•Childhood ALL chemotherapy can lead to neurocognitive deficits that persist into adulthood.•Animals exposed to ALL chemotherapy treatments provide models to study mechanisms of neurocognitive ...deficits in survivors.•Inflammation, oxidative stress, excitotoxicity and metabolic disruptions may lead to neurodegeneration and cognitive decline.•Future investigations should include juvenile animal models with long-term follow-up to capture effects of therapy on developing brains.•Animal models can be used to determine effective interventions to prevent neurocognitive decline in childhood ALL survivors.
Survival rates of childhood acute lymphoblastic leukemia (ALL) have improved greatly due to advanced therapies and supportive care. Intrathecal chemotherapy replaced cranial radiation due to radiation-induced neurotoxicity and late-effects. Survivors treated with chemotherapy-only experience neurologic and cognitive problems following cessation of treatment. Very long-term cognitive outcomes remain unclear. Animal models are being generated to assess late-effects of chemotherapy on cognitive function. Although, few address juvenile models of chemotherapy-induced cognitive impairment (CICI) and developing brain, results of this review outline neurocognitive effects of chemotherapy consistent with childhood ALL therapy. Studies demonstrate deficits across cognitive domains including spatial memory, executive function, short-term memory, anxiety and depression. Inflammation, oxidative stress, excitotoxity, and other metabolic disruptions may lead to neurodegeneration associated with cognitive impairment observed in ALL survivors. Interventions directly targeting these mechanisms may prevent and/or promote recovery of cognitive function and improve long-term outcomes. Evidence suggests success of anti-inflammatory and antioxidant treatments in reducing cognitive decline. Animal models provide basis for assessing effects of chemotherapy on neurologic processes to guide future clinical investigations.
Many individuals with autism spectrum disorder (ASD) exhibit motor difficulties, but it is unknown whether manual motor skills improve, plateau, or decline in ASD in the transition from childhood ...into adulthood. Atypical development of manual motor skills could impact the ability to learn and perform daily activities across the life span. This study examined longitudinal grip strength and finger tapping development in individuals with ASD (n = 90) compared to individuals with typical development (n = 56), ages 5 to 40 years old. We further examined manual motor performance as a possible correlate of current and future daily living skills. The group with ASD demonstrated atypical motor development, characterized by similar performance during childhood but increasingly poorer performance from adolescence into adulthood. Grip strength was correlated with current adaptive daily living skills, and Time 1 grip strength predicted daily living skills eight years into the future. These results suggest that individuals with ASD may experience increasingly more pronounced motor difficulties from adolescence into adulthood and that manual motor performance in ASD is related to adaptive daily living skills.
We investigated age‐related changes from early childhood into mid‐adulthood in manual motor skills in individuals with autism spectrum disorder (ASD) compared to typical development. We then examined if manual motor performance correlated with current and future daily living skills. We found evidence for atypical development of grip strength and finger tapping speed in ASD, atypically low grip strength in ~1/3 of the individuals with ASD, and correlations between manual motor performance and both current and future daily living skills.
Perceptual success depends on fast-spiking, parvalbumin-positive interneurons (FS/PVs). However, competing theories of optimal rate and correlation in pyramidal (PYR) firing make opposing predictions ...regarding the underlying FS/PV dynamics. We addressed this with population calcium imaging of FS/PVs and putative PYR neurons during threshold detection. In primary somatosensory and visual neocortex, a distinct PYR subset shows increased rate and spike-count correlations on detected trials (“hits”), while most show no rate change and decreased correlations. A larger fraction of FS/PVs predicts hits with either rate increases or decreases. Using computational modeling, we found that inhibitory imbalance, created by excitatory “feedback” and interactions between FS/PV pools, can account for the data. Rate-decreasing FS/PVs increase rate and correlation in a PYR subset, while rate-increasing FS/PVs reduce correlations and offset enhanced excitation in PYR neurons. These findings indicate that selection of informative PYR ensembles, through transient inhibitory imbalance, is a common motif of optimal neocortical processing.
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•>40% of PV+ inhibitory neurons predict perception with increased or decreased rate•Correlations increase among predictive pyramidal ensembles on successful trials•Modeling suggests enhanced feedback to rate-increasing interneurons drives imbalance•Selection of informative ensembles via inhibitory imbalance may be a common motif
Deister et al. study how rate and correlation changes among neocortical excitatory and inhibitory neurons predict perceptual success. Neurons with predictive rate changes show increased correlations. Neurons without predictive rate changes have decreased correlations. They propose a potential circuit motif where similar sensory, but variable contextual, inputs drive inhibitory imbalances and recruitment of distinct ensembles.
elapsing
ever (RF), caused by spirochetes of the genus
, is a globally distributed, vector-borne disease with high prevalence in developing countries. To date, signaling pathways required for ...infection and virulence of RF
spirochetes are unknown.
yclic
-
(c-di-AMP), synthesized by
i
denylate
yclases (DACs), is a second messenger predominantly found in Gram-positive organisms that is linked to virulence and essential physiological processes. Although
is Gram-negative, it encodes one DAC (CdaA), and its importance remains undefined. To investigate the contribution of c-di-AMP signaling in the RF bacterium
, a
mutant was generated. The mutant was significantly attenuated during murine infection, and genetic complementation reversed this phenotype. Because c-di-AMP is essential for viability in many bacteria, whole-genome sequencing was performed on
mutants, and single-nucleotide polymorphisms identified potential suppressor mutations. Additionally, conditional mutation of
confirmed that CdaA is important for normal growth and physiology. Interestingly, mutation of
did not affect expression of homologs of virulence regulators whose levels are impacted by c-di-AMP signaling in the Lyme disease bacterium
Finally, the
mutant had a significant growth defect when grown with salts, at decreased osmolarity, and without pyruvate. While the salt treatment phenotype was not reversed by genetic complementation, possibly due to suppressor mutations, growth defects at decreased osmolarity and in media lacking pyruvate could be attributed directly to
inactivation. Overall, these results indicate CdaA is critical for
pathogenesis and link c-di-AMP to osmoregulation and central metabolism in RF spirochetes.
•5-Fu significantly compromised the dendritic architecture.•5-Fu decreased spine density and modulated spine morphology throughout Hippocampus.•5-Fu upregulated pro-inflammatory and anti-inflammatory ...cytokines.
5-Fluorouracil (5-Fu) is commonly used chemotherapy drug, but it can lead to the impairment of cognitive function. The pathogenesis of this injury is unknown but may involve modifications to dendritic structure and/or alterations in dendritic spine density and morphology. Dendritic spines are sites of excitatory synaptic transmission and changes in spine structure and dendrite morphology are thought to represent a morphological correlate of altered brain functions associated with hippocampal dependent learning and memory. A total of 28 one-year-old C57BL6/J male mice were used in this study; 14 mice received 5-Fu treatment and 14 were given saline injections. One month post treatment, 14 cytokines were measured at the same time Golgi samples were taken. 8 analytes were significantly elevated in mice treated with 5-Fu. 5-Fu significantly compromised the dendritic architecture and reduced spine density throughout the hippocampal tri-synaptic network. The present data provide the evidence that 5-Fu has deleterious effects on mature neurons associated with hippocampal learning and memory.
•MTX/AraC significantly compromised the dendritic architecture.•MTX/AraC modulated spine morphology throughout Hippocampus.•MTX/AraC impaired hippocampal dependent behavior.
Acute lymphoblastic ...leukemia (ALL) is the most prevalent childhood cancer and accounts for 26.8% of cancer diagnoses among children, worldwide—approximately 3000 children each year. While advancements in treating ALL have led to a remission rate of more than 90%, many survivors experience adverse neurocognitive and/or neurobehavioral effects as a result of intrathecal chemotherapy. Methotrexate (MTX) is commonly administered with cytosine arabinoside (AraC, cytarabine) during intrathecal chemotherapy for ALL. To date, few studies exist that test the cognitive effects of intrathecal injections of MTX/AraC on juvenile populations. The purpose of our study was to investigate the combined effects of MTX/AraC on cognition and dendritic structure in the hippocampus in juvenile male mice. Twenty, 21-day-old male C57BL/6 mice were used in this study; 10 mice received intrathecal MTX/AraC treatment, and 10 were given intrathecal saline injections. Five weeks after injections, we tested the animals’ hippocampus-dependent cognitive performance in the Morris water maze. After the first day of hidden-platform training, we observed that the mice that received MTX/AraC treatment showed signs of significant impairment in spatial memory retention. MTX/AraC treatment significantly compromised the dendritic architecture and reduced mushroom spine density in the dorsal ganglion (DG), CA1, and CA3 areas of the hippocampus. The present data provided evidence that MTX/AraC compromised the dendritic architecture and impaired hippocampal dependent cognition. This could provide insight into chemotherapy-induced cognitive decline in juvenile patients treated for ALL.
Mounting evidence suggests that poorer motor skills may be related to more severe autism symptoms. This study investigated if atypical white matter microstructure in the brain mediated the ...relationship between motor skills and ASD symptom severity. Sixty-seven males with ASD and 42 males with typical development (5–33 years old) completed a diffusion tensor imaging scan and measures of grip strength, finger tapping, and autism symptom severity. Within the ASD group, weaker grip strength predicted more severe autism symptoms. Fractional anisotropy of the brainstem’s corticospinal tract predicted both grip strength and autism symptom severity and mediated the relationship between the two. These findings suggest that brainstem white matter may contribute to autism symptoms and grip strength in ASD.
For a disease process that affects so many, we continue to struggle to define optimal care for patients with diverticular disease. Part of this stems from the fact that diverticular disease requires ...different treatment strategies across the natural history- acute, chronic and recurrent.
To understand where we are currently, it is worth understanding how treatment of diverticular disease has evolved. Diverticular disease was rarely described in the literature prior to the 1900’s. In the late 1960’s and early 1970’s, Painter and Burkitt popularized the theory that diverticulosis is a disease of Western civilization based on the observation that diverticulosis was rare in rural Africa but common in economically developed countries. Previous surgical guidelines focused on early operative intervention to avoid potential complicated episodes of recurrent complicated diverticulitis (e.g., with free perforation) that might necessitate emergent surgery and stoma formation. More recent data has challenged prior concerns about decreasing effectiveness of medical management with repeat episodes and the notion that the natural history of diverticulitis is progressive. It has also permitted more accurate grading of the severity of disease and permitted less invasive management options to attempt conversion of urgent operations into the elective setting, or even avoid an operation altogether.
The role of diet in preventing diverticular disease has long been debated. A high fiber diet appears to decrease the likelihood of symptomatic diverticulitis. The myth of avoid eating nuts, corn, popcorn, and seeds to prevent episodes of diverticulitis has been debunked with modern data. Overall, the recommendations for “diverticulitis diets” mirror those made for overall healthy lifestyle – high fiber, with a focus on whole grains, fruits and vegetables.
Diverticulosis is one of the most common incidental findings on colonoscopy and the eighth most common outpatient diagnosis in the United States. Over 50% of people over the age of 60 and over 60% of people over age 80 have colonic diverticula. Of those with diverticulosis, the lifetime risk of developing diverticulitis is estimated at 10–25%, although more recent studies estimate a 5% rate of progression to diverticulitis. Diverticulitis accounts for an estimated 371,000 emergency department visits and 200,000 inpatient admissions per year with annual cost of 2.1–2.6 billion dollars per year in the United States. The estimated total medical expenditure (inpatient and outpatient) for diverticulosis and diverticulitis in 2015 was over 5.4 billion dollars. The incidence of diverticulitis is increasing.
Besides increasing age, other risk factors for diverticular disease include use of NSAIDS, aspirin, steroids, opioids, smoking and sedentary lifestyle. Diverticula most commonly occur along the mesenteric side of the antimesenteric taeniae resulting in parallel rows. These spots are thought to be relatively weak as this is the location where vasa recta penetrate the muscle to supply the mucosa. The exact mechanism that leads to diverticulitis from diverticulosis is not definitively known.
The most common presenting complaint is of left lower quadrant abdominal pain with symptoms of systemic unwellness including fever and malaise, however the presentation may vary widely. The gold standard cross-sectional imaging is multi-detector CT. It is minimally invasive and has sensitivity between 98% and specificity up to 99% for diagnosing acute diverticulitis. Uncomplicated acute diverticulitis may be safely managed as an out-patient in carefully selected patients. Hospitalization is usually necessary for patients with immunosuppression, intolerance to oral intake, signs of severe sepsis, lack of social support and increased comorbidities. The role of antibiotics has been questioned in a number of randomized controlled trials and it is likely that we will see more patients with uncomplicated disease treated with observation in the future
Acute diverticulitis can be further sub classified into complicated and uncomplicated presentations. Uncomplicated diverticulitis is characterized by inflammation limited to colonic wall and surrounding tissue. The management of uncomplicated diverticulitis is changing. Use of antibiotics has been questioned as it appears that antibiotic use can be avoided in select groups of patients. Surgical intervention appears to improve patient’s quality of life. The decision to proceed with surgery is recommended in an individualized manner.
Complicated diverticulitis is defined as diverticulitis associated with localized or generalized perforation, localized or distant abscess, fistula, stricture or obstruction. Abscesses can be treated with percutaneous drainage if the abscess is large enough. The optimal long-term strategy for patients who undergo successful non-operative management of their diverticular abscess remains controversial. There are clearly patients who would do well with an elective colectomy and a subset who could avoid an operation all together however, the challenge is appropriate risk-stratification and patient selection. Management of patients with perforation depends greatly on the presence of feculent or purulent peritonitis, the extent of contamination and hemodynamic status and associated comorbidities. Fistulas and strictures are almost always treated with segmental colectomy.
After an episode of acute diverticulitis, routine colonoscopy has been recommended by a number of societies to exclude the presence of colorectal cancer or presence of alternative diagnosis like ischemic colitis or inflammatory bowel disease for the clinical presentation. Endoscopic evaluation of the colon is normally delayed by about 6 weeks from the acute episode to reduce the risk associated with colonoscopy. Further study has questioned the need for endoscopic evaluation for every patient with acute diverticulitis. Colonoscopy should be routinely performed after complicated diverticulitis cases, when the clinical presentation is atypical or if there are any diagnostic ambiguity, or patient has other indications for colonoscopy like rectal bleeding or is above 50 years of age without recent colonoscopy.
For patients in whom elective colectomy is indicated, it is imperative to identify a wide range of modifiable patient co-morbidities. Every attempt should be made to improve a patient’s chance of successful surgery. This includes optimization of patient risk factors as well as tailoring the surgical approach and perioperative management. A positive outcome depends greatly on thoughtful attention to what makes a complicated patient “complicated”.
Operative management remains complex and depends on multiple factors including patient age, comorbidities, nutritional state, severity of disease, and surgeon preference and experience. Importantly, the status of surgery, elective versus urgent or emergent operation, is pivotal in decision-making, and treatment algorithms are divergent based on the acuteness of surgery. Resection of diseased bowel to healthy proximal colon and rectal margins remains a fundamental principle of treatment although the operative approach may vary.
For acute diverticulitis, a number of surgical approaches exist, including loop colostomy, sigmoidectomy with colostomy (Hartmann’s procedure) and sigmoidectomy with primary colorectal anastomosis. Overall, data suggest that primary anastomosis is preferable to a Hartman’s procedure in select patients with acute diverticulitis. Patients with hemodynamic instability, immunocompromised state, feculent peritonitis, severely edematous or ischemic bowel, or significant malnutrition are poor candidates. The decision to divert after colorectal anastomosis is at the discretion of the operating surgeon. Patient factors including severity of disease, tissue quality, and comorbidities should be considered. Technical considerations for elective cases include appropriate bowel preparation, the use of a laparoscopic approach, the decision to perform a primary anastomosis, and the selected use of ureteral stents.
Management of the patient with an end colostomy after a Hartmann’s procedure for acute diverticulitis can be a challenging clinical scenario. Between 20 – 50% of patients treated with sigmoid resection and an end colostomy after an initial severe bout of diverticulitis will never be reversed to their normal anatomy. The reasons for high rates of permanent colostomies are multifactorial. The debate on the best timing for a colostomy takedown continues. Six months is generally chosen as the safest time to proceed when adhesions may be at their softest allowing for a more favorable dissection. The surgical approach will be a personal decision by the operating surgeon based on his or her experience. Colostomy takedown operations are challenging surgeries. The surgeon should anticipate and appropriately plan for a long and difficult operation. The patient should undergo a full antibiotic bowel preparation. Preoperative planning is critical; review the initial operative note and defining the anatomy prior to reversal. When a complex abdominal wall closure is necessary, consider consultation with a hernia specialist. Open surgery is the preferred surgical approach for the majority of colostomy takedown operations. Finally, consider ureteral catheters, diverting loop ileostomy, and be prepared for all anastomotic options in advance.
Since its inception in the late 90’s, laparoscopic lavage has been recognized as a novel treatment modality in the management of complicated diverticulitis; specifically, Hinchey III (purulent) diverticulitis. Over the last decade, it has been the subject of several randomized controlled trials, retrospective studies, systematic reviews as well as cost-efficiency analyses. Despite being the subject of much debate and controversy, there is a clear role for laparoscopic lavage in the management of
Diverticulitis: An update from the age old Paradigm Hawkins, Alexander T.; Wise, Paul E.; Chan, Tiffany ...
Current problems in surgery,
October 2020, 2020-10-00, 20201001, Letnik:
57, Številka:
10
Journal Article
Chemotherapy has been successfully used to reduce radiation dose and volume for most pediatric patients. However, because of the failure of chemotherapeutic agents to cross the blood-brain barrier ...and the lack of response of some brain tumors to these agents, radiation therapy is still used to treat many childhood cancers with CNS involvement. In this study, we investigated the radiation effects on cognition and dendritic structure in the hippocampus in juvenile male mice. Twenty-one-day-old male C57BL/6 mice were irradiated using the small animal radiation research platform (SARRP). Animals were exposed to either a 10 Gy single dose or 10 Gy × 2 fractionated doses of X-ray cranial radiation. Five weeks after irradiation, animals were tested for hippocampus-dependent cognitive performance in the Morris water maze. Significant impairment in spatial memory retention was observed in the probe trial after the first day of hidden-platform training (first probe trial) in animals that received either 10 Gy single-dose or 10 Gy × 2 fractionated doses. However, by day 5, mice that received a 10 Gy single dose showed spatial memory retention in the probe trials, whereas mice that received the 20 Gy fractionated doses remained impaired. During Y-maze testing, animals exposed to radiation were impaired; the irradiated mice were not able to distinguish among the three Y-maze arms and spent approximately the same amount of time in all three arms during the retention trial. Radiation significantly compromised the dendritic architecture and reduced spine density throughout the hippocampal trisynaptic network.
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