Effect of quercetin administration during the first two weeks post-weaning on the development of non-alcoholic fatty liver disease and dyslipidaemia in Sprague Dawley rats fed a high fructose diet.

Hepatic steatosis and dyslipidaemia are associated with excessive fructose consumption. We investigated the effect of quercetin intake during the early pre-weaning period on metabolic dysfunction caused by a high fructose diet. Sprague Dawley rats, 21-day-old, were weaned onto standard rat chow and randomly allocated to four groups which either water or 20% fructose solution to drink with or without quercetin (100 mg/kg body mass). Quercetin was administered for two weeks. Thereafter, rats continued on their respective diets for six weeks without quercetin. Terminally, serum triglyceride concentrations were not significantly different (p > 0.05) between males across groups. However, females receiving quercetin alone had lower serum triglyceride levels than those receiving fructose (p < 0.01). Quercetin increased the incidence of hepatic steatosis in female rats. Quercetin intake in the immediate post-weaning period may prevent hypertriglyceridemia. However, female rats receiving quercetin alone are predisposed to hepatic steatosis associated with a high fructose diet.

A 3D-Printed Biomaterial Scaffold Reinforced with Inorganic Fillers for Bone Tissue Engineering: In Vitro Assessment and In Vivo Animal Studies.

This research aimed to substantiate the potential practicality of utilizing a matrix-like platform, a novel 3D-printed biomaterial scaffold, to enhance and guide host cells' growth for bone tissue regeneration. The 3D biomaterial scaffold was successfully printed using a 3D Bioplotter® (EnvisionTEC, GmBH) and characterized. Osteoblast-like MG63 cells were utilized to culture the novel printed scaffold over a period of 1, 3, and 7 days. Cell adhesion and surface morphology were examined using scanning electron microscopy (SEM) and optical microscopy, while cell viability was determined using MTS assay and cell proliferation was evaluated using a Leica microsystem (Leica MZ10 F). The 3D-printed biomaterial scaffold exhibited essential biomineral trace elements that are significant for biological bone (e.g., Ca-P) and were confirmed through energy-dispersive X-ray (EDX) analysis. The microscopy analyses revealed that the osteoblast-like MG63 cells were attached to the printed scaffold surface. The viability of cultured cells on the control and printed scaffold increased over time (p < 0.05); however, on respective days (1, 3, and 7 days), the viability of cultured cells between the two groups was not significantly different (p > 0.05). The protein (human BMP-7, also known as growth factor) was successfully attached to the surface of the 3D-printed biomaterial scaffold as an initiator of osteogenesis in the site of the induced bone defect. An in vivo study was conducted to substantiate if the novel printed scaffold properties were engineered adequately to mimic the bone regeneration cascade using an induced rabbit critical-sized nasal bone defect. The novel printed scaffold provided a potential pro-regenerative platform, rich in mechanical, topographical, and biological cues to guide and activate host cells toward functional regeneration. The histological studies revealed that there was progress in new bone formation, especially at week 8 of the study, in all induced bone defects. In conclusion, the protein (human BMP-7)-embedded scaffolds showed higher regenerative bone formation potential (week 8 complete) compared to the scaffolds without protein (e.g., growth factor; BMP-7) and the control (empty defect). At 8 weeks postimplantation, protein (BMP-7) significantly promoted osteogenesis as compared to other groups. The scaffold underwent gradual degradation and replacement by new bones at 8 weeks in most defects.

Neonatal administration of zingerone prevents the subsequent development of high dietary fructose-induced early features of nephropathy in rats.

Excessive consumption of fructose-rich diets in early life stages increases the risk for developing nephropathy in adulthood. We investigated the potential preventive effects of neonatally administered zingerone on the development of dietary fructose-induced nephropathy. Four-day-old suckling male and female rat pups were orally gavaged (10 ml/kg) with: distilled water (Con group), 20% fructose solution (Fru group), 20% fructose solution + 40 mg/kg zingerone in distilled water (ZFru group), or 40 mg/kg of zingerone (Zgr group) for 14 days. Thereafter, Con and Zgr groups continued on plain drinking water while Fru and ZFru groups drank 20% fructose solution ad libitum for 10 weeks. The Fru group had significantly increased plasma concentration of the renal injury marker kidney injury molecule one (KIM-1) and decreased glomerular urinary space area compared to the controls in both sexes (p < 0.05). These alterations were prevented by neonatally administered zingerone. Zingerone administration neonatally is a potential prophylaxis for longterm high-fructose diet-induced nephropathy.

ß-Sitosterol mitigates the development of high-fructose diet-induced nonalcoholic fatty liver disease in growing male Sprague-Dawley rats.

Fructose contributes to the development of nonalcoholic fatty liver disease (NAFLD). ß-Sitosterol (Bst), a naturally occurring phytosterol, has antihyperlipidaemic and hepatoprotective properties. This study interrogated the potential protective effect of ß-sitosterol against NAFLD in growing rats fed a high-fructose diet, modelling children fed obesogenic diets. Forty-four 21 day old male rat pups were randomly allocated to and administered the following treatments for 12 weeks: group I, standard rat chow (SRC) + plain drinking water (PW) + plain gelatine cube (PC); group II, SRC + 20% w/v fructose solution (FS) as drinking fluid + PC; group III, SRC + FS + 100 mg/kg fenofibrate in a gelatine cube; group IV, SRC + FS + 20 mg/kg ß-sitosterol gelatine cube (Bst); group V, SRC + PW + Bst. Terminally, the livers were dissected out, weighed, total liver lipid content determined, and histological analyses done. Harvested plasma was used to determine the surrogate biomarkers of liver function. The high-fructose diet caused increased (p < 0.05) hepatic lipid (total) accretion (>10% liver mass), micro- and macrovesicular hepatic steatosis, and hepatic inflammation. ß-Sitosterol and fenofibrate prevented the high-fructose diet-induced macrovesicular steatosis and prevented the progression of NAFLD to steatohepatitis. ß-Sitosterol can prospectively be used to mitigate diet-induced NAFLD.

The Potential Therapeutic Value of Medicinal Plants in the Management of Metabolic Disorders.

Metabolic syndrome (MetS) is a prevalent, multifactorial and complex disease that is associated with an increased risk of developing diabetes and other major cardiovascular complications. The rise in the global prevalence of MetS has been attributed to genetic, epigenetic, and environmental factors. The adoption of sedentary lifestyles that are characterized by low physical activity and the consumption of high-energy diets contributes to MetS development. Current management criteria for MetS risk factors involve changes in lifestyle and the use of pharmacological agents that target specific biochemical pathways involved in the metabolism of nutrients. Pharmaceutical drugs are usually expensive and are associated with several undesirable side effects. Alternative management strategies of MetS risk factors involve the use of medicinal plants that are considered to have multiple therapeutic targets and are easily accessible. Medicinal plants contain several different biologically active compounds that provide health benefits. The impact of phytochemicals present in local medicinal plants on sustainable health and well-being of individuals has been studied for many years and found to involve a plethora of complex biochemical, metabolic, and physiological mechanisms. While some of these phytochemicals are the basis of mainstream prescribed drugs (e.g., metformin, reserpine, quinine, and salicin), there is a need to identify more medicinal plants that can be used for the management of components of MetS and to describe their possible mechanisms of action. In this review, we assess the potential health benefits of South African ethnomedicinal plants in protecting against the development of health outcomes associated with MetS. We aim to provide the state of the current knowledge on the use of medicinal plants and their therapeutically important phytochemicals by discussing the current trends, with critical examples from recent primary references of how medicinal plants are being used in South African rural and urban communities.

The potential developmental programming effect of oral curcumin on the bone health and plasma total osteocalcin of male and female rats fed a high-fructose diet during suckling and post weaning.

We investigated the effect of oral curcumin, on bone health of rats fed a high-fructose diet. Suckling pups (males = 65, females = 63) were gavage with 0.5% DMSO, curcumin (500 mg/kg), fructose (20%, w/v) or a combination of curcumin and fructose daily from postnatal days 6 to 21. Then the rats were weaned onto normal rat feed for six weeks and each group was sub-divided into two subgroups: one had plain tap water and the other had fructose (20%, w/v) to drink. Blood was assayed for plasma total osteocalcin. Morphometry and radiographic bone density assessments were made on the femora and tibiae. The lengths, masses and Seedor indices of the bones were similar (p > 0.05, ANOVA) across the groups. Males that received curcumin with or without fructose during suckling and weaned onto a high-fructose diet had lower (p ≤ 0.05, ANOVA) osteocalcin concentration versus the other males. Similarly, in females rats, curcumin alone or administered with fructose resulted in lower (p ≤ 0.05, ANOVA) osteocalcin concentration versus female rats administered the vehicle control. Neonatal curcumin-induced decrease in plasma total osteocalcin concentration may predispose to adverse consequences on glucose metabolism and bone health.

Parturition and the perinatal period: can mode of delivery impact on the future health of the neonate?

Caesarean section and instrumental delivery rates are increasing in many parts of the world for a range of cultural and medical reasons, with limited consideration as to how 'mode of delivery' may impact on childhood and long-term health. However, babies born particularly by pre-labour caesarean section appear to have a subtly different physiology from those born by normal vaginal delivery, with both acute and chronic complications such as respiratory and cardio-metabolic morbidities being apparent. It has been hypothesized that inherent mechanisms within the process of labour and vaginal delivery, far from being a passive mechanical process by which the fetus and placenta are expelled from the birth canal, may trigger certain protective developmental processes permissive for normal immunological and physiological development of the fetus postnatally. Traditionally the primary candidate mechanism has been the hormonal surges or stress response associated with labour and vaginal delivery, but there is increasing awareness that transfer of the maternal microbiome to the infant during parturition. Transgenerational transmission of disease traits through epigenetics are also likely to be important. Interventions such as probiotics, neonatal gut seeding and different approaches to clinical care have potential to influence parturition physiology and improve outcomes for infants.

A comparison of the proximate, fibre, mineral content, amino acid and the fatty acid profile of Marula (Sclerocarya birrea caffra) nut and soyabean (Glycine max) meals.

BACKGROUND: As a result of shortages and the cost of the currently utilized conventional dietary protein sources in the Sub-Saharan Africa feed industry, the chemical evaluation of available non-conventional sources for feed is imperative. One such source is Marula nut meal (a by-product of Marula oil extraction). The present study chemically characterized the nutritional composition of two differently processed Marula nut meals (MNMs) and compared them with that of solvent extracted soyabean meal (SBM). RESULTS: The MNMs had higher dry matter, ether extract and gross energy but lower crude protein and ash contents compared to SBM. The cold press produced Marula nut meal (MNM2) had higher arginine than the hydraulic filter press produced Marula nut meal (MNM1) and SBM. The meals had similar neutral and acid detergent fibre contents. The MNMs had higher phosphorus, magnesium and copper concentrations than SBM. Although the total saturated fatty acid proportion was similar across the meals, total monounsaturated and polyunsaturated fatty acid proportions were higher in MNMs and SBM, respectively. Oleic acid was higher in MNMs than in SBM. CONCLUSION: The low crude protein content in MNMs compared to SBM is comparable with other conventional dietary protein sources. Thus, the MNMs could be used as protein and energy feed ingredients. © 2017 Society of Chemical Industry.

Prevention of ßeta-adrenergic-induced Adverse Cardiac Remodeling by Gonadectomy in Male but Not Female Spontaneously Hypertensive Rats.

Chronic ß-adrenergic stimulation induces left ventricular (LV) remodeling in male but not in female spontaneously hypertensive rats (SHRs). However, the role of sex steroids in mediating these effects has not been determined. The aim of the present study was to assess the impact of gonadectomy on isoproterenol (ISO)-induced LV remodeling in SHR. Gonadectomy was performed on 9-month-old male and female SHR. LV remodeling was induced by daily ISO injection (0.04 mg/kg) for 6 months. LV dimensions and functions were determined in vivo by echocardiography and ex vivo using isolated perfused heart preparations. In males, ISO increased LV end diastolic (LVED) diameter in sham-operated (in millimeter, ISO: 8.12 ± 0.26 vs. Con: 6.67 ± 0.20, P = 0.0002) but not in castrated SHR (ISO: 6.97 ± 0.31 vs. Con: 6.53 ± 0.15, P = 0.66). Similarly, ISO increased the volume intercept of the LVED pressure-volume relationship in sham-operated (in milliliters, ISO: 0.26 ± 0.02 vs. Con: 0.19 ± 0.01, P = 0.01) but not in castrated SHR (ISO: 0.17 ± 0.02 vs. Con: 0.17 ± 0.01, P = 0.99). In females, ISO only increased LVED diameter (ISO: 6.43 ± 0.13 vs. Con: 6.07 ± 0.09, P = 0.027). However, ovariectomy did not modify any LV dimensions measured in vivo and ex vivo. In conclusion, testosterone may be responsible for the chronic ß-adrenergic-induced LV dilation and eccentric remodeling observed in male but not female SHR.

Anticholinergic burden in schizophrenia and ability to benefit from psychosocial treatment programmes: a 3-year prospective cohort study.

BACKGROUND: Many medications administered to patients with schizophrenia possess anticholinergic properties. When aggregated, pharmacological treatments may result in a considerable anticholinergic burden. The extent to which anticholinergic burden has a deleterious effect on cognition and impairs ability to participate in and benefit from psychosocial treatments is unknown. METHOD: Seventy patients were followed for approximately 3 years. The MATRICS consensus cognitive battery (MCCB) was administered at baseline. Anticholinergic burden was measured with the Anticholinergic Cognitive Burden (ACB) scale. Ability to benefit from psychosocial programmes was measured using the DUNDRUM-3 Programme Completion Scale (D-3) at baseline and follow-up. Psychiatric symptoms were measured using the PANSS. Total antipsychotic dose was measured using chlorpromazine equivalents. Functioning was measured using the Social and Occupational Functioning Assessment Scale (SOFAS). RESULTS: Mediation analysis found that the influence of anticholinergic burden on ability to participate and benefit from psychosocial programmes was completely mediated by the MCCB. For every 1-unit increase on the ACB scale, change scores for DUNDRUM-3 decreased by -0.27 points. This relationship appears specific to anticholinergic burden and not total antipsychotic dose. Moreover, mediation appears to be specific to cognition and not psychopathology. Baseline functioning also acted as mediator but only when MCCB was not controlled for. CONCLUSIONS: Anticholinergic burden has a significant impact on patients' ability to participate in and benefit from psychosocial treatment programmes. Physicians need to be mindful of the cumulative effect that medications can have on patient cognition, functional capacity and ability to benefit from psychosocial treatments.

Childbirth and consequent atopic disease: emerging evidence on epigenetic effects based on the hygiene and EPIIC hypotheses.

BACKGROUND: In most high and middle income countries across the world, at least 1:4 women give birth by cesarean section. Rates of labour induction and augmentation are rising steeply; and in some countries up to 50% of laboring women and newborns are given antibiotics. Governments and international agencies are increasingly concerned about the clinical, economic and psychosocial effects of these interventions. DISCUSSION: There is emerging evidence that certain intrapartum and early neonatal interventions might affect the neonatal immune response in the longer term, and perhaps trans-generationally. Two theories lead the debate in this area. Those aligned with the hygiene (or 'Old Friends') hypothesis have examined the effect of gut microbiome colonization secondary to mode of birth and intrapartum/neonatal pharmacological interventions on immune response and epigenetic phenomena. Those working with the EPIIC (Epigenetic Impact of Childbirth) hypothesis are concerned with the effects of eustress and dys-stress on the epigenome, secondary to mode of birth and labour interventions. This paper examines the current and emerging findings relating to childbirth and atopic/autoimmune disease from the perspective of both theories, and proposes an alliance of research effort. This is likely to accelerate the discovery of important findings arising from both approaches, and to maximize the timely understanding of the longer-term consequences of childbirth practices.

Growth and hormone profiling in children with congenital melanocytic naevi.

BACKGROUND: Multiple congenital melanocytic naevi (CMN) is a rare mosaic RASopathy, caused by postzygotic activating mutations in NRAS. Growth and hormonal disturbances are described in germline RASopathies, but growth and hormone status have not previously been investigated in individuals with CMN. OBJECTIVES: To explore premature thelarche, undescended testes, and a clinically abnormal fat distribution with CMN through prospective endocrinological assessment of a cohort of subjects with CMN, and a retrospective review of longitudinal growth of a larger group of patients with CMN from outpatient clinics (which included all subjects in the endocrinological assessment group). PATIENTS AND METHODS: Longitudinal growth in a cohort of 202 patients with single or multiple CMN was compared with the U.K. National Child Measurement Programme 2010. Forty-seven children had hormonal profiling including measurement of circulating luteinizing hormone, follicle-stimulating hormone, thyroid stimulating hormone, adrenocorticotrophic hormone, growth hormone, prolactin, pro-opiomelanocortin, estradiol, testosterone, cortisol, thyroxine, insulin-like growth factor-1 and leptin; 10 had oral glucose tolerance testing 25 had dual-energy X-ray absorptiometry scans for body composition. RESULTS: Body mass index increased markedly with age (coefficient 0·119, SE 0·016 standard deviation scores per year), at twice the rate of the U.K. population, due to increased adiposity. Three per cent of girls had premature thelarche variant and 6% of boys had persistent undescended testes. Both fat and muscle mass were reduced in areas underlying large naevi, resulting in limb asymmetry and abnormal truncal fat distribution. Anterior pituitary hormone profiling revealed subtle and variable abnormalities. Oral glucose tolerance tests revealed moderate-severe insulin insensitivity in five of 10, and impaired glucose tolerance in one. CONCLUSIONS: Interpersonal variation may reflect the mosaic nature of this disease and patients should be considered individually. Postnatal weight gain is potentially related to the underlying genetic defect; however, environmental reasons cannot be excluded. Naevus-related reduction of fat and muscle mass suggests local hormonal or metabolic effects on development or growth of adjacent tissues, or mosaic involvement of these tissues at the genetic level. Premature thelarche and undescended testes should be looked for, and investigated, as for any child.

A weighted and directed interareal connectivity matrix for macaque cerebral cortex.

Retrograde tracer injections in 29 of the 91 areas of the macaque cerebral cortex revealed 1,615 interareal pathways, a third of which have not previously been reported. A weight index (extrinsic fraction of labeled neurons [FLNe]) was determined for each area-to-area pathway. Newly found projections were weaker on average compared with the known projections; nevertheless, the 2 sets of pathways had extensively overlapping weight distributions. Repeat injections across individuals revealed modest FLNe variability given the range of FLNe values (standard deviation <1 log unit, range 5 log units). The connectivity profile for each area conformed to a lognormal distribution, where a majority of projections are moderate or weak in strength. In the G29 × 29 interareal subgraph, two-thirds of the connections that can exist do exist. Analysis of the smallest set of areas that collects links from all 91 nodes of the G29 × 91 subgraph (dominating set analysis) confirms the dense (66%) structure of the cortical matrix. The G29 × 29 subgraph suggests an unexpectedly high incidence of unidirectional links. The directed and weighted G29 × 91 connectivity matrix for the macaque will be valuable for comparison with connectivity analyses in other species, including humans. It will also inform future modeling studies that explore the regularities of cortical networks.

Regulation of alternative VEGF-A mRNA splicing is a therapeutic target for analgesia.

Vascular endothelial growth factor-A (VEGF-A) is best known as a key regulator of the formation of new blood vessels. Neutralization of VEGF-A with anti-VEGF therapy e.g. bevacizumab, can be painful, and this is hypothesized to result from a loss of VEGF-A-mediated neuroprotection. The multiple vegf-a gene products consist of two alternatively spliced families, typified by VEGF-A165a and VEGF-A165b (both contain 165 amino acids), both of which are neuroprotective. Under pathological conditions, such as in inflammation and cancer, the pro-angiogenic VEGF-A165a is upregulated and predominates over the VEGF-A165b isoform. We show here that in rats and mice VEGF-A165a and VEGF-A165b have opposing effects on pain, and that blocking the proximal splicing event - leading to the preferential expression of VEGF-A165b over VEGF165a - prevents pain in vivo. VEGF-A165a sensitizes peripheral nociceptive neurons through actions on VEGFR2 and a TRPV1-dependent mechanism, thus enhancing nociceptive signaling. VEGF-A165b blocks the effect of VEGF-A165a. After nerve injury, the endogenous balance of VEGF-A isoforms switches to greater expression of VEGF-Axxxa compared to VEGF-Axxxb, through an SRPK1-dependent pre-mRNA splicing mechanism. Pharmacological inhibition of SRPK1 after traumatic nerve injury selectively reduced VEGF-Axxxa expression and reversed associated neuropathic pain. Exogenous VEGF-A165b also ameliorated neuropathic pain. We conclude that the relative levels of alternatively spliced VEGF-A isoforms are critical for pain modulation under both normal conditions and in sensory neuropathy. Altering VEGF-Axxxa/VEGF-Axxxb balance by targeting alternative RNA splicing may be a new analgesic strategy.

Comparative effect of cane syrup and natural honey on abdominal viscera of growing male and female rats.

The high intake of refined sugars, mainly fructose has been implicated in the epidemiology of metabolic diseases in adults and children. With an aim to determine whether honey can substitute refined sugars without adverse effect, the long-term effects of natural honey and cane syrup have been compared on visceral morphology in growing rats fed from neonatal age. Honey increased the caecum and pancreas weights in male rats, which could enhance enzymatic activities of pancreas and digestive functions by intestinal microflora of caecum. Unlike honey, cane syrup caused fatty degenerations in the liver of both male and female rats. Honey enhanced intestinal villi growth, and did not cause pathology in the rodents' abdominal viscera, suggesting potential nutritional benefit as substitution for refined sugars in animal feed.

ß-sitosterol as an alternative to oxytetracycline: Effect on growth performance, feed intake and utilization efficiency and viscera macromorphometry of Cobb 500 broiler chickens.

Antibiotics are used to fortify broiler chicken feeds as growth promoters. Chronic antibiotic use pollutes the environment and causes the development of antibiotic resistance. Natural alternatives that mimic the properties of antibiotics, without causing health and environmental challenges are required. ß-sitosterol has antimicrobial, antioxidant, digestive and immune system modulating and growth stimulating activities. We evaluated its potential to replace oxytetracycline as a growth-promoter in broiler chicken feeds. Two hundred and forty, one-day-old Cobb 500 broiler chicks were randomly allocated to four diets where ß-sitosterol replaced oxytetracycline at 0 mg/kg (control; fortified with 50 mg/kg oxytetracycline), 500 mg/kg, 1000 mg/kg and 1500 mg/kg (w/w) feed and fed for 6 weeks: 2 weeks for each growth phase. Each diet was replicated thrice with 20 chicks per replicate. Initial, weekly and terminal body mass (TBM) and daily feed intake (FI) were measured. Body mass gain (BMG), average daily gain (ADG) and feed conversion ratio were computed. Terminally, the chickens were fasted for 4 h then slaughtered and dressed. Gastrointestinal tract (GIT) and GIT accessory viscera masses and small and large intestine lengths were measured. Dietary fortification with ß-sitosterol had similar effects (P > 0.05) to oxytetracycline on the chickens' TBM, BMG, ADG, FI and utilisation efficiency and GIT organ macromorphometry. In conclusion, ß-sitosterol can replace oxytetracycline in Cobb 500 broiler chicken feeds without compromising growth performance, feed intake and utilisation efficiency and GIT organ growth and development.

The Revised PENIS Score and proposal of the PACKAGE Checklist: a meta-epidemiologic study on penile amputation and replantation.

INTRODUCTION: Penile amputation causes severe physical and psychosocial distress. Microsurgical implementation in penile replantation is presumed to be superior to surgical repair. This assumption has been difficult to verify. OBJECTIVES: The purpose of this study was threefold: (1) to produce an updated review of penile replantation, substantiated by the largest sample size to date; (2) to appraise the comparative value of the novel PENIS Score and propose the PACKAGE Checklist, a guide for standardization of future case reports and reviews; and (3) to improve confusing terminology and recommend the standardization of vocabulary. METHODS: A literature review assessed 432 full-text case reports in 20 languages and identified 123 microsurgical and 40 surgical cases of penile replantation. The novel PENIS Score stratified penile amputations based on 5 criteria: position along the shaft, extension through the penis, neurovascular repair, ischemia time and type, and severed edge condition and contamination. For the outcome measurements, a Kendall tau coefficient evaluated the association between each PENIS criterion for short-term postoperative complications and 3 outcome measures: erection, urination, and sensation. RESULTS: Less than half of surgical reports on penile replantation are sufficiently detailed to complete all PENIS Score criteria. The viability of microsurgical and surgical replantation was equivalent at 92% and 94%, respectively. A statistically significant correlation was found between microsurgical repair and the return of sensation but not with nerve repair. Return of sensation with nerve repair was 51%, and microsurgical replantation without nerve repair was 42%; both were significantly higher than the 14% for surgical replantation. Preservation of a skin bridge was associated with a 40% reduction in severe postoperative complications. CONCLUSION: Microsurgical replantation is superior in return of sensation, with or without nerve repair. Implementing the PACKAGE Checklist and PENIS Score will help inform case reports and reviews.

Long-term (37 years) clinical outcome of older women with early operable primary breast cancer managed in a dedicated clinic.

BACKGROUND: A dedicated clinic for older women with early primary breast cancer, established in 1973, has recently evolved into a combined surgical/oncology facility. This study aimed to compare the clinical outcome across these periods. METHODS: From 1973 to 2010, 1758 women were managed. Analysis was carried out based on retrospective review and continued update of patient records. RESULTS: In the recent decade, 56.3% had surgery, followed by primary endocrine therapy (PET; 41.1%) and primary radiotherapy (1.5%). Before 1999, 42.8%, 55.6% and 1% of patients had surgery, PET and primary radiotherapy, respectively. The use of adjuvant endocrine therapy and radiotherapy has increased from 33.6% to 54.9% and 5.8% to 34.6%, respectively. A significant improvement was seen in the annual rates of local (2.2% versus 0.5%, P < 0.001), regional (1.8% versus 0.4%, P < 0.001) and distant (2.9% versus 1.9%, P = 0.002) recurrences. Similarly, the 5-year breast cancer-specific and overall survival rates showed improvement [81% versus 91% (P < 0.001) and 56% versus 71% (P < 0.001), respectively]. CONCLUSIONS: In the recent decade, while surgery became the predominant treatment, a significant proportion of patients had non-operative therapies, selection of which was based on multidisciplinary assessment in the clinic. This management approach appears to produce excellent clinical outcome, which is significantly better than that in earlier period.

Weight consistency specifies regularities of macaque cortical networks.

To what extent cortical pathways show significant weight differences and whether these differences are consistent across animals (thereby comprising robust connectivity profiles) is an important and unresolved neuroanatomical issue. Here we report a quantitative retrograde tracer analysis in the cynomolgus macaque monkey of the weight consistency of the afferents of cortical areas across brains via calculation of a weight index (fraction of labeled neurons, FLN). Injection in 8 cortical areas (3 occipital plus 5 in the other lobes) revealed a consistent pattern: small subcortical input (1.3% cumulative FLN), high local intrinsic connectivity (80% FLN), high-input form neighboring areas (15% cumulative FLN), and weak long-range corticocortical connectivity (3% cumulative FLN). Corticocortical FLN values of projections to areas V1, V2, and V4 showed heavy-tailed, lognormal distributions spanning 5 orders of magnitude that were consistent, demonstrating significant connectivity profiles. These results indicate that 1) connection weight heterogeneity plays an important role in determining cortical network specificity, 2) high investment in local projections highlights the importance of local processing, and 3) transmission of information across multiple hierarchy levels mainly involves pathways having low FLN values.