Dying whilst on probation: a scoping review of mortality amongst those under community justice supervision.

AIM: Data suggest mortality rates of those under community justice services such as probation or parole have been increasing year on year. Little is known about why and how these individuals are dying. This scoping review explores the causes and contributing factors of mortality in those under community justice supervision. METHODS: Studies published between 2011 and 2021 were identified across CINAHL, Embase, Global Health, Ovid Medline and PsycINFO. Articles were included if they presented original data on either mortality rates among those under community justice supervision or risk factors associated with the mortality of those under community justice supervision. RESULTS: Searches identified 101 unique articles of which 13 were included in the review. Articles were representative of five countries. All articles were either retrospective reviews or retrospective cohort studies. The studies fell into the categories of all-cause mortality, self-inflicted deaths or drug-related deaths. CONCLUSION: Mortality rates of those under community justice supervision were found to be consistently higher than mortality rates for the general population regardless of cause of death. Factors identified as affecting mortality included history of drug use, history of self-harm and previous imprisonment including length of time in custody and experience of hospitalisation or solitary confinement while in custody.

Identifying the public health needs of a UK probation cohort: a cross-sectional analysis.

BACKGROUND: The health needs of those under probation are likely high, but they have received very little public health attention. Limited evidence exists on the public health needs and interventions to support this cohort. METHODS: Surveys were completed by 257 people on probation as part of a local health needs assessment. Results were compared with the general population responses from the National Survey for Wales (2021-22). RESULTS: People on probation were 4.2 times more likely to self-report not-good general health (fair, bad or very bad) than the general population (adjusted Odds Ratio [aOR] 4.2, 95% Confidence Intervals [CI] 3.2-5.4). The odds of having a mental health condition were over eight times higher than the general population (aOR 8.8, 95% CI 6.8-11.4). Prevalence of smoking (52%), drug use (60%), attention-deficit hyperactivity disorder (21%), autism (4%) and dyslexia (15%) were all higher than the general population. General Practitioner usage and hospital stays were higher, but dentist or optician usage lower than the general population (P < 0.05). Emergency departments were accessed by 35%, with 9% frequenting them three or more times. CONCLUSIONS: People on probation have poorer self-reported health, higher prevalence of unhealthy behaviours and higher accessing of reactive health services than the general population.

Quantifying cardiovascular disease risk and heart age predictions for men in the prison environment.

OBJECTIVES: Cardiovascular disease (CVD) and associated risk factors within the prison population often present at a younger age in this cohort. Given CVD is largely preventable, it warrants investigation to fully quantify this risk. This study explored the relative predicted 10-year CVD risk and examined the calculated heart age in a representative sample of male individuals aged 25-84 years within the prison environment. STUDY DESIGN: This was a cross-sectional study. METHODS: Data were collected on 299 men who underwent a cardiometabolic risk assessment in HMP Parc, Bridgend. The QRISK2 algorithm was used to calculate 10-year CVD risk, relative risk (to general population) and the predicted heart age of an individual. Between-group differences (prison population vs general community) in cardiovascular risk predictions (10-year CVD risk and heart age) were assessed. RESULTS: We observed that at all age groups, the relative risk of predicted 10-year CVD scores in the prison population was double that of the community risk (2.1 ± 0.6), and this was most apparent in the oldest age group (≥50 years: 17.0% compared to 8.8%; P < 0.001). Overall, the heart age of the sample was 7.5 (6.7-8.2) years higher than their own chronological age, and this difference increased to above 9 years in those aged ≥40 years. CONCLUSIONS: This study provides quantifiable evidence to the elevated CVD risk in prison. Heart age predictions were almost a decade higher in those aged ≥40 years. Lowering the screening age for CVD by around 5 years in the prison population should be considered.

The Five Nations model for prison health surveillance: lessons from practice across the UK and Republic of Ireland.

BACKGROUND: Prison populations experience an increased burden of physical, mental and social health needs compared to the community, further impacted by the prison environment. Surveillance systems to monitor health and well-being trends in prisons are lacking, presenting a challenge to services planners, and policy makers who often lack evidence to inform decisions. METHOD: The Five Nations Health and Justice Collaboration, a body of experts on prison health across the UK and Republic of Ireland (ROI), met to share and discuss challenges and opportunities to developing robust prison health surveillance systems that could inform local provision, guide national policy and enable cross-border comparisons. RESULTS: Challenges to robust prison health surveillance systems were shared across the UK and ROI. Methods of surveillance differed across nations and included performance indicators and outcome measures as part of local or national programs. All nations had strong public health infectious disease notification systems. CONCLUSIONS: The Five Nations Health and Justice Collaboration is proposing a new model for prison health surveillance, based on established guidelines for public health surveillance but with additional features that recognize the uniqueness of the prison environment and need for a whole prison approach, built on collaboration and sharing of data between health and justice sectors.

Pressure denaturation of the yeast prion protein Ure2.

Denaturation of the Saccharomyces cerevisiae prion protein Ure2 was investigated using hydrostatic pressure. Pressures of up to 600 MPa caused only limited perturbation of the structure of the 40-kDa dimeric protein. However, nondenaturing concentrations of GdmCl in combination with high pressure resulted in complete unfolding of Ure2 as judged by intrinsic fluorescence. The free energy of unfolding measured by pressure denaturation or by GdmCl denaturation is the same, indicating that pressure does not induce dimer dissociation or population of intermediates in 2 M GdmCl. Pressure-induced changes in 5 M GdmCl suggest residual structure in the denatured state. Cold denaturation under pressure at 200 MPa showed that unfolding begins below -5 degrees C and Ure2 is more susceptible to cold denaturation at low ionic strength. Results obtained using two related protein constructs, which lack all or part of the N-terminal prion domain, were very similar.

Conformational adjustments of SNase R and its N-terminal fragments probed by monoclonal antibodies.

Two monoclonal antibodies specific for staphylococcal nuclease R (SNase R) (McAb2C9 and McAb1B8) were prepared and used to probe protein folding during peptide elongation, by measuring antibody binding to seven N-terminal fragments (SNR141, SNR135, SNR121, SNR110, SNR102, SNR79 and SNR52) of SNase R. Comparative studies of the conformations of the N-terminal fragments have shown that all seven fragments of SNase R have a certain amount of residual structure, indicating that folding may occur during elongation of the nascent peptide chain. We show that the binding abilities of the intact enzyme and its seven fragments to the monoclonal antibodies are not simply proportional to the length of the peptide chain, suggesting that there may be continuous conformational adjustment in the nascent peptide chain as new C-terminal amino acids are added. A folding intermediate close in structure to the native state but with structural features in common with SNR121 is highly populated in 0.6 M GuHCl, and is also formed transiently during folding.

Relationship between kinetic and equilibrium folding intermediates of creatine kinase.

Creatine kinase (CK) is a dimeric enzyme important in ATP regeneration in cells where energy demands are high. The folding of CK under equilibrium and transient conditions has been studied in detail and is found to be complex. At equilibrium in 0.8 M GuHCl, 90% of CK molecules are in the form of a partially structured, monomeric intermediate. We exploit this property to measure kinetics of refolding and unfolding to and from this equilibrium intermediate (EI), using far-UV circular dichroism and intrinsic fluorescence as structural probes. We are thus able to compare the properties of EI and the kinetic intermediate formed during the burst phase in refolding. Native CK and EI unfold with rate constants in seconds and milliseconds, respectively. As is observed for refolding of fully-denatured CK, refolding from EI to the native state shows a burst phase followed by two exponential phases. The burst phase refolding intermediate is inferred to have more structure and greater stability than the equilibrium intermediate. When refolding from the fully-denatured state in 0.8 M GuHCl, the equilibrium intermediate is formed within the dead-time of mixing in the stopped-flow apparatus. The equilibrium intermediate may thus represent a kinetic intermediate formed early during folding.

Polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease (ADPKD), is a Ca2+-permeable nonselective cation channel.

Defects in polycystin-2, a ubiquitous transmembrane glycoprotein of unknown function, is a major cause of autosomal dominant polycystic kidney disease (ADPKD), whose manifestation entails the development of fluid-filled cysts in target organs. Here, we demonstrate that polycystin-2 is present in term human syncytiotrophoblast, where it behaves as a nonselective cation channel. Lipid bilayer reconstitution of polycystin-2-positive human syncytiotrophoblast apical membranes displayed a nonselective cation channel with multiple subconductance states, and a high perm-selectivity to Ca2+. This channel was inhibited by anti-polycystin-2 antibody, Ca2+, La3+, Gd3+, and the diuretic amiloride. Channel function by polycystin-2 was confirmed by patch-clamping experiments of polycystin-2 heterologously infected Sf9 insect cells. Further, purified insect cell-derived recombinant polycystin-2 and in vitro translated human polycystin-2 had similar ion channel activity. The polycystin-2 channel may be associated with fluid accumulation and/or ion transport regulation in target epithelia, including placenta. Dysregulation of this channel provides a mechanism for the onset and progression of ADPKD.

LTD induction in adult visual cortex: role of stimulus timing and inhibition.

One Hertz stimulation of afferents for 15 min with constant interstimulus intervals (regular stimulation) can induce long-term depression (LTD) of synaptic strength in the neocortex. However, it is unknown whether natural patterns of low-frequency afferent spike activity induce LTD. Although neurons in the neocortex can fire at overall rates as low as 1 Hz, the intervals between spikes are irregular. This irregular spike activity (and thus, presumably, irregular activation of the synapses of that neuron onto postsynaptic targets) can be approximated by stimulation with Poisson-distributed interstimulus intervals (Poisson stimulation). Therefore, if low-frequency presynaptic spike activity in the intact neocortex is sufficient to induce a generalized LTD of synaptic transmission, then Poisson stimulation, which mimics this spike activity, should induce LTD in slices. We tested this hypothesis by comparing changes in the strength of synapses onto layer 2/3 pyramidal cells induced by regular and Poisson stimulation in slices from adult visual cortex. We find that regular stimulation induces LTD of excitatory synaptic transmission as assessed by field potentials and intracellular postsynaptic potentials (PSPs) with inhibition absent. However, Poisson stimulation does not induce a net LTD of excitatory synaptic transmission. When the PSP contained an inhibitory component, neither Poisson nor regular stimulation induced LTD. We propose that the short bursts of synaptic activity that occur during a Poisson train have potentiating effects that offset the induction of LTD that is favored with regular stimulation. Thus, natural (i.e., irregular) low-frequency activity in the adult neocortex in vivo should not consistently induce LTD.

Equilibrium folding properties of the yeast prion protein determinant Ure2.

The yeast non-Mendelian factor [URE3] propagates by a prion-like mechanism, involving aggregation of the chromosomally encoded protein Ure2. The [URE3] phenotype is equivalent to loss of function of Ure2, a protein involved in regulation of nitrogen metabolism. The prion-like behaviour of Ure2 in vivo is dependent on the first 65 amino acid residues of its N-terminal region which contains a highly repetitive sequence rich in asparagine. This region has been termed the prion-determining domain (PrD). Removal of as little as residues 2-20 of the protein is sufficient to prevent occurrence of the [URE3] phenotype. Removal of the PrD does not affect the regulatory activity of Ure2. The C-terminal portion of the protein has homology to glutathione S -transferases, which are dimeric proteins. We have produced the Ure2 protein to high yield in Escherichia coli from a synthetic gene. The recombinant purified protein is shown to be a dimer. The stability, folding and oligomeric state of Ure2 and a series of N-terminally truncated or deleted variants were studied and compared. The stability of Ure2, DeltaGD-N, H2O, determined by chemical denaturation and monitored by fluorescence, is 12.1(+/-0.4) kcal mol-1at 25 degrees C and pH 8.4. A range of structural probes show a single, coincident unfolding transition, which is invariant over a 550-fold change in protein concentration. The stability is the same within error for Ure2 variants lacking all or part of the prion-determining domain. The data indicate that in the folded protein the PrD is in an unstructured conformation and does not form specific intra- or intermolecular interactions at micromolar protein concentrations. This suggests that the C-terminal domain may stabilise the PrD against prion formation by steric means, and implies that the PrD does not induce prion formation by altering the thermodynamic stability of the folded protein.

Temporal discrimination in the cerebellar cortex during conditioned eyelid responses.

Little is known about mechanisms used by the nervous system to encode time. In light of recent evidence, cerebellar cortex involvement in the learned timing of conditioned eyelid responses shows promise as an area of investigation into neural timing mechanisms. Lesion studies indicate that the cerebellar cortex is necessary for response timing, but do not rule out the possibility that response timing is encoded afferent to the cerebellum. To differentiate between precerebellar and cerebellar cortical timing mechanisms, rabbits were trained by pairing direct stimulation of mossy fibers in the cerebellum as the conditioned stimulus (CS) with an eyeshock unconditioned stimulus (US). We find that individual animals can produce differently timed conditioned responses when trained with a mossy fiber CS that has been paired with the US at various interstimulus intervals. The fact that differently timed responses can be conditioned using constant-frequency stimulation of an invariant subset of mossy fibers as the CS suggests that timing information in the afferent input to the cerebellum is not essential. Two rabbits trained with single-pulse stimulation in the cerebellum as the CS also learned differently timed conditioned responses; suggesting that fiber recruitment during a stimulus train does not convey the necessary temporal coding to the cerebellar cortex. Together with the lesion data, these findings suggest that the learned timing of conditioned eyelid responses occurs in the cerebellar cortex.

The contribution of head motion cues to localization of low-pass noise.

Localization of low-pass sounds was tested in relation to aspects of Wallach's (1939, 1940) hypotheses about the role of head movement in front/back and elevation discrimination. With a 3-sec signal, free movement of the head offered only small advantage over a single rotation through 45 degrees for detecting elevation differences. Very slight rotation, as observed using a 0.5-sec signal, seemed sufficient to prevent front/back confusion. Cluster analysis showed that, in detecting elevation, some listeners benefited from rotation, some benefited from natural movement, and some from both. Evidence was found indicating that a moving auditory system generates information for the whereabouts of sounds, even when the movement does not result in the listener facing the source. Results offer significant if partial support for Wallach's hypotheses.

Importance of electrostatic interactions in the rapid binding of polypeptides to GroEL.

The question of how chaperones rapidly bind non-native proteins of very different sequence and function has been examined by determining the effect of ionic strength on the refolding of barnase on GroEL, and on the thermal denaturation of barnase in the presence of GroEL and SecB. Both chaperones bind the denatured state of barnase, so lowering the T(m) value. The refolding of barnase in the presence of GroEL is multiphasic, the slowest phase corresponding to the refolding of a singly bound molecule of barnase in the complex with GroEL. The fastest phase is related to the association of barnase and GroEL. At high ratios of GroEL to barnase and low ionic strength (less than 200 mM) this fast phase corresponds to the observed rate of binding. The rate of association of barnase and GroEL was found to be highly dependent on ionic strength, and at high ionic strength (greater than 600 mM) the majority of barnase molecules escaped binding and refolded free in solution. The data are consistent with an initial, transient, ionic interaction between barnase and GroEL, before hydrophobic binding occurs, allowing diffusion-controlled association and slow dissociation of unfolded polypeptide.

The effect of head rotations on vertical plane sound localization.

Current understanding gives predominant weight to stationary cues for auditory localization. Two experiments were conducted to investigate the possible existence of a dynamic cue. The first experiment involved localization of concealed sources in the upper median vertical plane (MVP) and showed, as expected, that elevation was not detectable with motionless listening when high-frequency energy was absent or when normal pinna function was distorted. Elevation under such conditions did become detectable with horizontal head rotations, provided low-frequency energy was present in the signal. This indicates that the basis of the dynamic cue is variation in the rate of transformation of low-frequency interaural time/phase differences. The second experiment involved localization of sources arrayed throughout upper and lower regions of the MVP and in the left lateral vertical plane (LVP); it showed that upper hemisphere sources can be distinguished somewhat from those in the lower hemisphere, even in motionless listening conditions, but more so with rotation. The greatest benefit for localization from rotation of the head appears to be gained for sources positioned in the front MVP.

Chaperone activity and structure of monomeric polypeptide binding domains of GroEL.

The chaperonin GroEL is a large complex composed of 14 identical 57-kDa subunits that requires ATP and GroES for some of its activities. We find that a monomeric polypeptide corresponding to residues 191 to 345 has the activity of the tetradecamer both in facilitating the refolding of rhodanese and cyclophilin A in the absence of ATP and in catalyzing the unfolding of native barnase. Its crystal structure, solved at 2.5 A resolution, shows a well-ordered domain with the same fold as in intact GroEL. We have thus isolated the active site of the complex allosteric molecular chaperone, which functions as a "minichaperone." This has mechanistic implications: the presence of a central cavity in the GroEL complex is not essential for those representative activities in vitro, and neither are the allosteric properties. The function of the allosteric behavior on the binding of GroES and ATP must be to regulate the affinity of the protein for its various substrates in vivo, where the cavity may also be required for special functions.

Conformational states bound by the molecular chaperones GroEL and secB: a hidden unfolding (annealing) activity.

We have analysed the conformational states of barnase that are bound by the molecular chaperones GroEL and SecB. Line broadening in the NMR spectra of barnase in the presence of chaperone indicates binding of the native state of barnase to both GroEL and SecB, with a dissociation constant of > 3 x 10(-4) M for the GroEL-native barnase complex. GroEL and SecB catalyse the hydrogen-deuterium exchange of amide proteins of barnase that require global unfolding for exchange to occur, indicating that both chaperones bind to a fully unfolded state of barnase. Binding of the denatured state was also detected by a reversible lowering of the melting temperature of barnase in the presence of chaperone. The dissociation constant of the complex between denatured barnase and either chaperone is 5 x 10(-8) M. The chaperone-bound fully unfolded state is a minor conformation that would not be seen by direct observation under physiological conditions, as the folding intermediate of barnase is the most populated state in the complex. The rate-limiting step for exchange of buried amide protons of bound barnase is the unfolding of the folding intermediate, which is retarded > 2000-fold in the complex with GroEL. The reverse refolding step is retarded > 1000-fold by GroEL leading to an EX1 mechanism for exchange. In contrast, unfolding of native barnase is catalysed by > 1000-fold. Thus, molecular chaperones GroEL and SecB have the potential to act in vivo and in vitro as: (1) a folding/transport-scaffold to prevent aggregation of partially folded states by binding; (2) as an annealing-machine to generate continuous unfolding of misfolded states until a low-affinity state is formed; and (3) as an unfoldase to catalyse unfolding of the misfolded states.

Currently available molluscicides.

Views about the importance of the role of molluscicides in the integrated control of human schistosomiasis have passed through cyclical changes over the past 15 years. For a time, it was hoped that chemotherapy alone would achieve significant morbidity control; it has since become clear that molluscicides cannot be easily excluded from the anti-schistosome armoury. In this review, Sheena Perrett and Phil Whitfield summarize the evidence for this conclusion and provide an overview of currently available synthetic molluscicides and those natural product molluscicides currently under active investigation.

Catalysis of amide proton exchange by the molecular chaperones GroEL and SecB.

Hydrogen-deuterium exchange of 39 amide protons of Bacillus amyloliquefaciens ribonuclease (barnase) was analyzed by two-dimensional nuclear magnetic resonance in the presence of micromolar concentrations of the molecular chaperones GroEL and SecB. Both chaperones bound to native barnase under physiological conditions and catalyzed exchange of deeply buried amide protons with solvent. Such exchange required complete unfolding of barnase, which occurred in the complex with the chaperones. Subsequent collapse of unfolded barnase to the exchange-protected folding intermediate was markedly slowed in the presence of GroEL or SecB. Thus, both chaperones have the potential to correct misfolding in proteins by annealing.

Activity of the molluscicidal plant Millettia thonningii (Leguminosae) toward Biomphalaria glabrata eggs.

A dichloromethane extract of the seeds of the molluscicidal west African legume Millettia thonningii was tested for ovicidal activity toward Biomphalaria glabrata egg masses. The extract was found to be highly ovicidal at concentrations as low as 5 mg/L. Embryonic development of the snails in egg masses was monitored using photomicrographs from which embryonic diameters were estimated. Such measurements revealed that ovicidal effects were developmentally stage specific and normally induced a curtailment of development during the gastrula to trochophore transition.