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Purpose: We describe a simple and effective method to reduce the risk of infection after prostate biopsy. Materials and Methods: A total of 1,642 consecutive prostate biopsy procedures during a 4-year period (2008 to 2012) were included in the study. Inclusion criteria consisted of pre-biopsy negative urine culture, bisacodyl enema and fluoroquinolone antibiotics (3 days). Formalin (10%) was used to disinfect the needle tip after each biopsy core. All patients were monitored for post-biopsy infection. The rate of infection was compared to that of a historical series of 990 procedures. Two ex vivo experiments were conducted to test the disinfectant effectiveness of formalin against fluoroquinolone resistant Escherichia coli, and another experiment was performed to quantitate formalin exposure. Results: Post-biopsy clinical sepsis with positive urine and blood cultures (quinolone resistant E. coli) developed in 2 patients (0.122%). Both patients were hospitalized, treated with intravenous antibiotics and had a full recovery without long-term sequelae. Mild uncomplicated urinary infection developed in 3 additional patients (0.183%). All were treated with outpatient oral antibiotics and had a complete recovery. The overall rate of urinary infection and sepsis using formalin disinfection was approximately a third of that of a prior series (0.30% vs 0.80%, p = 0.13). Ex vivo experiments showed a complete lack of growth of fluoroquinolone resistant E. coli on blood and MacConkey agars after exposure to formalin. The amount of formalin exposure was negligible and well within the safe parameters of the Environmental Protection Agency. Conclusions: Formalin disinfection of the biopsy needle after each prostate biopsy core is associated with a low incidence of urinary infection and sepsis. This technique is simple, effective and cost neutral. [Copyright &y& Elsevier]

PYY is a gutderived putative satiety signal released in response to nutrient ingestion and is implicated in the regulation of energy homeostasis. Pyy-expressing neurons have been identified in the hindbrain of river lamprey, rodents, and primates. Despite this high evolutionary conservation, little is known about central PYY neurons. Using in situ hybridization, PYY-Cre;ROSA-EYFP mice, and immunohistochemistry, we identified PYY cell bodies in the gigantocellular reticular nucleus region of the hindbrain. PYY projections were present in the dorsal vagal complex and hypoglossal nucleus. In the hindbrain, Pyy mRNA was present at E9.5, and expression peaked at P2 and then decreased significantly by 70% at adulthood. We found that, in contrast to the circulation, PYY-(1-36) is the predominant isoform in mouse brainstem extracts in the ad libitum-fed state. However, following a 24-h fast, the relative amounts of PYY-(1-36) and PYY-(3- 36) isoforms were similar. Interestingly, central Pyy expression showed nutritional regulation and decreased significantly by acute starvation, prolonged caloric restriction, and bariatric surgery (enterogastroanastomosis). Central Pyy expression correlated with body weight loss and circulating leptin and PYY concentrations. Central regulation of energy metabolism is not limited to the hypothalamus but also includes the midbrain and the brainstem. Our findings suggest a role for hindbrain PYY in the regulation of energy homeostasis and provide a starting point for further research on gigantocellular reticular nucleus PYY neurons, which will increase our understanding of the brain stem pathways in the integrated control of appetite and energy metabolism. [ABSTRACT FROM AUTHOR]

OBJECTIVE--AMP-activated protein kinase (AMPK) signaling acts as a sensor of nutrients and hormones in the hypothalamus, thereby regulating whole-body energy homeostasis. Deletion of Ampka2 in pro-opiomelanocortin (POMC) neurons causes obesity and defective neuronal glucose sensing. LKB1, the Peutz-Jeghers syndrome gene product, and Ca2+ -calmodulin-dependent protein kinase kinase β (CaMKKβ) are key upstream activators of AMPK. This study aimed to determine their role in POMC neurons upon energy and glucose homeostasis regulation. RESEARCH DESIGN AND METHODS--Mice lacking either Camkkβ or Lkb1 in POMC neurons were generated, and physiological, electrophysiological, and molecular biology studies were performed. RESULTS--Deletion of Camkkβ in POMC neurons does not alter energy homeostasis or glucose metabolism. In contrast, female mice lacking Lkb1 in POMC neurons (PomcLkb1KO) display glucose intolerance, insulin resistance, impaired suppression of hepatic glucose production, and altered expression of hepatic metabolic genes. The underlying cellular defect in PomcLkb1KO mice involves a reduction in melanocortin tone caused by decreased β-melanocyte-stimulating hormone secretion. However, Lkb1-deficient POMC neurons showed normal glucose sensing, and body weight was unchanged in PomcLkb1KO mice. CONCLUSIONS--Our findings demonstrate that LKB1 in hypothalamic POMC neurons plays a key role in the central regulation of peripheral glucose metabolism but not body-weight control. This phenotype contrasts with that seen in mice lacking AMPK in POMC neurons with defects in body-weight regulation but not glucose homeostasis, which suggests that LKB1 plays additional functions distinct from activating AMPK in POMC neurons. [ABSTRACT FROM AUTHOR]

AMPK (AMP-activated protein kinase) signalling plays a key role in whole-body energy homoeostasis, although its precise role in pancreatic β-cell function remains unclear. In the present stusy, we therefore investigated whether AMPK plays a critical function in β-cell glucose sensing and is required for the maintenance of normal glucose homoeostasis. Mice lacking AMPKα2 in β-cells and a population of hypothalamic neurons (RIPCreα2KO mice) and RIPCreα2KO mice lacking AMPKα1 (α1KORIPCreα2KO) globally were assessed for whole-body glucose homoeostasis and insulin secretion. Isolated pancreatic islets from these mice were assessed for glucose-stimulated insulin secretion and gene expression changes. Cultured β-cells were examined electrophysiologically for their electrical responsiveness to hypoglycaemia. RIPCreα2KO mice exhibited glucose intolerance and impaired GSIS (glucose-stimulated insulin secretion) and this was exacerbated in α1KORIPCreα2KO mice. Reduced glucose concentrations failed to completely suppress insulin secretion in islets from RIPCreα2KO and α1KORIPCreα2KO mice, and conversely GSIS was impaired. β-Cells lacking AMPKα2 or expressing a kinase-dead AMPKα2 failed to hyperpolarize in response to low glucose, although KATP (ATP-sensitive potassium) channel function was intact. We could detect no alteration of GLUT2 (glucose transporter 2), glucose uptake or glucokinase that could explain this glucose insensitivity. UCP2 (uncoupling protein 2) expression was reduced in RIPCreα2KO islets and the UCP2 inhibitor genipin suppressed low-glucose-mediated wild-type mouse β-cell hyperpolarization, mimicking the effect of AMPKα2 loss. These results show that AMPKα2 activity is necessary to maintain normal pancreatic β-cell glucose sensing, possibly by maintaining high β-cell levels of UCP2. [ABSTRACT FROM AUTHOR]

Recent evidence suggests that alterations in insulin/insulin-like growth factor 1 (IGF1) signaling (IIS) can increase mammalian life span. For example, in several mouse mutants, impairment of the growth hormone (GH)/IGF1 axis increases life span and also insulin sensitivity. However, the intracellular signaling route to altered mammalian aging remains unclear. We therefore measured the life span of mice lacking either insulin receptor substrate (IRS) 1 or 2, the major intracellular effectors of the IIS receptors. Our provisional results indicate that female Irs1-/- mice are long-lived. Furthermore, they displayed resistance to a range of age-sensitive markers of aging including skin, bone, immune, and motor dysfunction. These improvements in health were seen despite mild, lifelong insulin resistance. Thus, enhanced insulin sensitivity is not a prerequisite for IIS mutant longevity. Irs1-/- female mice also displayed normal anterior pituitary function, distinguishing them from long-lived somatotrophic axis mutants. In contrast, Irs2-/- mice were short-lived, whereas Irs1+/- and Irs2+/- mice of both sexes showed normal life spans. Our results therefore suggest that IRS1 signaling is an evolutionarily conserved pathway regulating mammalian life span and may be a point of intervention for therapies with the potential to delay age-related processes. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is a fatal inherited autosomal dominant neurodegenerative disorder caused by an expansion in the number of CAG trinucleotide repeats in the huntingtin gene. The disease is characterized by motor, behavioural and cognitive symptoms for which at present there are no disease altering treatments. It has been shown that manipulating the mTOR (mammalian target of rapamycin) pathway using rapamycin or its analogue CCI-779 can improve the cellular and behavioural phenotypes of HD models. Ribosomal protein S6 kinase 1 (S6K1) is a major downstream signalling molecule of mTOR, and its activity is reduced by rapamycin suggesting that deregulation of S6K1 activity may be beneficial in HD. Furthermore, S6k1 knockout mice have increased lifespan and improvement in age-related phenotypes. To evalute the potential benefit of S6k1 loss on HD-related phenotypes, we crossed the R6/2 HD model with the long-lived S6k1 knockout mouse line. We found that S6k1 knockout does not ameliorate behavioural or physiological phenotypes in the R6/2 mouse model. Additionally, no improvements were seen in brain mass reduction or mutant huntingtin protein aggregate levels. Therefore, these results suggest that while a reduction in S6K1 signalling has beneficial effects on ageing it is unlikely to be a therapeutic strategy for HD patients. [ABSTRACT FROM AUTHOR]

Background: The presence of hypoxic areas is common in all breast lesions but no data clearly correlate low oxygenation with the acquisition of malignant features by non-invasive cells, particularly by cells from ductal carcinoma in situ (DCIS), the most frequently diagnosed tumor in women.Methods: By using a DCIS-derived cell line, we evaluated the effects of low oxygen availability on malignant features of non-invasive breast tumor cells and the possible role of all-trans retinoic acid (ATRA), a well-known anti-leukemic drug, in counteracting the effects of hypoxia. The involvement of the β2 isoform of PI-PLC (PLC-β2), an ATRA target in myeloid leukemia cells, was also investigated by specific modulation of the protein expression.Results: We demonstrated that moderate hypoxia is sufficient to induce, in DCIS-derived cells, motility, epithelial-to-mesenchymal transition (EMT) and expression of the stem cell marker CD133, indicative of their increased malignant potential. Administration of ATRA supports the epithelial-like phenotype of DCIS-derived cells cultured under hypoxia and keeps down the number of CD133 positive cells, abrogating almost completely the effects of poor oxygenation. We also found that the mechanisms triggered by ATRA in non-invasive breast tumor cells cultured under hypoxia is in part mediated by PLC-β2, responsible to counteract the effects of low oxygen availability on CD133 levels.Conclusions: Overall, we assigned to hypoxia a role in increasing the malignant potential of DCIS-derived cells and we identified in ATRA, currently used in treatment of acute promyelocytic leukemia (APL), an agonist potentially useful in preventing malignant progression of non-invasive breast lesions showing hypoxic areas. [ABSTRACT FROM AUTHOR]

Initially correlated with hematopoietic precursors, the surface expression of CD133 was also found in epithelial and nonepithelial cells from adult tissues in which it has been associated with a number of biological events. CD133 is expressed in solid tumors as well, including breast cancer, in which most of the studies have been focused on its use as a surface marker for the detection of cells with stem-like properties (i.e., cancer stem cells (CSCs)). Differently with other solid tumors, very limited and in part controversial are the information about the significance of CD133 in breast cancer, the most common malignancy among women in industrialized countries. In this review, we summarize the latest findings about the implication of CD133 in breast tumors, highlighting its role in tumor cells with a triple negative phenotype in which it directly regulates the expression of proteins involved in metastasis and drug resistance. We provide updates about the prognostic role of CD133, underlining its value as an indicator of increased malignancy of both noninvasive and invasive breast tumor cells. The molecular mechanisms at the basis of the regulation of CD133 levels in breast tumors have also been reviewed, highlighting experimental strategies capable to restrain its level that could be taken into account to reduce malignancy and/or to prevent the progression of breast tumors. [ABSTRACT FROM AUTHOR]

Flexible cystoscopy under local anaesthesia is standard for the surveillance of bladder cancer. Frequently, several reusable cystoscopes fail to reprocess. With the new grasper incorporated single-use cystoscope for retrieval of ureteric stents, we explored the feasibility of using it off-label for diagnosis and the detection of bladder cancer. Consecutive diagnostic flexible cystoscopies between Mar 2016 and Nov 2018 were reviewed comparing the reusable versus the disposable cystoscopes. A total of 390 patients underwent 1211 cystoscopies. Median age was 61.5 years (SD 14.2, 18.8–91.4), males 331 (84.9%) and females 59 (15.1%). Indication for cystoscopy was prior malignancy in 1183 procedures (97.7%), haematuria 19 (1.6%) or bladder mass 7 (0.6%). There were 608 reusable and 603 disposable cystoscopies. There was no significant difference between groups at baseline in age, sex, BMI, smoking status, or prior tumor risk category. There was no significant difference in positive findings (123/608, 20.2% vs 111/603, 18.4%, p = 0.425) or cancer detection rates (95/608, 15.6% vs 88/603, 14.4%, p 0.574) among the two groups, respectively. We conclude that the disposable grasper integrated cystoscope is comparable to reusable cystoscope in the detection of bladder cancer. [ABSTRACT FROM AUTHOR]

Toxic proteinaceous deposits and alterations in excitability and activity levels characterize vulnerable neuronal populations in neurodegenerative diseases. Using in vivo two-photon imaging in behaving spinocerebellar ataxia type 1 (Sca1) mice, wherein Purkinje neurons (PNs) degenerate, we identify an inhibitory circuit element (molecular layer interneurons [MLINs]) that becomes prematurely hyperexcitable, compromising sensorimotor signals in the cerebellum at early stages. Mutant MLINs express abnormally elevated parvalbumin, harbor high excitatory-to-inhibitory synaptic density, and display more numerous synaptic connections on PNs, indicating an excitation/inhibition imbalance. Chemogenetic inhibition of hyperexcitable MLINs normalizes parvalbumin expression and restores calcium signaling in Sca1 PNs. Chronic inhibition of mutant MLINs delayed PN degeneration, reduced pathology, and ameliorated motor deficits in Sca1 mice. Conserved proteomic signature of Sca1 MLINs, shared with human SCA1 interneurons, involved the higher expression of FRRS1L, implicated in AMPA receptor trafficking. We thus propose that circuit-level deficits upstream of PNs are one of the main disease triggers in SCA1. • Increased molecular layer interneuron (MLIN) activity drives SCA1 pathophysiology • Inhibition of MLIN ameliorates network and behavioral SCA1 phenotypes • Mimicking MLIN hyperexcitability in healthy mice generates SCA1-like pathophysiology • MLIN hyperexcitability is conserved in human SCA1 patient-derived GABAergic neurons Pilotto et al. identify early hyperexcitability of molecular layer interneurons (MLINs) in SCA1 driving circuit dysfunction and motor deficits. Inhibition of MLINs in SCA1 mice induced lasting improvements of circuit pathology and behavior. MLIN proteomics revealed a signature accounting for hyperexcitability, conserved in patient-derived GABAergic neurons. [ABSTRACT FROM AUTHOR]

Caloric restriction (CR) protects against aging and disease, but the mechanisms by which this affects mammalian life span are unclear. We show in mice that deletion of ribosomal S6 protein kinase 1 (S6K1), a component of the nutrient-responsive mTOR (mammalian target of rapamycin signaling pathway, led to increased life span and resistance to age-related pathologies, such as bone, immune, and motor dysfunction and loss of insulin sensitivity. Deletion of S6KY induced gene expression patterns similar to those seen in CR or with pharmacological activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), a conserved regulator of the metabolic response to CR. Our results demonstrate that S6K1 influences healthy mammalian life span and suggest that therapeutic manipulation of S6K1 and AMPK might mimic CR and could provide broad protection against diseases of aging. [ABSTRACT FROM AUTHOR]

Insulin receptor substrate 2 (Irs2) plays complex roles in energy homeostasis. We generated mice lacking Irs2 in beta cells and a population of hypothalamic neurons (RIPCreIrs2KO), in all neurons (NesCreIrs2KO), and in proopiomelanocortin neurons (POMCCreIrs2KO) to determine the role of Irs2 in the CNS and beta cell. RIPCreIrs2KO mice displayed impaired glucose tolerance and reduced beta cell mass. Overt diabetes did not ensue, because beta cells escaping Cre-mediated recombination progressively populated islets. RIPCreIrs2KO and NesCreIrs2KO mice displayed hyperphagia, obesity, and increased body length, which suggests altered melanocortin action. POMCCreIrs2KO mice did not display this phenotype. RIPCreIrs2KO and NesCreIrs2KO mice retained leptin sensitivity, which suggests that CNS Irs2 pathways are not required for leptin action. NesCreIrs2KO and POMCCreIrs2KO mice did not display reduced beta cell mass, but NesCreIrs2KO mice displayed mild abnormalities of glucose homeostasis. RIPCre neurons did not express POMC or neuropeptide Y. Insulin and a melanocortin agonist depolarized RIPCre neurons, whereas leptin was ineffective. Insulin hyperpolarized and leptin depolarized POMC neurons. Our findings demonstrate a critical role for IRS2 in beta cell and hypothalamic function and provide insights into the role of RIPCre neurons, a distinct hypothalamic neuronal population, in growth and energy homeostasis. [ABSTRACT FROM AUTHOR]

Child abuse is one of the medico-legal issues a physician may face during his/her clinical practice. It has devastating effects on both the child and family, especially psychological. If falsely identified as a child abuse case, it could result in detrimental consequences. Therefore, physicians must recognise and be able to rule out child abuse mimickers, which are often conditions that are mistakenly confused with true physical child abuse. Injuries like bruises and burns are common presentations and therefore it is important to consider cutaneous abuse mimics to avoid incorrect diagnosis of child abuse. This review article sheds light on the most common cutaneous conditions that can mimic physical child abuse, where patients present with patterns of various skin lesions that raise a suspicion of child abuse.

OBJECTIVE: We evaluated glycemic control among T1DM pediatric patients attending the endocrinology pediatrics clinics at King Fahd Hospital of the University (KFHU) prior to and during COVID-19 restraining regulations. In addition, we assessed the trends and variations in the incidence of T1DM during 2017-2021, including the COVID-19 years by identifying newly diagnosed patients presenting to pediatrics emergency department (ED) in KFHU. METHODS: To estimate the effect of COVID-19 on the incidence of T1DM, we identified newly diagnosed cases of T1DM among pediatric patients attending the ED during the years 2017- 2021. The participants' data were collected through electronic medical records. Information collected included patient age, sex, and HbA1c readings. Three HbA1c readings of interest that were defined and collected are pre-COVID reading, in-COVID reading, and post-COVID reading. RESULTS: The difference of female participants' readings was statistically non-significant (Z= -0.416, p = 0.678), with a pre- and post-COVID median of 10.70 (Q1= 9.00, Q3= 12.15), and 10.50 (Q1= 8.80, Q3= 12.35), respectively. In contrast, the difference was statistically significant among male participants (Z= -2.334, p = 0.02), with a pre- and post-COVID median of 10.20 (Q1= 8.70, Q3= 11.80), and 10.65 (Q1= 9.00, Q3= 12.70), respectively. There was a statistically significant increase in HbA1c of persons > 11 years old (Z= -2.471, p= 0.013), with a pre- and post-COVID median of 10.40 (Q1= 9.00, Q3= 12.10), and 10.90 (Q1= 9.00, Q3= 12.60), respectively. Conversely, persons ≤ 11 years old showed no statistically significant change in HbA1c (Z= -.457, p= 0.648), with a pre- and post-COVID median of 10.45 (Q1= 8.70, Q3= 11.85), and 10.20 (Q1= 8.40, Q3= 12.075), respectively. Disregarding any influence of time, the effect of sex showed no statistically significant difference in HbA1c between males and females [F (1,125) = 0.008, p = 0.930]. Meanwhile, the age effect on HbA1c, regardless of time influence, was statistically significant [F (1,125) = 4.993, p = 0.027]. There was no statistically significant interaction between time and sex on HbA1c levels [F (1.74, 217) = 0.096, p = 0.883] and between age and time [F (3.92,289.57) = 1.693, p = 0.190]. CONCLUSIONS: The number of visits to healthcare facilities dropped significantly during the COVID-19 pandemic, but the rate of newly diagnosed T1DM increased. There was a variable effect on HbA1c levels of those patients, which suggests that each demographic group in the population might have been affected differently by the pandemic. Future research should determine factors associated with better glycemic control and measures to sustain these changes the pandemic might have created.

Background and Aim: Papillary thyroid carcinoma accounts for 85% of thyroid follicular epithelial-derived cancers. The identification of pathogenetic mechanisms improved the understating of papillary thyroid carcinoma pathogenesis. The current study aims to examine the research productivity and trends in the genetics of papillary thyroid carcinoma from 1991 to 2020., Methods: The Web of Science Core Collection database was searched to retrieve the relevant literature. A search string was applied and 1,741 relevant records were selected for the analysis. Bibliometric techniques were used in the statistical analysis with the help of Biblioshiny (RStudio)., Results: The growth in the number of publications was observed to be over a hundred publications per year since 2015. 'Thyroid' published the highest number of publications, followed by 'Journal of Clinical Endocrinology & Metabolism'. 'Nikiforov YE' was identified as the most productive researcher with a total of 49 publications. Out of the top 20 most contributing researchers, seven belonged to Italy, and four were from the USA. 'University of Pittsburgh' contributed the highest number of publications. The top contributing countries in this field were the USA, China, and Italy. BRAF and RAS were among the frequently used keywords., Conclusions: This bibliometric review demonstrates that investigating the genetics underlying papillary thyroid carcinoma is a rapidly growing area of research. During the last two decades, China has been a significant contributor to the field. Besides, institutions in USA and Italy have significantly contributed to research in the genetics of papillary thyroid carcinoma. (www.actabiomedica.it).