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Background: Taken together, prior publications on the association between symptoms of depression and anxiety and contact with the criminal justice system (CJS) suggest a bi-directional relationship, but all the studies only focus on one direction in this relationship., Aims: To examine, in longitudinally collected data, period-specific within-individual change in anxiety and depression measures preceding arrest measurement and, separately, following arrest measurement., Methods: Data were obtained from the National Longitudinal Study of Youth 1997, a nationally representative sample of people born between 1980 and 1984 and first interviewed between ages 12-17 and a publicly accessible database. Our focus was on data for the 11 years 2000-2010. Using whole sample data, we tested for a reciprocal association between depression and anxiety during each 2-year period and arrests during the following year, and vice versa, allowing for relatively fixed characteristics such as sex, age and socio-economic indicators. We used period-specific change modelling to test relationships., Results: We found that within-individual increases in depression and anxiety scores over short periods (2-year periods) of time was associated with an increase in the number of arrests subsequent over the following year, consistently throughout the whole of the 10 years studies. The reciprocal association was also observed, albeit the magnitude of the effects was much smaller., Conclusion: This study adds to the literature on the association between mental health and CJS contact by showing that they may be reciprocally associated. This suggests that facilitating co-working or even formal partnerships between community mental health services and justice-related services could be beneficial., (© 2024 John Wiley & Sons Ltd.)

Rationale: Community gun violence significantly shapes public health and collective well-being. Understanding how gun violence is associated with community health outcomes like mental health and sleep is crucial for developing interventions to mitigate disparities exacerbated by violence exposure., Objective: This study examines the associations between community gun violence , insufficient sleep, and poor mental health across neighborhoods in the United States., Methods: We utilized a novel database covering nearly 16,000 neighborhoods in 100 US cities from 2014 through 2019. Correlated trait fixed-effects models were employed to conduct all analyses while considering various neighborhood covariates such as concentrated disadvantage, demographic composition, population density, and proximity to trauma centers., Results: Our analysis revealed that greater gun violence is associated with both insufficient sleep and poor mental health in subsequent years. There is a reciprocal relationship between poor mental health and insufficient sleep, with each partially mediating the other's association with community gun violence. Notably, gun violence exhibits the strongest direct association with poor sleep rather than with poor mental health. We found a consistent reciprocal relationship between sleep and mental health at the community level., Conclusions: The findings highlight a complex interplay between community violence, sleep, and mental health, underlining the importance of reducing community violence through numerous long-term interventions to address health disparities across the US., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: To examine the relationship between youth incarceration in adult correctional facilities and mental health in early adulthood., Methods: We analyzed nationally representative data from 1997 through 2019 (N = 8,961) using the National Longitudinal Survey of Youth 1997. An ordinary least squares regression model using inverse probability weights was used to assess the influence of youth incarceration in an adult facility on average mental health scores from age 18 to 37., Results: Respondents incarcerated in an adult facility as a youth had poorer average mental health than those not held in adult prisons or jails over the course of the study period. Those incarcerated for longer in adult facilities also exhibited more mental health symptoms., Discussion: Young people incarcerated in adult correctional facilities experience poorer long-term mental health related to depression and anxiety in early adulthood., (Copyright © 2024 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: Some scholars have criticized pretrial assessments for perpetuating racial bias in the criminal legal system by offering biased predictions of future legal system outcomes. Although these critiques have some empirical support, the scholarship has yet to examine the predictive validity and differential prediction of pretrial assessments across individuals by their age. Following the guidance of the life-course literature, the present study serves as the first age-graded evaluation of the Public Safety Assessment (PSA) focused on assessing whether the predictive validity and scoring predictions of the tool vary across the lifespan., Hypotheses: We expected that the predictive validity of the PSA scores would vary across the lifespan, such that the PSA underpredicts for younger individuals and overpredicts for older individuals., Method: The present study relied on pretrial information collected from 31,527 individuals during the Advancing Pretrial Policy and Research project. Logistic regression models were estimated to evaluate the differential prediction of the PSA for individuals ranging from 18 to 68 years of age. The results of bivariate models were used to produce area under the curve estimates at each year of age., Results: The results of the present study provided some evidence that the PSA differentially predicted pretrial outcomes for individuals from 18 to 68 years of age. Specifically, the predictive validity of the New Criminal Arrest and the New Violent Criminal Arrest scales appears to improve as individuals become older, suggesting that these instruments are better able to predict pretrial outcomes for older individuals relative to younger individuals., Conclusion: The results suggest that the PSA is a valid predictor of pretrial outcomes and that the predictive validity of some PSA scores is impacted by age. These findings suggest that the age of the defendant should be accounted for when interpreting the new criminal arrest and new violent criminal arrest scores. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Gun violence imparts a tremendous human and financial toll on local communities. Researchers have documented extensive mental and physical health consequences of generalized violence exposure but few studies have analyzed the particular impacts of gun violence on community well-being using nationally comprehensive data. We leverage a unique database of almost 16,000 neighborhoods in 100 US cities (2014-2019) to examine how year-over-year rates of gun violence correspond to overall neighborhood well-being and three aspects of community health: (1) health behaviors, (2) physical and mental health status, and (3) health prevention efforts. We simultaneously consider the reciprocal influence of neighborhood well-being on subsequent gun violence while accounting for concentrated disadvantage in communities. The results demonstrate that gun violence is associated with poorer community health in subsequent years, particularly health behaviors and mental/physical health status. Furthermore, we find substantial reciprocal effects for both gun violence and community health in their relationship to neighborhood concentrated disadvantage. These findings highlight the consequential role of gun violence in perpetuating cycles of harm in local communities., (© 2023. The Author(s).)

Importance: Youths incarcerated in adult correctional facilities are exposed to a variety of adverse circumstances that could diminish psychological and physical health, potentially leading to early mortality., Objective: To evaluate whether being incarcerated in an adult correctional facility as a youth was associated with mortality between 18 and 39 years of age., Design, Setting, and Participants: This cohort study relied on longitudinal data collected from 1997 to 2019 as part of the National Longitudinal Survey of Youth-1997, a nationally representative sample of 8984 individuals born in the United States between January 1, 1980, and December 1, 1984. The data analyzed for the current study were derived from annual interviews between 1997 and 2011 and interviews every other year from 2013 to 2019 (19 interviews in total). Participants were limited to respondents aged 17 years or younger during the 1997 interview and alive during their 18th birthday (8951 individuals; >99% of the original sample). Statistical analysis was performed from November 2022 to May 2023., Intervention: Incarceration in an adult correctional facility before the age of 18 years compared with being arrested before the age of 18 years or never arrested or incarcerated before the age of 18 years., Main Outcomes and Measures: The main outcome for the study was age at mortality between 18 and 39 years of age., Results: The sample of 8951 individuals included 4582 male participants (51%), 61 American Indian or Alaska Native participants (1%), 157 Asian participants (2%), 2438 Black participants (27%), 1895 Hispanic participants (21%), 1065 participants of other race (12%), and 5233 White participants (59%). A total of 225 participants (3%) died during the study period, with a mean (SD) age at death of 27.7 (5.9) years. Incarceration in an adult correctional facility before the age of 18 years was associated with an increased risk of earlier mortality between 18 and 39 years of age compared with individuals who were never arrested or incarcerated before the age of 18 years (time ratio, 0.67; 95% CI, 0.47-0.95). Being arrested before the age of 18 years was associated with an increased risk of earlier mortality between 18 and 39 years of age when compared with individuals who were never arrested or incarcerated before the age of 18 years (time ratio, 0.82; 95% CI, 0.73-0.93)., Conclusions and Relevance: In this cohort study of 8951 youths, the survival model suggested that being incarcerated in an adult correctional facility may be associated with an increased risk of early mortality between 18 and 39 years of age.

The co-occurrence of illegal drug use, symptoms of depression, and a lower perception of general health among adolescents continues to be of substantive interest for researchers and the general public alike. Research on this topic, however, remains relatively stagnant, focusing on narrow developmental periods and each association independently, with limited consideration for the existence of a nexus between the three constructs as individuals age. Considering these limitations, the current study examines the longitudinal progression, from adolescence to early adulthood, of illegal drug use, symptoms of depression, and a lower perception of general health. The National Longitudinal Survey of Youth 1997 (NLSY97; N = 8,984), measures over an eleven-year data collection period, and between-and within-individual analytical strategies were used to evaluate the nexus between the constructs. The findings suggested that illegal drug use, depressive symptoms, and general health at previous time periods directly and indirectly predicted illegal drug use, depressive symptoms, and general health at subsequent time periods. Moreover, the within-individual change in illegal drug use was associated with the change in depressive symptoms, and the change in depressive symptoms was associated with the change in general health. Practitioners should consider this co-occurrence when treating symptoms related to illegal drug use, symptoms of depression, and physical health.

Introduction: Recent trends in reproductive rights have contributed to lasting concerns about adolescent childrearing in American society. Beyond being generally unprepared when raising a child, having a child during adolescence is associated with a variety of environmental, social, and psychological consequences for both the parents and the child. It is important to understand the factors contributing to adolescent childrearing. Although research has identified many factors that contribute to adolescent childrearing, a notable gap remains when considering the role of the correctional system and, in particular, the age-specific effects of confining adolescents in adult correctional facilities., Methods: The current study examined the age-specific effects of time spent in adult correctional facilities from 13 to 34 years of age on childrearing between 14 and 35 years of age using the National Longitudinal Survey of Youth-1997 (NLSY97). The NLSY97 is a nationally representative sample of Males (51%) and Females (49%) born in the United States. Respondents of the NLSY97 were interviewed about life events beginning at age 7 and continued to participate in the study as recently as 2021., Results: The results of the lagged growth curve models suggest that the time spent incarcerated between 13 and 17 years of age heightens the risk of childrearing between 14 and 18 years of age, an effect that is not observed during adulthood., Conclusion: Overall, the results suggest that the conditions adolescents are exposed to during incarceration in an adult correctional facility could contribute to a heightened likelihood of adolescent childrearing., (© 2022 The Authors. Journal of Adolescence published by Wiley Periodicals LLC on behalf of Foundation for Professionals in Services to Adolescents.)

Discordant monozygotic (MZ) twin methodologies are considered one of the foremost statistical approaches for estimating the influence of environmental factors on phenotypic variance. Limitations associated with the discordant MZ twin approach generates an inability to estimate particular relationships and adjust estimates for the confounding influence of gene-nonshared environment interactions. Recent advancements in molecular genetics, however, can provide the opportunity to address these limitations. The current study reviews an alternative technique, genetically adjusted propensity scores (GAPS) matching, that integrates observed genetic and environmental information to adjust for the confounding of these factors in nonkin individuals. Simulations and a real data example were used to compare the GAPS matching approach to the discordant MZ twin method. Although the results of the simulated comparisons demonstrated that the discordant MZ twin approach remains the more robust statistical technique to adjust for shared environmental and genetic factors, GAPS matching - under certain conditions - could represent a viable alternative when MZ twin samples are unavailable. Overall, the findings suggest that GAPS matching can potentially provide an alternative to the discordant MZ twin approach when limited variation exists between identical twin pairs. Moreover, the ability to adjust for gene-nonshared environment interactions represents a potential advancement associated with the GAPS approach. The limitations of the approach, as well as polygenic risk scores, are also discussed.

Inmate misconduct continues to threaten safety and order within correctional institutions. Yet few studies have examined its longitudinal nature. In this paper we explore the correspondence between correctional programming and inmate misconduct. To do this, we draw from Linning et al.'s time-course framework devised to improve the design and evaluation of interventions by considering effects that can occur before, during, and after programming. We provide the first empirical demonstration of their framework using prisoner misconduct data collected from all Ohio prisons between January 2008 and June 2012. A cross-lagged panel analysis provides support for the use of a time-course framework. Results show that misconduct decreased during programming. However, we observed increases in misconduct prior to and following exposure to programming. Our results suggest that future work needs to improve our understanding of causal mechanisms of inmate misconduct and when their effects are expected.

Heteropaternal superfecundation (HP) occurs when two or more ova are fertilized by sperm from separate males. The resulting siblings are genetically equivalent to half-siblings and share, on average, 25% of their inherited genetic material. In the absence of genetic testing HP siblings could be treated as dizygotic (DZ) twins in behavioral genetic analyses and bias heritability estimates in phenotypic decomposition models. However, the extent to which such misclassification could affect calculated estimates of heritability is currently unknown. Employing simulation analyses, the current study assessed the potential biasing impact across a variety of conditions varying by proportions of DZ twins, sample sizes, and low, moderate, and high levels of genetic and environmental contribution to phenotypic variance. Overall, the results indicated that misclassified HP siblings had minimal impact on estimates of heritability. Nonetheless, greater attention should be paid to the identification of HP siblings within existing and future twin datasets.

Although many studies have highlighted the deleterious outcomes associated with access to firearms, others suggest gun ownership and carrying can have protective effects. This study attempts to adjudicate between these countervailing points and address several important gaps in the literature. To do so, data from the National Longitudinal Study of Adolescent to Adult Health were used to assess the long-term associations between gun ownership and gun carrying in late adolescence and violence and violent victimization in early adulthood. Results from propensity score matching analyses suggest gun carrying, but not gun ownership, is associated with a higher risk of experiencing a violent victimization ( b = 0.080, 95% CI = .032, .127) and engaging in violence with a weapon ( b = 0.885, 95% CI = .392, 1.378). Efforts to curb firearm-related violence should consider focusing on those who carry guns for additional counseling about these risks., (© Copyright 2021 Springer Publishing Company, LLC.)

Contemporary scholarship has demonstrated an association between traumatic brain injury (TBI) during adolescence and aggressive offending. Research, however, has yet to identify any mechanisms linking TBI to subsequent aggressive offending. Consequently, the current study hypothesized that adverse psychological effects is one such pathway. The current study used the Pathways to Desistance data set (n = 416) to examine the pathway of TBI to aggressive offending through adverse psychological effects. The findings of the structural equation model supported the hypothesized association. Specifically, increased exposure to TBI was indirectly associated with aggressive offending through adverse psychological effects. An additional supplemental analysis illustrated that a direct link between TBI and aggressive offending did not exist for the analytical sample. The findings suggested that the neurological disruptions commonly associated with TBI could result in direct increases in negative psychological outcomes and indirect increases in subsequent negative behavioral outcomes., (© 2020 Wiley Periodicals, Inc.)

Primary Objective : Prior research has demonstrated that traumatic brain injury (TBI) is associated with individual psychological symptoms. These findings, however, may not pertain to the influence of TBI during key developmental stages on the co-occurrence of negative psychological symptoms. Research Design : It was hypothesized that (H1) self-reported TBI is associated with adverse psychological effects, that (H2) self-reported TBI during adolescences is associated with both immediate and delayed adverse psychological effects, and finally, (H3) self-reported TBI during the early stages of adulthood is not associated with immediate psychological effects. Methods and Procedures : The current study employed a sample of adjudicated youth (N: 419 to 562) and structural equation modeling to estimate the association between self-reported TBI and subsequent adverse psychological effects. Results : Findings suggested that higher levels of self-reported TBI during adolescence were associated with higher levels of adverse psychological effects. These effects were both immediate and delayed. However, higher levels of self-reported TBI during adulthood were not associated with immediate adverse psychological effects. Conclusion : Overall, the findings suggest that deleterious outcomes related to self-reported TBI during key developmental stages include proximal and long-term adverse psychological effects.

Aim of the Study: Large tendon defects involving extensive tissue loss present complex clinical problems. Surgical reconstruction of such injuries is normally performed by transplanting autogenous and allogenous soft tissues that are expected to remodel to mimic a normal tendon. However, the use of grafts has always been associated with significant limitations. Tissue engineering employing artificial scaffolds may provide acceptable alternatives. Gelatin is a hydrolyzed form of collagen that is bioactive, biodegradable, and biocompatible. The present study has investigated the suitability of gelatin scaffold for promoting healing of a large tendon-defect model in rabbits., Materials and Methods: An experimental model of a large tendon defect was produced by partial excision of the Achilles tendon of the left hind leg in adult rabbits. To standardize and stabilize the length of the tendon defect a modified Kessler core suture was anchored in the sectioned tendon ends. The defects were either left untreated or filled with three-dimensional gelatin scaffold. Before euthanasia 60 days after injury, the progress of healing was evaluated clinically. Samples of healing tendon were harvested at autopsy and evaluated by gross, histopathologic, scanning, and transmission electron microscopy, and by biomechanical testing., Results: The treated animals showed superior weight-bearing and physical activity compared with those untreated, while frequency of peritendinous adhesions around the healing site was reduced. The gelatin scaffold itself was totally degraded and replaced by neo-tendon that morphologically had significantly greater numbers, diameters, density, and maturation of collagen fibrils, fibers, and fiber bundles than untreated tendon scar tissue. It also had mechanically higher ultimate load, yield load, stiffness, maximum stress and elastic modulus, when compared to the untreated tendons., Conclusion: Gelatin scaffold may be a valuable option in surgical reconstruction of large tendon defects.

This study was designed to investigate the effectiveness of hybridized, three-dimensional (3D) collagen implants in repair of experimentally-induced tendon defects in rabbits. Seventy-five mature New Zealand albino rabbits were divided into treated (n = 50) and control (n = 20) groups. The left Achilles tendon was completely transected and 2 cm excised. In treated animals defects were filled with hybridized collagen implants and repaired with sutures. In control rabbits tendon defects were sutured similarly but the gap was left untreated. Changes in injured and normal contralateral tendons were assessed weekly by ultrasonography. Among the treated animals, small pilot groups were euthanized at 5, 10, 15, 20, 30, 40 (n = 5 at each time interval) and the remainder (n = 20) at 60 days post-injury. All control animals were euthanized at 60 days. Tendon lesions of all animals were examined morphologically and histologically immediately after death. Those of the experimental groups (n = 20 for each) were examined for gross pathological, histopathological and ultrastructural changes together with dry matter content at 60 days post-injury, as were the normal, contralateral tendons of both groups. In comparison with healing lesions of control animals, the treated tendons showed greater numbers of mature tenoblasts and tenocytes, minimal peritendinous adhesions and oedema, together with greater echogenicity, homogeneity and fibril alignment. Fewer chronic inflammatory cells were present in treated than control tendons. Hybridized collagen implants acted as scaffolds for tenoblasts and longitudinally-orientated newly-formed collagen fibrils, which encouraged tendon repair with homogeneous, well-organized highly aligned scar tissue that was histologically and ultrastructurally more mature than in untreated controls. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Caprine besnoitiosis, caused by the cyst-forming protozoal apicomplexan Besnoitia caprae appears to be endemic in Kenya, Nigeria and Iran, but has yet to be detected in other parts of the world. The infection causes an important parasitic disease of goats in affected developing countries. Bovine besnoitiosis, is a widespread disease of cattle in Africa, Asia (but not Iran) and southern Europe. Recent epidemiological data confirm that the incidence and geographical range of bovine besnoitiosis in Europe is increasing, which is why growing attention has been given to the condition during the past decade. This paper reviews pertinent information on the biology, epidemiology, pathology, clinical signs, diagnosis and control of caprine besnoitiosis, together with its similarities to, and differences from, bovine besnoitiosis. The serious economic consequences of besnoitiosis on goat breeding and local meat and hide industries is also considered., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Aim: This study was designed to investigate the effect of novel 3-dimensional (3-D) collagen implants on the healing of large, experimentally-induced, tendon-defects in rabbits., Methods: Forty mature male white New Zealand rabbits were divided randomly into treated and control groups. Two cm of the left Achilles tendon was excised and the gap was spanned by Kessler suture. In the treated group, a novel 3-D collagen implant was inserted between the cut ends of the tendon. No implant was used in the control group. During the course of the experiment the bioelectrical characteristics of the healing and normal tendons of both groups were investigated weekly. At 120 days post injury (DPI), the tendons were dissected and inspected for gross pathology, examined by transmission and scanning electron microscopy, and their biomechanical properties, percentage dry matter and hydroxyproline concentration assessed., Results: The collagen implant significantly improved the bioelectrical characteristics, gross appearance and tissue alignment of the healed, treated tendons, compared to the healed, control scars. It also significantly increased fibrillogenesis, diameter and density of the collagen fibrils, dry matter content, hydroxyproline concentration, maximum load, stiffness, stress and modulus of elasticity of the treated tendons, as compared to the control tendons. Treatment also significantly decreased peri-tendinous adhesions, and improved the hierarchical organization of the tendon from the collagen fibril to fibre-bundle level. 3-D xenogeneic-based collagen implants induced newly regenerated tissue that was ultrastructurally and biomechanically superior to tissue that was regenerated by natural unassisted healing., Conclusion: This type of bioimplant was biocompatible, biodegradable and appeared suitable for clinical use.

This study was designed to investigate the effectiveness of a novel tissue-engineered three-dimensional collagen implant on healing of a large tendon-defect model, in vivo. Forty rabbits were divided into two equal groups: treated and control. A 2cm full-thickness gap was created in the left Achilles tendons of all the rabbits. To maintain the gap at the desired length (2cm), a Kessler suture was anchored within the proximal and distal ends of the remaining tendon. In the treated group a collagen implant was inserted in the gap while in the control group the gap was left unfilled. At weekly intervals the animals were examined clinically and their Achilles tendons tested bioelectrically. The hematological parameters and the serum Platelet-Derived Growth Factor of the animals were analyzed at 60 days post injury (DPI) immediately prior to euthanasia. Their injured (left) and normal contralateral Achilles tendons were harvested and examined at gross morphologic level before being subjected to biomechanical testing, and biophysical and biochemical analysis. The treated animals showed superior weight-bearing and greater physical activity than their controls. New dense tendinous tissue with a transverse diameter comparable to that of intact tendons filled the defect area of the treated tendons and had entirely replaced the collagen implant, at 60 DPI. In control lesions the defect was filled with loose areolar connective tissue similar to subcutaneous fascia. Treatment significantly improved the electrical resistance, dry matter, hydroxyproline content, water uptake and water delivery characteristics, of the healing tissue, as well as maximum load, yield load, maximum stress, yield stress and modulus of elasticity of the injured treated tendons compared to those of the control tendons (P<0.05). Use of this three-dimensional collagen implant improved the healing of large tendon defects in rabbits., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The experimental procedure by which the valve cusp hypoxia (VCH) hypothesis of the etiology of deep venous thrombosis (DVT) was confirmed lends itself to testing of methods of prophylaxis. Similar animal experiments could end the present exclusive reliance on statistical analysis of data from large patient cohorts to evaluate prophylactic regimes. The reduction of need for such (usually retrospective) analyses could enable rationally-based clinical trials of prophylactic methods to be conducted more rapidly, and the success of such trials would lead to decreased incidences of DVT-related mortality and morbidity. This paper reviews the VCH hypothesis ("VCH thesis", following its corroboration) and its implications for understanding DVT and its sequelae, and outlines the experimental protocol for testing prophylactic methods. The advantages and limitations of the protocol are briefly discussed.

The distribution pattern and associated tissue reactions with progressive changes in Besnoitia caprae cysts were investigated in 6 experimentally infected 16- to 20-month-old male goats. Each goat was subcutaneously inoculated with approximately 13 × 10(8) B caprae bradyzoites. The animals were examined daily for development of clinical besnoitiosis, and skin biopsies from distal parts of the limbs were taken at weekly intervals. At 15, 30, 60, 120, 180, and 365 days postinfection (DPI), 1 goat was euthanized. Samples were collected at autopsy from various organs for histologic and ultrastructural studies. No cysts were seen in tissue sections on 15, 30, and 365 DPI, but large numbers were present at 60, 120, and 180 DPI in the skin of the distal limbs, scrotum, and ears, with fewer in the tongue, palate, sclera, testicles, and spermatic cord. No cysts were seen in the lungs, liver, kidneys, spleen, central nervous system, or lymph nodes. Cyst numbers peaked at 60 DPI, then declined from 120 to 180 DPI. Degenerated cysts were relatively rare at 60 DPI but more numerous at 180 compared with 120. A granulomatous reaction--predominantly characterized by macrophages, lymphocytes, and plasma cells--surrounded each degenerated cyst. All goats showed testicular tubular degeneration with little or no spermatogenic activity. The sizes of cysts and their wall thickness, with the size of bradyzoites and some of their organelles, exhibited progressive chronologic changes.

The British Equine Veterinary Association (BEVA) was established in 1961 and launched the Equine Veterinary Journal (EVJ) in 1968. This review outlines some of the major advances in equine science and practice that have occurred in that time and the role played by the Journal in facilitating those developments., (© 2011 EVJ Ltd.)

A 40-year-old man was admitted to hospital with a scalp wound but died 22 days later after unsuccessful treatment. Initial assessment of the cranial fragments removed during surgery revealed fine fracture lines on the endocranial surface, and a dark arcuate line on the ectocranial surface. To investigate the extent of the fractures a μCT scan of the fragments was taken, examined in 3D, and compared to plain radiographs. Some fractures were found to extend through the full thickness of the skull. This case presents a novel application of μCT technology to forensic radiology., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Introduction: This study evaluated the effects of metrenperone on healing of unilateral, collagenase-induced lesions in the Superficial Digital Flexor Tendons (SDFT) of rabbits., Methods: After controlled injury of the left SDFT, nine rabbits received daily treatment with metrenperone for 28 days. Another nine were untreated controls; in both groups the contra-lateral tendons served as uninjured controls. Histological and ultrastructural changes, mechanical properties, dry weight, collagen content, and amount of DNA in healing and control tendons were assessed 28 days after injury., Results: Restoration of structural hierarchy was more organized in treated than in untreated tendons while cellularity was greater in the latter. At the ultrastructural level, collagen in treated lesions was predominantly in the form of small-diameter, new fibrils, with few large, old fibrils; in untreated lesions there was a high proportion of large, old fibrils but relatively few small, new ones. The amount of DNA in untreated injuries was much greater than in normal tendons, while in treated lesions it was not significantly different from that of uninjured controls. There were no significant differences in total collagen, stiffness and ultimate strength of injured, treated, and untreated tendons 28 days after injury. Both were significantly weaker than their corresponding contralaterals., Conclusions: The findings suggest that metrenperone had positive effects on collagen turnover, remodelling, and organization during acute inflammation and fibroplasia. Provided that the new fibrils subsequently matured in a normal manner, mechanical characteristics of the organized scar should be better than those of an untreated lesion.

The beneficial effects of serotonin S(2)-receptor blockers on healing skin and muscle ulcers and refractory lesions such as leprosy and diabetic and ischemic ulcers have been reported previously, but their mechanisms of actions are not clear. The present study sought to elucidate the action of an S(2)-receptor blocker, metrenperone, on the healing of collagenase-induced injuries in superficial digital flexor tendons of two groups of rabbits. In one group, oral and topical therapy for 28 days with metrenperone, was started within 48 hr of a single acute injury. The animals were then left untreated for another 60 days, when it was found that most of the morphological, biochemical, and biomechanical characteristics of the healed tendons matched those of their normal uninjured controls. Injured, untreated controls showed poor healing. In the second group of animals, tendon injury was induced by four separate injections of collagenase at weekly intervals. The rabbits were left for another 60 days, before being treated with metrenperone for 26 days. This delayed treatment had no apparent effect on the biomechanical, biochemical, or morphological characteristics of the healing tendons. It appeared that metrenperone had a significant effect on collagen turnover and organization of scar tissue, but only while the inflammatory and fibroplastic processes were active in the early stages of healing. S(2)-receptor blockers may, therefore, be of potential value for modulating repair in acutely injured collagenous tissue.

This study explored the hypothesis that local administration of a polysulphated glycosaminoglycan (PSGAG) in the early phase of healing of a standard collagenase-induced tendon injury in the superficial digital flexor tendon of the rabbit would reduce the degenerative effects of inflammatory mediators and proteases and preserve normal tendon morphology, composition, and biomechanical properties. Histological and ultrastructural changes together with the mechanical properties, dry weight, collagen content, and amount of DNA in healing tissue at the site of the lesion were assessed in treated and untreated animals. In treated lesions 28 days after injury, the normal orientation of tenoblasts and collagen fibrils was well preserved compared with the disorganized scar formation seen in untreated animals. The degree of cellularity was significantly higher in the untreated lesions. At the ultrastructural level the collagen in the healing tissue of the treated animals consisted of a mixture of small diameter, new regenerated fibrils intermingled with well-preserved large diameter, old fibrils, aligned to the long axis of the tendon; in untreated animals small, randomly arranged new fibrils predominated. The diameters of treated tendons had returned to normal, but in untreated animals the injured tendons remained significantly thicker than their controls. The percentage dry weight and collagen contents of treated injured tendons approximated those of control normal tendons, whereas those of untreated tendons were significantly less than those of the control values. The DNA content of injured treated tendons was not significantly different from that of normal contralateral controls, while in the untreated tendons it was significantly higher. There were no significant differences between the normal and the contralateral treated injured tendons in ultimate strength, fatigue strength, stiffness, and maximum absorbed energy. However in the untreated animals, although the tendon diameter was significantly greater, the ultimate strength, fatigue strength, stiffness, and maximum absorbed energy were significantly lower than the contralateral control. These data suggest that polysulphated glycosaminoglycans are effective in restoring the morphological, biochemical, and biomechanical properties of injured soft connective tissues and may be of clinical value in the treatment of acute tendon injury.

Posthaemorrhagic ventricular dilatation (PHVD) is a common complication of intraventricular haemorrhage in premature infants. The aim of this study was to investigate the role of transforming growth factor-betas (TGF-betas), a family of polypeptides with potent desmoplastic properties, in the aetiology of PHVD in a newly developed neonatal rat model of this disorder. Pups were injected with citrated rat blood or artificial cerebrospinal fluid (ACSF) into alternate lateral ventricles on postnatal days 7 and 8. The brains were perfusion-fixed 14 days later and immunohistochemistry was performed for TGF-beta1, -beta2 and -beta3, p44/42 mitogen-activated protein (MAP) kinases, and the extracellular matrix proteins laminin, vitronectin and fibronectin. Ventricular dilatation occurred in 58.3% of animals injected with blood and 36.7% of those injected with ACSF. Periventricular immunoreactivity for TGF-beta1 and -beta2 increased in injected animals irrespective of the presence or absence of ventricular dilatation, although the levels of both isoforms tended to be higher in animals with hydrocephalus. TGF-beta3 immunoreactivity was elevated in hydrocephalic rats only. The immunolabelling for phosphorylated p44/42 MAP kinases rose in a pattern similar to that for TGF-beta1 and -beta2. Expression of TGF-betas was accompanied by deposition of the extracellular matrix proteins fibronectin, laminin and vitronectin. The changes caused by injection of ACSF were the same as those caused by injection of blood. Our results raise the possibility that expression of TGF-betas, together with extracellular matrix protein deposition, may be involved in the development and/or maintenance of hydrocephalus after ventricular distension due to haemorrhage in the neonate.

Production of energy for the maintenance of ionic disequilibria necessary for generation and transmission of nerve impulses is one of the primary functions of the brain. This review attempts to link the plethora of information on the maturation of the central nervous system with the ontogeny of ATP metabolism, placing special emphasis on variations that occur during development in different brain regions and across the mammalian species. It correlates morphological events and markers with biochemical changes in activities of enzymes and pathways that participate in the production of ATP. The paper also evaluates alterations in energy levels as a function of age and, based on the tenet that ATP synthesis and utilization cannot be considered in isolation, investigates maturational profiles of the key processes that utilize energy. Finally, an attempt is made to assess the relevance of currently available animal models to improvement of our understanding of the etiopathology of various disease states in the human infant. This is deemed essential for the development and testing of novel strategies for prevention and treatment of several severe neurological deficits.

This review analyzes, in some depth, results of studies on the effect of lowered temperatures on cerebral energy metabolism in animals under normal conditions and in some selected pathologic situations. In sedated and paralyzed mammals, acute uncomplicated 0.5- to 3-h hypothermia decreases the global cerebral metabolic rate for glucose (CMR(glc)) and oxygen (CMRo(2)) but maintains a slightly better energy level, which indicates that ATP breakdown is reduced more than its synthesis. Intracellular alkalinization stimulates glycolysis and independently enhances energy generation. Lowering of temperature during hypoxia-ischemia slows the rate of glucose, phosphocreatine, and ATP breakdown and lactate and inorganic phosphate formation, and improves recovery of energetic parameters during reperfusion. Mild hypothermia of 12 to 24-h duration after normothermic hypoxic-ischemic insults seems to prevent or ameliorate secondary failures in energy parameters. The authors conclude that lowered head temperatures help to protect and maintain normal CNS function by preserving brain ATP supply and level. Hypothermia may thus prove a promising avenue in the treatment of stroke and trauma and, in particular, of perinatal brain injury.

Intraventricular hemorrhage is a common complication of prematurity. Posthemorrhagic ventricular dilation (PHVD) has a high rate of disability and no safe and effective treatment. Its pathogenesis is poorly understood, largely because of the lack of a satisfactory animal model. We have developed a model of neonatal PHVD in the rat. Seven-day-old (P7) Wistar rat pups were given 80-microl injections of citrated rat blood or artificial cerebrospinal fluid (CSF) into alternate lateral ventricles on P7 and P8. Intracranial pressure was monitored and increased briefly by over 8-fold. Some rats received further 10-microl intraventricular injections of India ink on P21. Animals were weighed daily and simple neurologic tests performed. On P21 (or P22 if India ink had been injected), the rats were perfusion-fixed and blocks processed for paraffin histology. Sixty-five percent of pups injected with blood and 50% injected with artificial CSF developed dilated lateral ventricles, with patchy loss of ependyma, marked astrocytic gliosis, and rarefaction of periventricular white matter. India ink injection revealed slow transit of CSF from the dilated lateral ventricles but eventual passage into the subarachnoid space. Pups that had received intraventricular injections but did not develop ventricular dilation nonetheless had lighter brains than littermate controls (p < 0.001). Body weights were not significantly different from controls. Hydrocephalic animals had reduced motor performance as assessed by a grip traction test (p = 0.0002). This model is well suited to studying the pathogenesis of PHVD.

Hypothermia is potentially therapeutic in the management of neonatal hypoxic-ischemic brain injury. However, not all studies have shown a neuroprotective effect. It is suggested that the stress of unsedated hypothermia may interfere with neuroprotection. We propose that selective head cooling (SHC) combined with mild total-body hypothermia during anesthesia enhances local neuroprotection while minimizing the occurrence of systemic side effects and stress associated with unsedated whole-body cooling. Our objective was to determine whether SHC combined with mild total-body hypothermia while anesthetized for a period of 24 hours reduces cerebral damage in our piglet survival model of global hypoxia-ischemia. Eighteen anesthetized piglets received a 45-minute global hypoxic-ischemic insult. The pigs were randomized either to remain normothermic or to receive SHC. We found that the severity of the hypoxic-ischemic insult was similar in the SHC versus the normothermic group, and that the mean neurology scores at 30 and 48 hours and neuropathology scores were significantly better in the SHC group versus the normothermic group. We conclude that selective head cooling combined with mild systemic hypothermia and anesthesia is neuroprotective when started immediately after the insult in our piglet model of hypoxic-ischemic encephalopathy.

Objective: Selective head cooling (SHC) combined with mild body cooling is currently being evaluated as a potentially therapeutic option in the management of neonatal hypoxic-ischemic encephalopathy. It is proposed that SHC enables local hypothermic neuroprotection while minimizing the deleterious side effects of systemic hypothermia. However, there is little evidence that it is possible to cool the brain more than the body for a prolonged period of time. The aim of this study was to examine whether the brain (T(deep brain)) could be cooled to below the rectal temperature (T(rectal)) in our piglet hypoxia ischemia (HI) model for a period of 24 hours, using a head-cooling cap., Methods: Eight anesthetized piglets (median age: 15 hours) had subdural and intracerebral basal ganglia temperature probes inserted. After a 45-minute global HI insult (known to produce permanent brain damage), SHC using a cap perfused with cold water (5 degrees C-24 degrees C) combined with overhead body heating to maintain T(rectal) at 34 to 35 degrees C was performed for 24 hours., Results: The piglets were cooled to a median T(rectal) of 35.0 degrees C (interquartile range [IQR]: 34.7-35.3) for 24 hours. During this time, the median T(deep brain) was 31.4 degrees C (IQR: 30 degrees C-32.2 degrees C), with a median T(rectal) to T(deep brain) gradient of 3.4 degrees C (IQR: 2.7 degrees C-4.8 degrees C). At the end of the cooling period, this gradient was still maintained at a median of 3.3 degrees C (IQR: 2.9 degrees C-3.7 degrees C). The ability to obtain the gradient was not influenced by the size of the piglet (1300-1840 g). Cap cooling lowered scalp temperature (T(scalp)) to a median of 24.9 degrees C (IQR: 22.2 degrees C-29.2 degrees C) and subdural temperature to a median of 28.1 degrees C (IQR: 25.8 degrees C-29.5 degrees C) but did not result in either skin injury or superficial brain hemorrhage. There was no clinically useful correlation between T(scalp) and T(deep brain) or between T(scalp) and T(subdural)., Conclusions: This study using our piglet HI model shows that it is possible by means of a head-cooling cap to cool the brain more than the body for a 24-hour period while keeping the core temperature mildly hypothermic. However, we were unable to predict temperatures inside the brain using surface temperature probes on the head.

Mammalian brain is a highly oxidative organ and although it constitutes only a small fraction of total body weight it accounts for a disproportionately large percentage of bodily oxygen consumption (in humans about 2 and 20%, respectively). Yet, the partial pressure and concentration of oxygen in the brain are low and non-uniform. There is a large number of enzymes that use O(2) as a substrate, the most important of which is cytochrome c oxidase, the key to mitochondrial ATP production. The affinity of cytochrome c oxidase for oxygen is very high, which under normal conditions ensures undiminished activity of oxidative phosphorylation down to very low P(O(2)). By contrast, many other relevant enzymes have K(m) values for oxygen within, or above, the ambient cerebral gas tension, thus making their operations very dependent on oxygen level in the physiological range. Among its multiple, versatile functions, oxygen partial pressure and concentration control production of reactive oxygen species, expression of genes and functions of ion channels. Limitation of oxygen supply to the brain below a 'critical' level reduces, and eventually blocks oxidative phosphorylation, drastically decreases cellular (ATP) and leads to a collapse of ion gradients. Neuronal activity ceases and if oxygen is not re-introduced quickly, cells die. The object of this review is to discuss briefly the central oxygen-dependent processes in mammalian brain and the short-term consequences of O(2) deprivation, but not the mechanisms of long-term adaptation to chronic hypoxia. Particular emphasis is placed on issues which have been the focus of recent attention and/or controversy.

Selective head cooling has been proposed as a neuroprotective intervention after hypoxia-ischemia in which the brain is cooled without subjecting the rest of the body to significant hypothermia, thus minimizing adverse systemic effects. There are little data showing it is possible to cool the brain more than the body. We have therefore applied selective head cooling to our hypoxia-ischemia piglet model to establish whether it is possible. Nine piglets were anesthetized, and brain temperature was measured at the surface and in the superficial (0.2 cm) and deep (1.7-2.0 cm) gray matter. Rectal (6-cm depth), skin, and scalp temperatures (T) were recorded continuously. Lowering T-rectal from normothermia (39 degrees C) to hypothermia (33.5-33.8 degrees C) using a head cap perfused with cold (6-24 degrees C) water was undertaken for up to 6 h. To assess the impact of the 45-min hypoxia-ischemia insult on the effectiveness of selective head cooling, four piglets were cooled both before and after the insult, and four, only afterward. During selective head cooling, it was possible to achieve a lower T-deep brain than T-rectal in all animals both before and after hypoxia. However, this was only possible when overhead body heating was used. The T-rectal to T-deep brain gradient was significantly smaller after the insult (median, 5.3 degrees C; range, 4.2-8.5 degrees C versus 3.0 degrees C; 1.7-7.4 degrees C; p = 0.008). During rewarming to normothermia, the gradient was maintained at 4.5 degrees C. We report for the first time a study, which by direct measurement of deep intracerebral temperatures, validates the cooling cap as an effective method of selective brain cooling in a newborn animal hypoxia-ischemia model.

In a cell culture model of murine osteoblasts three particulate bioactive glasses were evaluated and compared to glass (either borosilicate or soda-lime-silica) particles with respect to their effect on metabolic activity, cell viability, changes in intracellular ion concentrations, proliferation and differentiation. 45S5 Bioglass caused extra- and intracellular alkalinization, a rise in [Ca2+]i and [K+]i, a small plasma membrane hyperpolarization, and an increase in lactate production. Glycolytic activity was also stimulated when cells were not in direct contact with 45S5 Bioglass particles but communicated with them only through the medium. Similarly, raising the pH of culture medium enhanced lactate synthesis. 45S5 Bioglass had no effect on osteoblast viability and, under most conditions, did not affect either proliferation or differentiation. Bioactive glasses 58S and 77S altered neither the ion levels nor enhanced metabolic activity. It is concluded that: (1) some bioactive glasses exhibit well-defined effects in osteoblasts in culture which are accessible to experimentation; (2) 45S5 Bioglass causes marked external and internal alkalinization which is, most likely, responsible for enhanced glycolysis and, hence, cellular ATP production; (3) changes in [H+] could contribute to alternations in concentrations of other intracellular ions; and (4) the rise in [Ca2+]i may influence activities of a number of intracellular enzymes and pathways. It is postulated that the beneficial effect of 45S5 on in vivo bone growth and repair may be due to some extent to alkalinization, which in turn increases collagen synthesis and crosslinking, and hydroxyapatite formation.

Several inhibitors of mitochondrial complex II cause neuronal death in vivo and in vitro. The goal of the present work was to characterize in vitro the effects of malonate (a competitive blocker of the complex) which induces neuronal death in a pattern similar to that seen in striatum in Huntington's disease. Exposure of striatal and cortical cultures from embryonic rat brain for 24 h to methylmalonate, a compound which produces malonate intracellularly, led to a dose-dependent cell death. Methylmalonate (10 mM) caused >90% mortality of neurons although cortical cells were unexpectedly more vulnerable. Cell death was attenuated in a medium containing antioxidants. Further characterization revealed that DNA laddering could be detected after 3 h of treatment. Morphological observations (videomicroscopy and Hoechst staining) showed that both necrotic and apoptotic cell death occurred in parallel; apoptosis was more prevalent. A decrease in the ATP/ADP ratio was observed after 3 h of treatment with 10 mM methylmalonate. In striatal cultures it occurred concomitantly with a decline in GABA and a rise in aspartate content and the aspartate/glutamate ratio. Changes in ion concentrations were measured in similar cortical cultures from mouse brain. Neuronal [Na+]i increased while [K+]i and membrane potential decreased after 20 min of continuous incubation in 10 mM methylmalonate. These changes progressed with time, and a rise in [Ca2+]i was also observed after 1 h. The results demonstrate that malonate collapses cellular ion gradients, restoration of which imposes an additional load on the already compromised ATP-generation machinery. An early elevation in [Ca2+]i may trigger an increase in activity of proteases, lipases and endonucleases and production of free radicals and DNA damage which, ultimately, leads to cells death. The data also suggest that maturational and/or extrinsic factors are likely to be critical for the increased vulnerability of striatal neurons to mitochondrial inhibition in vivo.

In the lateral hypothalamic area (LHA) of rat brain, approximately 30% of cells showed sensitivity to small changes in local concentrations of glucose. These "glucose-sensitive" neurons demonstrated four types of behavior, three of which probably represent segments of a continuous spectrum of recruitment in response to ever more severe changes in blood sugar. Type I cells showed maximum activity

Changes in neuronal activity and extracellular concentrations of ions were measured in rat striatum for 60-90 min after intrastriatal injection of quinolinic acid, an agonist of the N-methyl-D-aspartate receptor. The excitotoxin induced bursts of synchronous electrical activity which were accompanied by rises in [K+]e (to approximately 6 mM) and decreases in [Ca2+]e (by less than 0.1 mM); [H+]e usually increased (0.1-0.3 pH unit) after a short and small (< 0.1 pH unit) alkaline shift. The magnitude and frequency of these periodic changes decreased with time; after 90 min the amplitudes fell to 10-20% of the early values and the frequency to about one every 8 min as compared to one every 2-3 min immediately after quinolinate injection. By 90 min there was an increase in [K+]e from 3.3 mM to 4.2 mM and a decrease in [Ca2+]e from 1.34 mM to 1.30 mM. It is postulated that activation of the N-methyl-D-aspartate receptor causes disturbances in neuronal activity and ion gradients; restoration of the original ionic balances raises utilization of ATP and places an additional demand on energy-producing pathways. Increased influx of calcium into neurons may lead to an enhanced accumulation and subsequent overload of mitochondria with the cation. This, in turn, could result in dysfunction of the organelles and account for the decrease in respiration and [ATP]/[ADP] that have been observed previously in this model. The results of the present study lead to the conclusion that quinolinic acid produces early changes in activity of striatal neurons and movements of several cations which may contribute to subsequent abnormalities in energy metabolism and ultimately, cell death.

Cultured astrocytes and cell lines derived therefrom maintain a high energy level ([ATP]/[ADP]) through operation of oxidative phosphorylation and glycolysis. The contribution from the latter to total ATP production is 25-32%. A powerful Na+/K+ pump maintains potassium, sodium, and calcium gradients out of equilibrium. [Na+]i is about 20 mM, [K+]i is 130 mM and [Ca2+]i is less than 100 nM. Under non-stimulated conditions, the Na+/K+ ATPase consumes 20% of astrocytic ATP production. Inhibition of the pump by ouabain decreases energy expenditure, raises [creatine phosphate]/[creatine], and leads to a leakage of sodium, potassium, and calcium ions. Decrease in the pump function via a fall in [ATP] also collapses ion gradients; the rate and extent of the fall correlates positively with cellular energy state. Under "normal" conditions (i.e., when ATP production pathways are not inhibited), there appears to be no preferential utilization of energy produced by either glycolysis or oxidative phosphorylation for the support of pump function.

Intracellular concentrations of sodium, potassium and calcium together with membrane potentials were measured in cultured murine cortical neurons and glial cells under conditions which mimicked in vivo hypoxia, ischemia and hypoglycemia. These included; glucose omission with and without added pyruvate, addition of rotenone in the presence and absence of glucose and substitution of 2-deoxyglucose for glucose with and without rotenone. Cellular energy levels ([ATP], [ADP], [phosphocreatine], [creatine]) were measured in suspensions of C6 cells incubated in parallel under identical conditions. [Na+]i and [Ca2+]i rose while [K+]i fell and plasma membrane depolarized when energy production was limited. Intracellular acidification was observed when glycolysis was the sole source for ATP synthesis. There was a positive correlation between the extent of energy depletion in glial cells and the magnitude and velocity of alterations in ion levels. Neither glycolysis alone nor oxidative phosphorylation alone were able to ensure unaltered ion gradients. Since oxidative phosphorylation is much more efficient in generating ATP than glycolysis, this finding suggests a specific requirement of the Na pump for ATP generated by glycolysis. Changes in [Na+]i and [K+]i observed during energy depletion were gradual and progressive whereas those in [Ca2+]i were initially slow and moderate with large elevations occurring only as a late event. Increases in [Na+]i were usually smaller than reductions in [K+]i, particularly in the glia, suggestive of cellular swelling. Glia were less sensitive to identical insults than were neurons under all conditions. Results presented in this study lead to the conclusion that the response to energy deprivation of the two main types of brain cells, neurons and astrocytes, is a complex function of their capacity to produce ATP and the activities of various pathways which are involved in ion homeostasis.

Incubation of rat brain synaptosomes under conditions of either increased energy utilization (addition of Na+ channel opener, veratridine, or ionophores, monensin and nigericin) or inhibition of oxidative phosphorylation (addition of rotenone), or a combination thereof, decreased [ATP], increased [ADP] and stimulated glycolysis. The rates of lactate generation were linear over a 15-min interval in the presence of rotenone alone but decreased in the other two conditions. During the first 5 min, the amount of lactate formed with veratridine, monensin or nigericin was as high or higher than with rotenone, but it was lower in the last 10 min. With a combination of one of the stimulators of ion movements and rotenone the rate of glycolysis was always markedly lower than with each compound added singly. The stimulated rates of lactate formation correlated positively with the synaptosomal content of [ATP]. After 15 min, [ATP] was 0.9-1.0 nmol/mg with rotenone, 0.5-0.9 nmol/mg with veratridine (or ionophores), and <0.3 nmol/mg with a combination of the two. Under the conditions used, calcium did not affect glycolytic activity directly. The Lineweaver-Burk plot of the rate of lactate formation against [ATP] yielded a straight line with a Km for ATP of about 0.1 mM, which is very similar to the Km for this nucleotide of brain hexokinase bound to mitochondria. In C6 cells glycolytic rate measured with a combination of an ionophore and rotenone was higher than with each of these compounds added singly while [ATP] never declined below about 9 nmol/mg prot. It is concluded that in synaptosomes, the high rate of energy utilization required for intense ion movement decreases [ATP] to a level that limits hexokinase activity kinetically. This may contribute to a reduction in the rate of glycolysis and hence energy production in brain hypoxia and ischemia.

Despite the complexity of the mechanisms that control free calcium concentration in neural cells, considerable advances have been made recently in the understanding of the entry and exit pathways of the ion through application of selective channel and receptor blockers. In addition, useful knowledge has been gained of the internal regulation of calcium movements and the factors that lead to mobilization of the ions into, or their sequestration from, the cytosol. It is clear that calcium homeostasis is crucial to cell metabolism and survival, and that relatively small deviations from the norm can have serious or lethal consequences. It appears that many of the experimental tools are now available to assist in the elucidation of the mechanisms controlling intracellular calcium concentration in vitro. Nevertheless, it has to be accepted that however valuable results from model systems may be, the final testing of any hypothesis concerning the importance of calcium homeostasis in the intact brain requires extensive experimental and clinical investigations in vivo. Information obtained in vitro, if convincingly confirmed by in vivo studies, may well be crucial in formulating strategies to combat a wide range of pathologic conditions.

The effect of [H+] on the rate of glycolysis was investigated in glioma C6 and fibroblast BHK-21 cells and in synaptosomes from rat brain. The rates of lactate production at an extracellular pH (pHe) of 6.2, 7.4, and 7.8 were correlated with intracellular [ATP], [ADP], and [P(i)] ([ATP]i, [ADP]i, and [P(i)]i, respectively) and, when relevant, creatine phosphate (PCr) as well as with the levels of several glycolytic intermediates. In C6 cells cytosolic [H+] was measured simultaneously together with [Ca2+], [K+], [Na+], and membrane potentials. In all three systems studied, an increase in [H+]e suppressed whereas a fall enhanced the rate of lactate generation. Changes in pHe produced no simple correlation between the amount of lactate formed and alterations either in the absolute [ATP], [ADP], [P(i)], and [PCr] or their ratios but did correlate with the levels of glycolytic intermediates. Higher [fructose-1,6-bisphosphate] and [glyceraldehyde-3-phosphate] and lower [glucose-6-phosphate] and [fructose-6-phosphate] accompanied faster glycolytic activity. Addition of rotenone markedly enhanced glycolysis at all pHe values studied. The increases were larger at higher [H+] so that the rate of lactate generation was only slightly lower at pH 6.2 than at 7.4 or 7.8. With rotenone present, [ATP] (and where relevant [PCr]) fell and [ADP] and [P(i)] rose under all pHe conditions. Simultaneously [glucose-6-phosphate] and [fructose-6-phosphate] decreased whereas [fructose-1,6-bisphosphate] and [glyceraldehyde-3-phosphate] increased; the levels of the last two were similar at pH 6.2 and 7.4.(ABSTRACT TRUNCATED AT 250 WORDS)