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Evidence on long-term influences of maternal vitamin B12 deficiency or concentrations on infant cognition is limited. We examined associations between maternal plasma vitamin B12 and cognitive development in 24-month-old infants. Maternal plasma vitamin B12 concentrations were measured at 26–28 weeks’ gestation; infant cognitive development was assessed with the Bayley Scales of Infant and Toddler Development-III at 24 months, for 443 mother–infant pairs from the Growing Up in Singapore Towards Healthy Outcomes cohort. Linear regressions adjusted for key confounders examined associations of maternal vitamin B12 with cognitive, receptive and expressive language, fine and gross motor subscales. Co-occurrence of maternal vitamin B12 with folate or vitamin B6 insufficiencies on child’s cognition was explored. Average maternal plasma vitamin B12 concentrations was 220·5 ± 80·5 pmol/l; 15 % and 41 % of mothers were vitamin B12 deficient (<148 pmol/l) and insufficient (148–220·9 pmol/l), respectively. Infants of mothers with vitamin B12 deficiency had 0·42 (95 % CI −0·70, −0·14) sd lower cognitive scores, compared with infants of mothers with sufficient vitamin B12. Co-occurrence of maternal vitamins B12 and B6 insufficiencies was associated with 0·37 (95 % CI −0·69, −0·06) sd lower cognitive scores in infants compared with infants of mothers sufficient in both vitamins. No significant associations were observed with other subscales. Study findings suggest the possible need to ensure adequate vitamin B12 during pregnancy. The impact of co-occurrence of maternal B-vitamins insufficiencies on early cognitive development warrants further investigation.
Background: Topiramate is an antiepileptic frequently used in pediatrics with multiple mechanisms of action. This includes carbonic anhydrase inhibition, which has unclear relevance to its antiepileptic effect. Metabolic acidosis, hypocitraturia and nephrolithiasis are known side-effects of carbonic anhydrase inhibition and can limit therapeutic effect. Alkali therapy may normalize acidosis, increase urinary citrate, and reduce nephrolithiasis risk. We hypothesize that provision of sodium bicarbonate supplementation to patients with topiramate-induced acidosis will mitigate these side-effects without worsening seizure frequency or severity. Methods: Pediatric patients on antiepileptic therapy with topiramate are being recruited from outpatient pediatric neurology clinics at McMaster Children’s Hospital. We aim to recruit 20 patients with metabolic acidosis and 20 control patients. Measures include blood gas, electrolytes, urine electrolytes and citrate. Patients with metabolic acidosis will be given daily sodium bicarbonate for one month, followed by repeat bloodwork. Seizure frequency will be prospectively documented in all participants throughout the three-month period. Results: Recruitment is ongoing, and three patients (1 with acidosis) have been recruited thus far. Results will be analyzed with chi-squared and paired T tests. Conclusions: This pilot study is the first to evaluate the safety and efficacy of sodium bicarbonate supplementation in patients receiving topiramate for seizure control.
Introduction: Current data on utilization of CT imaging point to a trend of increasing overutilization of CT Angiography for the diagnosis of pulmonary embolism (CTPA) over time. Multiple educational and institution-wide interventions addressing this overutilization have been proposed, implemented and evaluated, with mixed results in terms of long-term impact on physician ordering behaviour. The objective of this study is to examine the inter-physician variability in ordering rates and diagnostic yield of CTPA, under a working hypothesis that a small number of physicians are responsible for a disproportionately high number of CTPA ordered in the ED. Methods: Data was collected on all CTPA studies ordered by ED physicians at two very high volume community hospitals and an affiliated urgent care centre during the 2-year period between January 1, 2016 and December 31, 2017. Analysis was limited to those ED physicians who had a total of greater than 500 ED visits over the course of the 2-year period. For each physician, two calculations were made: 1) CT PE ordering rate (total number of CTPA ordered divided by the total number of ED visits), and 2) CTPA diagnostic yield (total number of CTPA positive for PE divided by the total number CTPA ordered). Additional analysis was carried out in order to identify the highest orderers of CTPA and their diagnostic yield. Results: A total of 2,789 CTPA were ordered by 84 physicians for 461,045 total ED visits. Preliminary results show a great deal of variation in ordering rates, ranging from 0.9 to 22.2 CTPA per 1000 ED visit (median = 4.8, IQR = 4.5). Similarly, there was high variation in CT PE yield, ranging from 0% to 50% (median = 9.6%, IQR = 13.1%). Those physicians in the top quartile for ordering rate had a lower mean diagnostic yield, when compared to the lower quartiles (8.9% when compared to 11.5%, 11.9% and 18.2% for the physicians in the third, second, and first quartile respectively). Conclusion: The findings of this study indicate a wide degree of variability in CTPA ordering patterns and diagnostic yield among physicians working within the same clinical environment. There is some suggestion that those physicians who order disproportionately higher numbers of CTPAs have lower diagnostic yields. However, the more interesting lessons from this initial study center on the challenges in creating an audit-and-feedback program targeting CTPA ‘overutilizers’.
Prenatal adversity shapes child neurodevelopment and risk for later mental health problems. The quality of the early care environment can buffer some of the negative effects of prenatal adversity on child development. Retrospective studies, in adult samples, highlight epigenetic modifications as sentinel markers of the quality of the early care environment; however, comparable data from pediatric cohorts are lacking. Participants were drawn from the Maternal Adversity Vulnerability and Neurodevelopment (MAVAN) study, a longitudinal cohort with measures of infant attachment, infant development, and child mental health. Children provided buccal epithelial samples (mean age = 6.99, SD = 1.33 years, n = 226), which were used for analyses of genome-wide DNA methylation and genetic variation. We used a series of linear models to describe the association between infant attachment and (a) measures of child outcome and (b) DNA methylation across the genome. Paired genetic data was used to determine the genetic contribution to DNA methylation at attachment-associated sites. Infant attachment style was associated with infant cognitive development (Mental Development Index) and behavior (Behavior Rating Scale) assessed with the Bayley Scales of Infant Development at 36 months. Infant attachment style moderated the effects of prenatal adversity on Behavior Rating Scale scores at 36 months. Infant attachment was also significantly associated with a principal component that accounted for 11.9% of the variation in genome-wide DNA methylation. These effects were most apparent when comparing children with a secure versus a disorganized attachment style and most pronounced in females. The availability of paired genetic data revealed that DNA methylation at approximately half of all infant attachment-associated sites was best explained by considering both infant attachment and child genetic variation. This study provides further evidence that infant attachment can buffer some of the negative effects of early adversity on measures of infant behavior. We also highlight the interplay between infant attachment and child genotype in shaping variation in DNA methylation. Such findings provide preliminary evidence for a molecular signature of infant attachment and may help inform attachment-focused early intervention programs.
Introduction: Delays in transfer to an in-patient bed of admitted patients boarded in the ED has been identified as one of the chief drivers of ED overcrowding. Our study aims to replicate findings from a previous study in identifying patient characteristics associated with increased boarding time, and the impact of increased boarding time on in-patient length of stay (IPLOS). Methods: We conducted a retrospective single-centre observational study during the period between January 1, 2015 December 31, 2015 at a very high volume community hospital (~ 75,000 ED visits/year). All patients admitted from the ED to Medicine, Pediatrics, Surgery, and Critical Care were identified. The mean time to in-patient bed (TTB), as well as patient-specific and institutional factors that were associated with prolonged boarding times ( 12 hours) were identified. Mean IP LOS was calculated for those with prolonged boarding times and compared to those without prolonged boarding times. Results: There were 8,096 unique admissions during the study period. Patients admitted to the Medicine service exhibited significantly higher boarding times than those admitted to other services, with a mean boarding time of 17.4 hrs, as compared to 4.2 hrs, 5.7 hrs, and 4.0 hrs for those admitted to Surgery, Critical Care and Pediatrics respectively. Within Medicine patients, there was a statistically significant greater odds of prolonged boarding time for patients who were older, had a greater comorbidity burden, and required more specialized in-patient care (i.e. an isolation bed or telemetry bed). Medicine patients with prolonged boarding times also experienced 0.7 days longer IP LOS, even after correcting for age and comorbidity (mean adjusted IP LOS 10.6 days versus 11.3 days). Conclusion: Within our study period, older, sicker patients and those patients requiring more resource-intensive in-patient care have the longest ED boarding times. These prolonged ‘boarding’ times are associated with significantly increased IP LOS.
Cognitive remediation (CR) training has emerged as a promising approach to improving cognitive deficits in schizophrenia and related psychosis. The limited availability of psychological services for psychosis is a major barrier to accessing this intervention however. This study investigated the effectiveness of a low support, remotely accessible, computerised working memory (WM) training programme in patients with psychosis.
Ninety patients were enrolled into a single blind randomised controlled trial of CR. Effectiveness of the intervention was assessed in terms of neuropsychological performance, social and occupational function, and functional MRI 2 weeks post-intervention, with neuropsychological and social function again assessed 3–6 months post-treatment.
Patients who completed the intervention showed significant gains in both neuropsychological function (measured using both untrained WM and episodic task performance, and a measure of performance IQ), and social function at both 2-week follow-up and 3–6-month follow-up timepoints. Furthermore, patients who completed MRI scanning showed improved resting state functional connectivity relative to patients in the placebo condition.
CR training has already been shown to improve cognitive and social function in patient with psychosis. This study demonstrates that, at least for some chronic but stable outpatients, a low support treatment was associated with gains that were comparable with those reported for CR delivered entirely on a 1:1 basis. We conclude that CR has potential to be delivered even in services in which psychological supports for patients with psychosis are limited.
Faster eating rates are associated with increased energy intake, but little is known about the relationship between children’s eating rate, food intake and adiposity. We examined whether children who eat faster consume more energy and whether this is associated with higher weight status and adiposity. We hypothesised that eating rate mediates the relationship between child weight and ad libitum energy intake. Children (n 386) from the Growing Up in Singapore Towards Healthy Outcomes cohort participated in a video-recorded ad libitum lunch at 4·5 years to measure acute energy intake. Videos were coded for three eating-behaviours (bites, chews and swallows) to derive a measure of eating rate (g/min). BMI and anthropometric indices of adiposity were measured. A subset of children underwent MRI scanning (n 153) to measure abdominal subcutaneous and visceral adiposity. Children above/below the median eating rate were categorised as slower and faster eaters, and compared across body composition measures. There was a strong positive relationship between eating rate and energy intake (r 0·61, P<0·001) and a positive linear relationship between eating rate and children’s BMI status. Faster eaters consumed 75 % more energy content than slower eating children (Δ548 kJ (Δ131 kcal); 95 % CI 107·6, 154·4, P<0·001), and had higher whole-body (P<0·05) and subcutaneous abdominal adiposity (Δ118·3 cc; 95 % CI 24·0, 212·7, P=0·014). Mediation analysis showed that eating rate mediates the link between child weight and energy intake during a meal (b 13·59; 95 % CI 7·48, 21·83). Children who ate faster had higher energy intake, and this was associated with increased BMI z-score and adiposity.
Visual hallucinations are a common phenomenon, among the older adult population. They can be functional or organic in aetiology. However, new onset visual hallucinations in this population are strongly suggestive of organic brain disease. Visual impairment, cerebrovascular disease and Parkinson’s disease are three causes of visual hallucinations, considered in this case series. The evidence in the literature, for the treatment of these conditions is scant at best. There is a paucity of randomised controlled trials available concerning possible therapeutic options.
We describe three case reports of visual hallucinations due to diverse underlying aetiologies. We then discuss the aetiologies of visual hallucinations in general and then in these particular cases and finally include results of a literature search examining the available evidence for any therapeutic options proposed.
Our three cases have different, underlying aetiologies. One case is of Charles Bonnet syndrome. The next is of visual hallucinations associated with vascular dementia. The final case is of visual hallucinations associated with Parkinson’s disease. The first two cases are of particular interest due to the efficacy of Amisulpride in both clinical scenarios.
Visual hallucinations are a common phenomenon in the elderly population
They can be due to a myriad of underlying causes. There are a number of neurochemical factors and neuroanatomical structures implicated. The evidence for psychopharmacological interventions is scanty. Randomised controlled trials are lacking in the area. An interesting finding in this case series, was of the clinical utility of Amisulpiride. Given this agent’s unique psychopharmacological profile it is possible that it may be efficacious in other cases of visual hallucinations associated with particular neurochemical factors.
Early life environments interact with genotype to determine stable phenotypic outcomes. Here we examined the influence of a variant in the brain-derived neurotropic factor (BDNF) gene (Val66Met), which underlies synaptic plasticity throughout the central nervous system, on the degree to which antenatal maternal anxiety associated with neonatal DNA methylation. We also examined the association between neonatal DNA methylation and brain substructure volume, as a function of BDNF genotype. Infant, but not maternal, BDNF genotype dramatically influences the association of antenatal anxiety on the epigenome at birth as well as that between the epigenome and neonatal brain structure. There was a greater impact of antenatal maternal anxiety on the DNA methylation of infants with the methionine (Met)/Met compared to both Met/valine (Val) and Val/Val genotypes. There were significantly more cytosine–phosphate–guanine sites where methylation levels covaried with right amygdala volume among Met/Met compared with both Met/Val and Val/Val carriers. In contrast, more cytosine–phosphate–guanine sites covaried with left hippocampus volume in Val/Val infants compared with infants of the Met/Val or Met/Met genotype. Thus, antenatal Maternal Anxiety × BDNF Val66Met Polymorphism interactions at the level of the epigenome are reflected differently in the structure of the amygdala and the hippocampus. These findings suggest that BDNF genotype regulates the sensitivity of the methylome to early environment and that differential susceptibility to specific environmental conditions may be both tissue and function specific.
A study has been carried out to investigate whether the action of triclabendazole (TCBZ) against Fasciola hepatica is altered by inhibition of P-glycoprotein (Pgp)-linked drug efflux pumps. The Sligo TCBZ-resistant fluke isolate was used for these experiments and the Pgp inhibitor selected was R(+)-verapamil [R(+)-VPL]. In the first experiment, flukes were initially incubated for 2 h in R(+)-VPL (100 μm), then incubated in R(+)-VPL+triclabendazole sulphoxide (TCBZ.SO) (50 μg mL−1, or 133·1 μm) until flukes ceased movement (at 9 h post-treatment). In a second experiment, flukes were incubated in TCBZ.SO alone and removed from the incubation medium following cessation of motility (after 15 h). In the third experiment, flukes were incubated for 24 h in R(+)-VPL on its own. Changes to the testis tubules and vitelline follicles following drug treatment and following Pgp inhibition were assessed by means of light microscope histology and transmission electron microscopy. Incubation of the Sligo isolate in either R(+)-VPL or TCBZ.SO on their own had a limited impact on the morphology of the two tissues. Greater disruption was observed when the drugs were combined, in terms of the block in development of the spermatogenic and vitelline cells and the apoptotic breakdown of the remaining cells. Sperm formation was severely affected and abnormal. Large spaces appeared in the vitelline follicles and synthesis of shell protein was disrupted. The results of this study support the concept of altered drug efflux in TCBZ-resistant flukes and indicate that drug transporters may play a role in the development of drug resistance.
A study was carried out to investigate whether the action of triclabendazole sulphoxide (TCBZ.SO) against the liver fluke, Fasciola hepatica is altered by inhibition of P-glycoprotein (Pgp)-linked drug efflux pumps. The Oberon TCBZ-resistant and Cullompton TCBZ-susceptible fluke isolates were used for this in vitro study and the Pgp inhibitor selected was R(+)-verapamil [R(+)-VPL]. For experiments with the Oberon isolate, flukes were incubated for 24 h with either R(+)-VPL (1×10−4m) on its own, TCBZ.SO (15 μg mL−1) alone, a combination of R(+)-VPL (1×10−4m) plus TCBZ.SO (15 μg mL−1), TCBZ.SO (50 μg mL−1) on its own, or a combination of TCBZ.SO (50 μg mL−1) plus R(+)-VPL (1×10−4m). They were also incubated in TCBZ.SO (50 μg mL−1) alone or in combination with R(+)-VPL (1×10−4m) until they became inactive; and in TCBZ.SO (50 μg mL−1) alone for a time to match that of the combination inactivity time. Flukes from the Cullompton isolate were treated with either TCBZ.SO (50 μg mL−1) alone or in combination with R(+)-VPL (1×10−4m) until they became inactive, or with TCBZ.SO (50 μg mL−1) alone time-matched to the combination inactivity time. Morphological changes resulting from drug treatment and following Pgp inhibition were assessed by means of scanning electron microscopy. Incubation in R(+)-VPL alone had a minimal effect on either isolate. TCBZ.SO treatment had a relatively greater impact on the TCBZ-susceptible Cullompton isolate. When R(+)-VPL was combined with TCBZ.SO in the incubation medium, however, the surface disruption to both isolates was more severe than that seen after TCBZ.SO treatment alone; also, the time taken to reach inactivity was shorter. More significantly, though, the potentiation of drug activity was greater in the Oberon isolate; also, it was more distinct at the higher concentration of TCBZ.SO. So, the Oberon isolate appears to be particularly sensitive to efflux pump inhibition. The results of this study suggest that enhanced drug efflux in the Oberon isolate may be involved in the mechanism of resistance to TCBZ.
Quercetin, a flavonol in fruits and vegetables, has been demonstrated to have antioxidant, anti-inflammatory and immunomodulating influences. The purpose of the present study was to determine if quercetin, vitamin C and niacin supplements (Q-500 = 500 mg/d of quercetin, 125 mg/d of vitamin C and 5 mg/d of niacin; Q-1000 = 1000 mg/d of quercetin, 250 mg/d of vitamin C and 10 mg/d of niacin) would alter small-molecule metabolite profiles and serum quercetin conjugate levels in adults. Healthy adults (fifty-eight women and forty-two men; aged 40–83 years) were assigned using a randomised double-blinded placebo-controlled trial to one of three supplement groups (Q-1000, Q-500 or placebo). Overnight fasted blood samples were collected at 0, 1 and 3 months. Quercetin conjugate concentrations were measured using ultra-performance liquid chromatography (UPLC)-MS/MS, and metabolite profiles were measured using two MS platforms (UPLC-quadrupole time-of-flight MS (TOFMS) and GC-TOFMS). Statistical procedures included partial least square discriminant analysis (PLS-DA) and linear mixed model analysis with repeated measures. After accounting for age, sex and BMI, quercetin supplementation was associated with significant shifts in 163 metabolites/quercetin conjugates (false discovery rate, P< 0·05). The top five metabolite shifts were an increase in serum guaiacol, 2-oxo-4-methylthiobutanoic acid, allocystathionine and two bile acids. Inflammatory and oxidative stress metabolites were not affected. PLS-DA revealed a clear separation only between the 1000 mg/d and placebo groups (Q2Y= 0·763). The quercetin conjugate, isorhamnetin-3-glucuronide, had the highest concentration at 3 months followed by quercetin-3-glucuronide, quercetin-3-sulphate and quercetin diglucuronide. In human subjects, long-term quercetin supplementation exerts disparate and wide-ranging metabolic effects and changes in quercetin conjugate concentrations. Metabolic shifts were apparent at the 1000 mg/d dose; further research is required to understand the health implications of these shifts.
This meta-analysis compared the efficacy and safety of desvenlafaxine and venlafaxine at the Australian approved doses.
A systematic literature search was conducted to identify all placebo-controlled studies of desvenlafaxine and venlafaxine in the treatment of major depression. The pivotal outcome measure used to assess comparative efficacy was the mean change in Hamilton Rating Scale for Depression-17 score from baseline. Tolerability and safety were compared by an evaluation of reported adverse events. Standard and Bayesian methods were used to conduct the indirect comparisons.
Using a mixed model repeated measures analysis, the pooled weighted mean difference for the mean change in Hamilton Rating Scale for Depression-17 score from baseline was −2.81 (−3.72, −1.91; p < 0.001) for desvenlafaxine and −2.61 (−3.17, −2.05; p < 0.001) for venlafaxine. An indirect Bayesian analysis adjusted for baseline Hamilton Rating Scale for Depression-17 score showed no significant difference between the two treatments (weighted mean difference −0.27; −1.17, 0.65). A standard indirect comparison of any adverse events showed no significant difference between desvenlafaxine and venlafaxine (relative risk 1.01; 0.96, 1.06; p = 0.70 and risk difference −0.01; −0.05, 0.03; p = 0.59). Standard indirect comparisons of both nausea and drop-outs identified potential differences between treatments, with the risk difference analyses suggesting a trend in favor of desvenlafaxine (nausea: relative risk 0.97; 0.77, 1.22; p = 0.80/RD −0.07; −0.12, −0.01; p = 0.02; and drop-outs due to adverse events: RR 0.86; 0.58, 1.29; p = 0.48/RD −0.04; −0.08, 0.00; p = 0.06).
Based on the results of this meta-analysis, desvenlafaxine was shown to be non-inferior to venlafaxine in terms of efficacy, and has an advantage in terms of less nausea.
Uptake of triclabendazole by the liver fluke, Fasciola hepatica has been studied by experiments designed to block either oral uptake of drug, by use of ligatures, or trans-tegumental diffusion, by allowing the drug to bind to an excess of bovine serum albumin (BSA) in the medium. Changes to the tegumental system, musculature and gut were assessed using transmission electron microscopy. Flukes were incubated in vitro for 24 h in TCBZ.SO (15 μg/ml). Disruption to the tegument and muscle was similar in ligatured and non-ligatured flukes, suggesting that closing the oral route did not affect drug uptake. The ultrastructure of the gastrodermal cells remained unchanged. Non-ligatured flukes were also incubated for 24 h in vitro in TCBZ.SO (15 μg/ml) in the presence of red blood cells (RBCs). Oral uptake of blood was demonstrated, but gut ultrastructure remained normal, whereas the tegument was severely disrupted. In separate experiments, ligatured and non-ligatured flukes were incubated in TCBZ.SO (15 μg/ml) in the presence of BSA (30 mg/ml) for 24 h in vitro. There was a marked decrease in the degree of tegumental disruption observed compared with TCBZ.SO action alone; again, the gut remained normal. The findings support previous morphological and pharmacological studies indicating that trans-tegumental uptake of triclabendazole predominates in the liver fluke.
This cross-sectional study at a tertiary-care hospital in Botswana from 2000 to 2007 was performed to determine the epidemiologic characteristics of Staphylococcus aureus bacteremia. We identified a high prevalence (11.2% of bacteremia cases) of methicillin-resistant S. aureus (MRSA) bacteremia. MRSA isolates had higher proportions of resistance to commonly used antimicrobials than did methicillin-susceptible isolates, emphasizing the need to revise empiric prescribing practices in Botswana.
Studies have been carried out to establish the relative importance of oral and trans-tegumental uptake of triclabendazole by the liver fluke, Fasciola hepatica. Experiments were designed to block either oral uptake of drug, by use of ligatures, or trans-tegumental diffusion, by allowing the drug to bind to bovine serum albumin (BSA) in the medium. Changes to the surface morphology of the tegument and gut were assessed by scanning electron microscopy. Flukes were incubated in vitro for 24 h in TCBZ.SO at a concentration of 15 μg/ml. Tegumental disruption in ligatured and non-ligatured flukes was similar, suggesting that closing the oral route did not affect drug uptake. The gut remained unaffected by drug treatment. When BSA (30 mg/ml) was present in the medium, there was a marked decline in the level of tegumental disruption. Again, the gut retained a normal morphology. Non-ligatured flukes were also incubated for 24 h in vitro in TCBZ.SO (15 μg/ml) in the presence of red blood cells. Oral ingestion of blood was demonstrated, although the gut surface retained a normal morphology. In contrast, the tegumental surface was severely affected by the drug. The findings support previous pharmacological studies which suggest that trans-tegumental uptake of triclabendazole predominates in the liver fluke.
The Irish milk payment system penalises against high milk somatic cell count (SCC). Previous studies have related farm management practices to herd SCC (Barkema et al., 1998); however similar study has never been undertaken in Ireland. Furthermore, these previous studies have generally been conducted in confined systems. The objective of this study was to investigate potential management factors affecting herd SCC in Irish, spring calving, grass based dairy herds.
High rates of osteoporosis in schizophrenia may result from the prolactin-raising effects of some antipsychotic medication.
To examine bone mineral density in relation to relevant endocrine variables in patients with schizophrenia taking prolactin-raising antipsychotics.
Fifty-five patients who had been receiving prolactin-raising antipsychotic medication for > 10 years underwent dual-energy X-ray absorptiometry of their lumbar and hip bones. Among the endocrine variables assessed were plasma prolactin and sex hormones.
Age-related reduced bone mineral density measures were found in 17 (57%) of the male and 8 (32%) of the female patients. Higher doses of medication were associated with increased rates of both hyperprolactinaemia and bone mineral density loss. Bone loss for the whole group was correlated with medication dose, and for men was inversely correlated with testosterone values.
These results suggestthat patients with schizophrenia on long-term prolactin-raising antipsychotic medication are at high risk of developing reduced bone mineral density as a consequence of hyperprolactinaemia-induced hypogonadism.
Milk contains the alkaline proteinase plasmin and lysosomal proteinases; the significance of the latter is ill-defined. The objective of this study was to investigate composition and activities of several different proteolytic enzymes in milk samples of varying somatic cell count (SCC). Increasing milk SCC was correlated with increased plasmin, cathepsin D and cysteine protease activities, with concomitant increases in proteolysis in milk. Addition of plasmin inhibitors confirmed the heterogeneity of proteinase activities in milk, as urea-PAGE analysis of milk samples showed casein hydrolysis in milk after 7 d storage even in samples with inhibitors added; extent and heterogeneity of proteolysis was correlated with milk SCC. Rennet coagulation properties were not significantly correlated with SCC, or activities of measured enzymes. Milk of increasing SCC also exhibited decreased physical stability during incubation of milk at 37 °C. Pasteurized milk was more stable than raw milk, suggesting that the enzyme(s) or mechanisms leading to such instability are impaired by pasteurization. Overall, milk has a very heterogeneous proteolytic enzyme population, with a higher significance of non-plasmin enzymes, such as cathepsin D and cysteine proteinases, than perhaps previously recognised.