protect vulnerable women and children.

Vaccine Derived Poliovirus (VDPV).

Poliomyelitis is caused by Poliovirus, a member of a large group of enteroviruses. Vaccine-derived polioviruses (VDPVs) stem from mutated live poliovirus, which is contained in the Oral Polio Virus vaccine (OPV). In addition, the emergence of VDPV is one of the global challenges for the eradication of poliomyelitis. VDPVs continue to affect different parts of the world; 1081 cases occurred in 2020 and 682 cases in 2021. There are several reasons that may have caused the increase in circulating vaccine-derived poliovirus (cVDPV) after the "switch" from the trivalent to the bivalent oral polio vaccine. One reason is the low vaccination rate among the targeted population, which has been further aggravated by the COVID-19 pandemic. Several strategies could control the spread of VDPV including the use of the monovalent OPV (mOPV-2). The risk of VDPV can be minimized through increased immunization rates and the use of safer vaccine alternatives. The global effort to eradicate polio has made significant progress over the years, but continued vigilance and investment in immunization programs are needed to achieve the ultimate goal of a polio-free world.

Outbreak of an emerging zoonotic Nipah virus: An emerging concern.

The Nipah virus (NiV) infection is one of the newly emerging deadly zoonotic diseases which carries a significant weightage of mortality among its victims. Due to the relatively recent history of its emergence and only a few known outbreaks, we cannot predict but foresee its potential to create havoc, which can be far more dreadful than the current ongoing COVID-19 pandemic. Here we have tried to depict the fatal potential of the virus and the increased propensity with which it can spread to rest of the world.

Study of correlation between vitamin D3 levels and dry eye.

Purpose: Dry eye is a prevalent disorder of tear film resulting from either decreased tear production or increased tear evaporation. It is becoming a serious issue due to its disturbing symptoms, which become progressively troublesome affecting the work efficiency of patients and increasing financial burden due to lifelong dependency on eye drops. If not detected early, it can lead to sight-threatening complications. This study aims to explore serum vitamin D3 deficiency as a causative factor of dry eye. Methods: The study was conducted in the outpatient department of a tertiary care hospital in India, for a period of two years from September 2018 to September 2020. About 40 patients who had dry eye and 20 controls were enrolled in this study. They were given an Ocular Surface Disease Index (OSDI) questionnaire, examined for signs of dry eye on slit lamp with Schirmer's test and tear film break-up time. All 60 participants were subjected to serum vitamin D3 level laboratory test and its deficiency prevalence was correlated with dry eye and its severity. Results: Serum vitamin D3 deficiency was found to be more prevalent in patients with dry eye. There was no gender predilection or change in prevalence with increasing age. Vitamin D3 level was negatively correlated with OSDI and positively with Schirmer's test 1 and 2 and tear film break-up time (TBUT) scores. Conclusion: The prevalence of vitamin D3 deficiency was not consistently found to be associated with the increasing severity of dry eye.

A comprehensive review on space solar power satellite: an idiosyncratic approach.

Space solar power satellite (SSPS) is a prodigious energy system that collects and converts solar power to electric power in space, and then transmits the electric power to Earth wirelessly. The main principle of this system is to supply constant solar energy by placing collectors in geo-synchronous orbit and collecting it on an Earth-based receiver, known as a rectenna. This system can overcome serious drawbacks, especially the pseudo-random intermittent capacity factor of ground-based solar power or photovoltaic systems and modules. This paper discusses some old and new concepts of solar power satellite designs and the effects of various parameters on the efficiency of collecting medium, transmission media, and receivers' area. We evaluated and reviewed the three major components of the space-based satellite that have a hand in affecting the overall efficiency of the system, which are (1) collection unit, (2) power transmission unit, and (3) the receiving unit. This paper reviews the system as a whole, as proposed in the last three decades. Many of the microwave-based SSPS models that were proposed so far are based on solar concentrators. The required launch mass and system cost could be significantly reduced by using solar concentration and hence higher efficiency can be achieved. SSPS requires new microwave technology to achieve a high power conversion efficiency of over 80% and extremely accurate beam control from the 2 km phased array transmitting antenna. Such specifications are extremely demanding and therefore significant effort is required for proper research and development. Under this technology roadmap, current research and development lead to the beginning of the new SSPS era in the coming decades.

Evaluation of Infraorbital Nerve Recovery and its Effect on Quality of Life following Open Reduction and Internal Fixation of Zygomaticomaxillary Complex Fractures - An Evaluative Study.

Introduction: The zygomaticomaxillary complex (ZMC) fractures are the second most common fractures affecting the midfacial skeleton. Neurosensory disturbances of the infraorbital nerve are one of the most common signs of ZMC fractures. The aim of the study was to evaluate the neurosensory recovery of the infraorbital nerve and its effect on the quality of life (QoL) following open reduction and internal fixation of ZMC fractures. Methods: Thirteen patients clinically and radiologically diagnosed with unilateral ZMC fractures with neurosensory deficits of the infraorbital nerve were enrolled for this study. All patients were assessed presurgically for neurosensory deficits of the infraorbital nerve using the various neurosensory tests, followed by open reduction with two-point fixation under general anaesthesia. The patients were followed up at one, three and six months postoperatively to evaluate the recovery of neurosensory deficits. Results: Recovery of tactile and pain sensation was relatively complete in 84.62% and 76.92% of patients respectively by the end of six months postoperatively. The spatial mechanoreception of the affected side improved significantly. 61.54% of patients led an excellent QoL six months postoperatively. Discussion: The majority of the patients with ZMC fractures and neurosensory deficits of the infraorbital nerve, when treated with open reduction and internal fixation, have complete recovery of the neurosensory deficits by the end of six months postoperatively. However, some patients may continue to experience some long-term residual deficits, which can affect the patient's QoL.

Use of Marsupialisation for a Conservative Approach to Huge Cystic Lesions of the Jaws - A Report of three Cases.

Rationale: The management of cystic lesions of the jaws presents a challenge to the surgeon. Marsupialisation, one of the conservative management options, has been used as a single or combined surgical treatment modality for the cystic lesions of the jaws. Patient Concerns: All patients presented with a complaint of a firm swelling of the face with one of the patients presenting with paraesthesia in the affected area. Diagnosis: Clinical and radiographic examination was carried out followed by aspiration cytology. All lesions were provisionally diagnosed with odontogenic cystic lesions. Treatment: Marsupialisation under general anaesthesia was carried out for all patients. Postoperatively, a customised obturator was fabricated. Outcomes: All the patients showed good radiological ossification postoperatively. Take-Away Lessons: The approach to larger cysts remains controversial. The long-term results following the marsupialisation of extensive cysts of this report may help surgeons to opt for a conservative approach to such lesions before aggressive options.

In-silico and in-vivo evaluation of sesamol and its derivatives for benign prostatic hypertrophy.

Pharmacological treatment for BPH includes 5-α reductase inhibitors as Finasteride and Dutasteride as a monotherapy or in combination with antimuscarinic drugs, alpha-blockers, 5-phosphodiesterase inhibitor drugs. Androgen receptor inhibitors revealed several adverse events as decreased libido, erectile dysfunction, ejaculatory dysfunction, and gynecomastia. Hence, the emergence of complementary and alternative medications having safety profile-preferably, edible natural products-would be highly desirable. In-silico studies based on Maestro Molecular Modelling platform (version 10.5) by SchrÓ§dinger, LLC was used to identify the lead molecules. The in-vivo activity studied on rats gave the positive results. The findings based on experiments as antioxidant parameters showed the potential to quench the free radicals. The significant results were also seen in prostatic index and histopathological studies supported the above findings. Based on these data, sesamol and derivative have proven efficacy in protecting against testosterone induced BPH. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-021-02952-z.

Efficacy of free gingival graft in the augmentation of keratinized tissue around implants: A prospective clinical study.

BACKGROUND: Effectuating adequate width of keratinized tissue (WKT) can lead to a healthy and stable implant/soft tissue interface which is important for the long term success of the implant. The use of free gingival grafts (FGG) for widening the WKT around dental implants increases the amount of attached gingival tissue and prevents clinical attachment loss. AIM: The aim of the study was to assess the ability of FGG to create a healthy implant/soft tissue interface. METHODS AND MATERIAL: A total of 10 edentulous sites in 10 patients with inadequate keratinized tissue indicated for replacement of missing teeth were treated. An implant was placed in edentulous sites and the keratinized tissue was augmented using FGG at the second stage of implant surgery. WKT was recorded at baseline, 3rd month and 6th month post-operatively. Plaque index (PI), gingival index (GI), probing depth (PD) and papillary index (PPI) and were recorded at 3 and 6 months post-operatively to evaluate the health of peri-implant tissues. Paired t-test was used for standard deviation and the level of significance was taken as 5% (P < 0.05). RESULTS: The WKT at 3 (3.2±1.61mm) and 6 months (3±1.56 mm) compared to the baseline was statistically significant (P = 0.034). The other parameters PI, GI, PD, PPI showed no clinical significance from 3 and 6 months (P > 0.05). CONCLUSIONS: Augmentation of FGG created a significant gain in the WKT which resulted in a healthy implant/soft tissue interface.

Cyclodextrin based bone regenerative inclusion complex for resveratrol in postmenopausal osteoporosis.

Recent preclinical studies have shown that resveratrol (RSV), is a promising remedy for osteoporosis owing to its estrogenic, anti-inflammatory, and antioxidant properties. However, RSV has met limited success due to its poor oral bioavailability and inefficient systemic delivery. In this study, we prepared the inclusion complex of RSV with sulfo-butyl ether ß-cyclodextrin (SBE-ß-CD) to enhance the aqueous solubility of RSV. The in-silico docking studies and Physico-chemical characterization assays were performed to understand the interaction of RSV inside the SBE-ß-CD cavity. The in vivo safety assessment of RSV-SBE-ß-CD inclusion complex (R-CDIC) was performed in healthy Wistar rats. The efficacy of the inclusion complex against postmenopausal osteoporosis was further investigated in ovariectomized (OVX) rat model. The alteration in the bone micro-architectural structure was evaluated by microcomputed tomographic scanning, serum biochemical estimations, biomechanical strength and histopathological investigation. Administration of RSV-SBE-ß-CD inclusion complex was found to be safe and significantly improved micro-architectural deterioration induced by estrogen withdrawal. Results of bone morphometry and biomechanics study further emboldened the efficacy claim of the RSV-SBE-ß-CD complex. Thus, the present study demonstrated the efficacy of the RSV-SBE-ß-CD inclusion complex for treating osteolytic degradation in osteoporosis.

Evaluating Glycemic Control in Patients of South Asian Origin With Type 2 Diabetes Using a Digital Therapeutic Platform: Analysis of Real-World Data.

BACKGROUND: Digital therapeutics are evidence-based therapeutic interventions driven by high-quality software programs for the treatment, prevention, or management of a medical disorder or disease. Many studies in the western population have shown the effectiveness of mobile app-based digital therapeutics for improving glycemic control in patients with type 2 diabetes (T2D). However, few studies have assessed similar outcomes in the South Asian population. OBJECTIVE: This study aims to investigate the real-world effectiveness of the Wellthy CARE digital therapeutic for improving glycemic control among the South Asian population of Indian origin. METHODS: We analyzed deidentified data from 102 patients with T2D from India enrolled in a 16-week structured self-management program delivered using the Wellthy CARE mobile app. Patients recorded their meals, weight, physical activity, and blood sugar in the app, and they received lessons on self-care behaviors (healthy eating, being active, monitoring, medication adherence, problem solving, healthy coping, and reducing risks); feedback provided by an artificial intelligence-powered chatbot; and periodic interactions with certified diabetes educators via voice calls and chats. The primary outcome of the program was a change in glycated hemoglobin A1c (HbA1c). Secondary outcomes included the difference between preintervention and postintervention fasting blood glucose (FBG) and postprandial blood glucose (PPBG) levels; changes in BMI and weight at the completion of 16 weeks; and the association between program engagement and the changes in HbA1c, FBG, and PPBG levels. RESULTS: At the end of 16 weeks, the average change in HbA1c was -0.49% (n=102; 95% CI -0.73 to 0.25; P<.001). Of all the patients, 63.7% (65/102) had improved HbA1c levels, with a mean change of -1.16% (n=65; 95% CI -1.40 to -0.92; P<.001). The mean preintervention and postintervention FBG levels were 145 mg/dL (n=51; 95% CI 135-155) and 134 mg/dL (n=51; 95% CI 122-146; P=.02) and PPBG levels were 188 mg/dL (n=51; 95% CI 172-203) and 166 mg/dL (n=51; 95% CI 153-180; P=.03), respectively. The mean changes in BMI and weight were -0.47 kg/m2 (n=59; 95% CI -0.22 to -0.71; P<.001) and -1.32 kg (n=59; 95% CI -0.63 to -2.01; P<.001), respectively. There was a stepwise decrease in HbA1c, FBG, and PPBG levels as the program engagement increased. Patients in the highest tertile of program engagement had a significantly higher reduction in HbA1c (-0.84% vs -0.06%; P=.02), FBG (-21.4 mg/dL vs -0.18 mg/dL; P=.02), and PPBG levels (-22.03 mg/dL vs 2.35 mg/dL; P=.002) than those in the lowest tertile. CONCLUSIONS: The use of the Wellthy CARE digital therapeutic for patients with T2D showed a significant reduction in the levels of HbA1c, FBG, and PPBG after 16 weeks. A higher level of participation showed improved glycemic control, suggesting the potential of the Wellthy CARE platform for better management of the disease.

Organ histopathological associations with hyperostosis frontalis interna in humans / Asociaciones histopatológicas de órganos con hiperostosis frontal interna en humanos

SUMMARY: An increased thickening of the frontal bone by irregular laminar additions on the inner surface just deep to the dura mater have been known in the archaeological and medical record as hyperostosis frontalis interna (HFI). The distribution of this is idiosyncratically restricted to the frontal and has no known etiology. The prevalence among post-menopausal females and rarity in males suggests that it is hormonally driven. Here we report histopathological findings of particularly hormonally active organs (pituitaries, gonads and liver) from a geriatric cadaveric sample in which HFI is assessed. HFI was present in 50 % of males (7/14) and 95 % (21/22) of females. All males with HFI had testicular atrophy or had testes absent. Males with HFI category C or D had moderate to severe testicular atrophy. Decreased numbers of interstitial cells (Leydig cells) were present in 83.3 % of males with HFI. All but one female (21/22) from this study exhibited evidence of HFI, and ovarian pathologies were unevenly distributed (fibromas in two) and most exhibited signs of being healthy and post-menopausal. Liver pathologies had opposite patterns between the sexes, with more liver pathologies occurring among males without HFI (particularly passive congestion and bile stasis). The only exceptions were that the one case of liver neoplasia was found in a male with HFI and steotosis was found in two cases with HFI and one case without HFI. In females all cases of liver pathologies (steotosis, hepatitis, passive congestion, fibrosis, and bile stasis) were associated with HFI. It appears that gonadal pathology is most closely associated with HFI in males but not females, suggesting that the role of estradiol in this unusual growth of bone in geriatric humans may be worth investigating further.

RESUMEN: Un aumento del engrosamiento del hueso frontal, por adiciones laminares irregulares en la superficie interna, justo en la profundidad de la duramadre, se conoce en los registros arqueológicos y médicos como hiperostosis frontal interna (HFI). La distribución de ésta, se restringe idiosincráticamente al hueso frontal y no tiene etiología conocida. La prevalencia entre las mujeres posmenopáusicas y la rareza en los hombres sugiere que se debe a las hormonas. Aquí informamos los hallazgos histopatológicos de órganos hormonalmente activos (hipófisis, gónadas e hí- gado) de una muestra de cadáveres geriátricos en la que se evaluó HFI. La HFI estuvo presente en el 50 % de los hombres (7/14) y el 95 % (21/22) de las mujeres. Todos los hombres con HFI tenían atrofia testicular o no tenían testículos. En los hombres con HFI categoría C o D se observó atrofia testicular de moderada a grave. Hubo una disminución en el número de células intersticiales (células de Leydig) en el 83,3 % de los hombres con HFI. En 21de 22 mujeres se observó evidencia de HFI, y las patologías ováricas se distribuyeron de manera desigual (fibromas en dos) y la mayoría exhibió signos de estar sana y posmenopáusica. Las patologías hepáticas tenían patrones opuestos entre los sexos, con más patologías hepáticas entre los hombres sin HFI (particularmente congestión pasiva y estasis biliar). Las excepciones fueron que el único caso de neoplasia hepática se encontró en un varón con HFI y se presentó esteatosis en dos casos con HFI y un caso sin HFI. En las mujeres, todos los casos de patologías hepáticas (esteatosis, hepatitis, congestión pasiva, fibrosis y estasis biliar) se asociaron con HFI. Al parecer la patología gonadal está más estrechamente asociada con la HFI en los hombres que en las mujeres, lo que sugiere un rol del estradiol en este crecimiento inusual de hueso en hombres de avanzada edad. Sería importante realizar investigaciones más detalladas precisas respecto a la hiperostosis frontal interna.

Histone Deacetylase Inhibitors Prevented the Development of Morphine Tolerance by Decreasing IL6 Production and Upregulating µ-Opioid Receptors.

BACKGROUND: Morphine tolerance on long-term usage leads to chronic pain conditions. Preclinical studies demonstrated that the upregulation of HDACs is associated with a decrease in the sensitivity of µ-opioid receptors, which results in morphine tolerance. OBJECTIVE: The present study was designed to assess the influence of the selected known HDAC inhibitors (NMJ2 and NMJ3) on the pain tolerance induced by chronic administration of morphine in Balb/c mice. METHODS: In the present study, morphine was administered in incremental doses 1, 2, 3.6, 6.5, 11.2, 21, and 21 mg/kg daily for seven days to develop morphine tolerance. The nociceptive thresholds, analgesia, and tolerance were assessed 30 min after morphine administration alternatively from 1st day to 7th day using the hot plate and mechanical allodynia methods. RESULTS: The morphine control group showed a reduction in the Paw Withdrawal Threshold (PWT) and the percentage Maximum Possible Effects (MPEs). In contrast, the combination of SAHA and test drugs with morphine increased the PWT and MPEs as compared to the morphine alone group. Administration of morphine alone also showed an increase in the production of the pro-inflammatory mediator, IL-6, and down-regulation of the µ-opioid receptor in the brain tissues. Treatment with HDAC inhibitors, SAHA, and test drugs showed a reversal in these changes. CONCLUSION: Results indicated that HDAC inhibitors were involved in the prevention of morphine tolerance in normal mice by inhibiting pro-inflammatory marker production and by increasing the sensitivity of neurons towards morphine in producing an analgesic effect in morphine tolerated mice.

Mechanistic targets for BPH and prostate cancer-a review.

All men, almost, suffer from prostatic disorders in average life expectancy. In the year of 1950s, the first autopsy of prostate gland discovered the link between Benign prostatic hyperplasia (BPH) and Prostate Cancer (PCa). After that, many histology, biochemistry, epidemiology studies explained the association and associated risk factor for the same. From the various scientific evidence, it is proved that both diseases share some common transcription factors and signalling pathways. Still, BPH cannot be considered as the first step of PCa progression. To define, the relationship between both of the diseases, a well-defined large epidemiological study is needed. Along with androgen signalling, imbalanced apoptosis, oxidative stress, and microbial infection also crucial factors that significantly affect the pathogenesis of BPH. Various signalling pathways are involved in the progression of BPH. Androgen signalling is the driving force for the progress of PCa. In PCa androgen signalling is upregulated as compared to a healthy prostate. Some dominant Androgen-regulated genes and their functions have been discussed in this work.

Acquired Cystic Kidney Disease-associated Renal Cell Carcinoma (ACKD-RCC) Harbor Recurrent Mutations in KMT2C and TSC2 Genes.

Individuals with acquired cystic kidney disease (ACKD) in the setting of end-stage renal disease (ESRD) have a high risk of developing renal cell carcinoma (RCC). ACKD-RCC is considered a distinct renal neoplasm in the International Society of Urologic Pathologists (ISUP)-World Health Organization (WHO) classification of kidney tumors which may behave aggressively. Since its original description, there have been multiple case reports and series published; however, the pathogenesis of this neoplasm is uncertain and there is limited data on the genetic aberrations of this tumor. Herein, we present our experience with ESRD kidneys, with emphasis on ACKD-RCC, associated cysts, and the somatic mutation analysis of a subset of ACKD-RCCs using next-generation sequencing. Our data on 59 cases with ESRD that underwent nephrectomy, shows that ACKD-RCC represents more than half of the tumors (25/46; 54%) developing in ESRD, followed by papillary RCC (13; 28%). History of dialysis, male sex, and African American race were potential risk factors for developing ACKD-RCCs. Further, ACKD-RCC-like cysts are possible precursors of RCCs in the ACKD setting noted in 40 of 46 (87%) cases with tumors. Next-generation sequencing analysis revealed recurrent mutations in the KMT2C gene in 4 of 5 ACKD-RCCs (80%), exclusively exhibiting cribriform "sieve-like" morphology; whereas the case negative for KMT2C mutations exhibited "type 2" papillary RCC morphology and lacked "sieve-like" growth pattern. Pathogenic mutations in TSC2 were the second common abnormality (3/5; 60%), often coexisting with KMT2C mutations. Deleterious mutations in additional genes such as CBL, PDGFRA, and SYNE1, etc. were noted but were nonrecurrent and always coexisted with mutations in KMT2C or TSC2. To conclude, our study highlights that mutations in a chromatin-modifying gene KMT2C may potentially be oncogenic drivers for the development of ACKD-RCC with classic sieve-like morphology. In addition, pathogenic mutations in TSC2 possibly play a role in the development of cysts/tumors in a subset of ACKD patients. If corroborated in larger cohorts, these findings would be useful in planning surveillance and early intervention in ESRD patients developing ACKD.

Sex-specific neurobiological actions of prophylactic (R,S)-ketamine, (2R,6R)-hydroxynorketamine, and (2S,6S)-hydroxynorketamine.

Enhancing stress resilience in at-risk populations could significantly reduce the incidence of stress-related psychiatric disorders. We have previously reported that the administration of (R,S)-ketamine prevents stress-induced depressive-like behavior in male mice, perhaps by altering α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated transmission in hippocampal CA3. However, it is still unknown whether metabolites of (R,S)-ketamine can be prophylactic in both sexes. We administered (R,S)-ketamine or its metabolites (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) and (2S,6S)-hydroxynorketamine ((2S,6S)-HNK) at various doses 1 week before one of a number of stressors in male and female 129S6/SvEv mice. Patch clamp electrophysiology was used to determine the effect of prophylactic drug administration on glutamatergic activity in CA3. To examine the interaction between ovarian hormones and stress resilience, female mice also underwent ovariectomy (OVX) surgery and a hormone replacement protocol prior to drug administration. (2S,6S)-HNK and (2R,6R)-HNK protected against distinct stress-induced behaviors in both sexes, with (2S,6S)-HNK attenuating learned fear in male mice, and (2R,6R)-HNK preventing stress-induced depressive-like behavior in both sexes. (R,S)-ketamine and (2R,6R)-HNK, but not (2S,6S)-HNK, attenuated large-amplitude AMPAR-mediated bursts in hippocampal CA3. All three compounds reduced N-methyl-D-aspartate receptor (NMDAR)-mediated currents 1 week after administration. Furthermore, ovarian-derived hormones were necessary for and sufficient to restore (R,S)-ketamine- and (2R,6R)-HNK-mediated prophylaxis in female mice. Our data provide further evidence that resilience-enhancing prophylactics may alter AMPAR-mediated glutamatergic transmission in CA3. Moreover, we show that prophylactics against stress-induced depressive-like behavior can be developed in a sex-specific manner and demonstrate that ovarian hormones are necessary for the prophylactic efficacy of (R,S)-ketamine and (2R,6R)-HNK in female mice.