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Objective: High fibrinogen levels are associated with an increased risk of ischaemic stroke (IS). We used mendelian randomisation (MR) to explore a potential causal relationship., Materials and Methods: Data for assessing the relationship between gene variant, disease and biological levels needed for a MR approach was collected using a meta-analytical approach. Inverse-variance weighted (IVW) approach was used for the main analyses and alternative approach for sensitivity analyses. The relationship between fibrinogen levels and IS was assessed using Odds Ratio (OR), while mean difference (g/L) was used for the relationship between SNP (rs1800790) and fibrinogen levels., Results: The variant FGB rs1800790 SNP was interrogated as an instrumental variable of fibrinogen levels. A meta-analysis with 24 studies (12 case-control and 12 cohort studies, totalling 20,902 cases and 76,510 controls was conducted. Homozygotes (AG) of rs1800790 have 0.14g/L (95%CI: 0.08-0.19, P<0.001) and minor allele (AA) have 0.18g/L (95%CI: 0.01-0.35, P=0.037) higher levels of plasma fibrinogen concentration compared with homozygous for the major allele (GG). The risk of IS was significantly increased in 1-g/L (OR=1.83, 95%CI: 0.92-3.62, P=0.084), or 1-SD of fibrinogen levels (OR=1.39, 95%CI: 1.03-1.87, P=0.030), or above median levels (OR=1.22, 95%CI: 1.02-1.46, P=0.029) or categorical levels tertiles (OR=1.50, 95%CI: 1.26-1.79, P<0.001). Each 1-g/L increase in fibrinogen levels was causally associated with a higher risk of ischemic stroke (OR=2.28, 95%CI: 1.53-3.03, P<0.001) in the Mendelian randomisation analysis., Conclusions: Elevated fibrinogen levels are a causative risk factor for ischaemic stroke with each 1g/L increase doubling its risk., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (Copyright © 2024. Published by Elsevier Inc.)

Neurovascular coupling (NVC) is the perturbation of cerebral blood flow (CBF) to meet varying metabolic demands induced by various levels of neural activity. NVC may be assessed by Transcranial Doppler ultrasonography (TCD), using task activation protocols, but with significant methodological heterogeneity between studies, hindering cross-study comparisons. Therefore, this review aimed to summarise and compare available methods for TCD-based healthy NVC assessments. Medline (Ovid), Scopus, Web of Science, EMBASE (Ovid) and CINAHL were searched using a predefined search strategy (PROSPERO: CRD42019153228), generating 6006 articles. Included studies contained TCD-based assessments of NVC in healthy adults. Study quality was assessed using a checklist, and findings were synthesised narratively. 76 studies (2697 participants) met the review criteria. There was significant heterogeneity in the participant position used (e.g., seated vs supine), in TCD equipment, and vessel insonated (e.g. middle, posterior, and anterior cerebral arteries). Larger, more significant, TCD-based NVC responses typically included a seated position, baseline durations >one-minute, extraneous light control, and implementation of previously validated protocols. In addition, complementary, combined position, vessel insonated and stimulation type protocols were associated with more significant NVC results. Recommendations are detailed here, but further investigation is required in patient populations, for further optimisation of TCD-based NVC assessments., Competing Interests: Data availabilityThis was a systematic review of existing research studies and no primary research was conducted. Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Diabetes in pregnancy is associated with short and long-term adverse health outcomes for mothers and babies. The condition disproportionately impacts Pacific, Maaori, and Indian pregnancies. Those with diabetes are offered intensive support during pregnancy, but in many centres, no additional support following birth beyond routine care. The aim of this study was to determine the postpartum needs for mothers and whaanau (family) impacted by diabetes in pregnancy, to inform co-design of a new service to improve metabolic and developmental outcomes for infants., Methods: Pregnancies complicated by diabetes were identified using a local diabetes registry. Mothers with a diagnosis of GDM or T2DM and gave birth between January 2022 -June 2022 were eligible for the study. A total of 19 parents (18 mothers, 1 father) were interviewed. Participants primarily identified as Maaori (6), Pacific (6), Indian (3), Asian (2), and New Zealand European (2). Interviews took place between December 2022 and February 2023, between 5-13 months post-pregnancy. Interviews facilitated by an externally contracted local Pacific mother, with a professional background in social work were conducted using Koorero and Talanoa, Maaori and Pacific methods of qualitative data collection, to capture the lived experiences of participants. A multidisciplinary group reviewed and coded interview transcripts. Themes were presented back to participants and stakeholders for feedback and refinement. Four over-arching themes were illustrated with exemplar quotes., Results: Four themes described the importance of 1) Finding a balance between what is "best practice" and what is best for me, my baby and my whaanau, 2) The need for individualised and culturally appropriate care, 3) Centrality of whaanau and family to the pregnancy and postpartum journey, 4) The pervasive negative impact of diabetes on taha hinegaro (well-being) beyond childbirth., Conclusion: People who are affected by diabetes in pregnancy have ongoing physical, psychological, and social needs. A holistic, whaanau-centred approach is required to ensure optimal health and well-being outcomes of mothers, infants and whaanau. The findings of this study will inform a new targeted model of care for infants and whaanau affected by diabetes in pregnancy., (© 2024. The Author(s).)

Background: The relationship between dynamic cerebral autoregulation (dCA) and functional outcome after acute ischemic stroke (AIS) is unclear. Previous studies are limited by small sample sizes and heterogeneity., Methods: We performed a 1-stage individual patient data meta-analysis to investigate associations between dCA and functional outcome after AIS. Participating centers were identified through a systematic search of the literature and direct invitation. We included centers with dCA data within 1 year of AIS in adults aged over 18 years, excluding intracerebral or subarachnoid hemorrhage. Data were obtained on phase, gain, coherence, and autoregulation index derived from transfer function analysis at low-frequency and very low-frequency bands. Cerebral blood velocity, arterial pressure, end-tidal carbon dioxide, heart rate, stroke severity and sub-type, and comorbidities were collected where available. Data were grouped into 4 time points after AIS: <24 hours, 24 to 72 hours, 4 to 7 days, and >3 months. The modified Rankin Scale assessed functional outcome at 3 months. Modified Rankin Scale was analyzed as both dichotomized (0 to 2 versus 3 to 6) and ordinal (modified Rankin Scale scores, 0-6) outcomes. Univariable and multivariable analyses were conducted to identify significant relationships between dCA parameters, comorbidities, and outcomes, for each time point using generalized linear (dichotomized outcome), or cumulative link (ordinal outcome) mixed models. The participating center was modeled as a random intercept to generate odds ratios with 95% CIs., Results: The sample included 384 individuals (35% women) from 7 centers, aged 66.3±13.7 years, with predominantly nonlacunar stroke (n=348, 69%). In the affected hemisphere, higher phase at very low-frequency predicted better outcome (dichotomized modified Rankin Scale) at <24 (crude odds ratios, 2.17 [95% CI, 1.47-3.19]; P <0.001) hours, 24-72 (crude odds ratios, 1.95 [95% CI, 1.21-3.13]; P =0.006) hours, and phase at low-frequency predicted outcome at 3 (crude odds ratios, 3.03 [95% CI, 1.10-8.33]; P =0.032) months. These results remained after covariate adjustment., Conclusions: Greater transfer function analysis-derived phase was associated with improved functional outcome at 3 months after AIS. dCA parameters in the early phase of AIS may help to predict functional outcome., Competing Interests: Disclosures None.

Background and Objectives : Menstrual cycle tracking is essential for reproductive health and overall well-being. However, there is still an over-reliance on estimations that standard cycles are 28 days long, divided evenly between the follicular and luteal phases. Due to the variability of cycle length and cycle phase lengths, common methods of identifying where an individual is in their cycle are often inaccurate. This study used daily hormone monitoring obtained through a remote hormone-monitoring platform to evaluate hormone levels across a menstrual cycle to identify nuances in the follicular and luteal phases in individuals of different age groups. Materials and Methods : This study used a remote fertility testing system that quantitatively tracks luteinizing hormone (LH) and pregnanediol-3-glucuronide (PdG) through urine tests read by an AI-powered smartphone app. The study analyzed cycle data from 1233 users with a total of 4123 evaluated cycles. Daily levels for LH and PdG were monitored across multiple cycles. Results : This study determined that calculated cycle lengths tended to be shorter than user-reported cycle lengths. Significant differences were observed in cycle phase lengths between age groups, indicating that follicular phase length declines with age while luteal phase length increases. Finally, the study found that if an individual's age, first cycle day, and current hormone levels are known, population-level hormone data can be used to pinpoint which cycle phase and cycle day they are in with 95% confidence. Conclusions : At-home hormone monitoring technologies can allow patients and clinicians to track their cycles with greater precision than when relying on textbook estimations. The study's findings have implications for fertility planning, clinical management, and general health monitoring. Prior to this study, no standard existed for pinpointing where a person was in their cycle through only one measure of LH and PdG. These findings have the potential to fill significant gaps within reproductive healthcare and beyond.

Background: Processes that activate the immune system during lung transplantation can lead to primary graft dysfunction (PGD) or allograft rejection., Methods: We analyzed cytokine expression profiles after reperfusion and allograft outcomes in a cohort of patients (n = 59) who underwent lung transplantation off-pump (n = 26), with cardiopulmonary bypass (CPB; n = 18), or with extracorporeal membrane oxygenation (ECMO; n = 15). Peripheral blood was collected from patients at baseline and at 6 and 72 h after reperfusion. To adjust for clinical differences between groups, we utilized a linear mixed model with overlap weighting., Results: PGD3 was present at 48 or 72 h after reperfusion in 7.7% (2/26) of off-pump cases, 20.0% (3/15) of ECMO cases, and 38.9% (7/18) of CPB cases (p = 0.04). The ECMO and CPB groups had greater reperfusion-induced increases in MIP-1B, IL-6, IL-8, IL-9, IL1-ra, TNF-alpha, RANTES, eotaxin, IP-10, and MCP-1 levels than the off-pump group. Cytokine expression profiles after reperfusion were not significantly different between ECMO and CPB groups., Conclusion: Our data suggest that, compared with an off-pump approach, the intraoperative use of ECMO or CPB during lung transplantation is associated with greater reperfusion-induced cytokine release and graft injury., (© 2022 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Antibiotic resistance is a growing threat to public health, making the development of antibiotics of critical importance. One promising class of potential new antibiotics are ribosomally synthesized and post-translationally modified peptides (RiPPs), which include klebsidin, a lasso peptide from Klebsiella pneumoniae that inhibits certain bacterial RNA polymerases. We develop a high-throughput assay based on growth inhibition of Escherichia coli to analyze the mutational tolerance of klebsidin. We transform a library of klebsidin variants into E. coli and use next-generation DNA sequencing to count the frequency of each variant before and after its expression, thereby generating functional scores for 320 of 361 single amino acid changes. We identify multiple positions in the macrocyclic ring and the C-terminal tail region of klebsidin that are intolerant to mutation, as well as positions in the loop region that are highly tolerant to mutation. Characterization of selected peptide variants scored as active reveals that each adopts a threaded lasso conformation; active loop variants applied extracellularly as peptides slow the growth of E. coli and K. pneumoniae . We generate an E. coli strain with a mutation in RNA polymerase that confers resistance to klebsidin and similarly carry out a selection with the klebsidin library. We identify a single variant, klebsidin F9Y, that maintains activity against the resistant E. coli when expressed intracellularly. This finding supports the utility of this method and suggests that comprehensive mutational analysis of lasso peptides can identify unique and potentially improved variants.

Aim: We systematically reviewed the literature to identify the benefits of early skin-to-skin contact (SSC) for all gestational ages., Methods: The MEDLINE, Embase and CINAHL databases were searched for papers published in English from 1 January 1975 to 31 March 2020. Early SSC was defined as when the infant was placed directly onto the mother's chest within 180 min of birth. Two authors independently searched the databases, appraised study quality and extracted the study design and outcome data. The primary outcomes were the infants' physiological stability after birth: thermoregulation and stabilisation. The secondary outcomes were exclusive breastfeeding and mother-infant interaction., Results: We reviewed 30 studies that assessed the benefits of early SSC: 22 comprised term-born healthy infants and eight focused on preterm or ill infants. These included various gestational ages, birth methods and cultural backgrounds. The studies demonstrated that early SSC stabilised neonatal physiological parameters, promoted exclusive breastfeeding and supported bonding. Most of the data were from term and late preterm births., Conclusion: This systematic review showed that early SSC could be beneficial. Further studies that focus on providing very and extremely preterm infants with SSC, and parental experiences, are needed to enable SSC to be adopted as routine practice., (©2021 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Metastasized cancer cells have an increased resistance to therapies leading to a drastic decrease in patient survival rates. However, our understanding of the cause for this enhanced resistance is lacking. In this study, we report that physically tight confinement during cancer cell migration triggers therapeutic resistance and induces cancer stem cell-like behavior including up-regulation in efflux proteins and in cancer stem cell related markers. Moreover, the re-localization of Yes-associated protein (YAP) to the cell nucleus indicated an elevated level of cytoskeletal tension. The increased cytoskeletal tension suggested that mechanical interactions between cancer cells and tight surroundings during metastasis is one of the factors that contributes to therapeutic resistance and acquisition of cancer stem cell (CSC) like features. With this system and supporting data, we are able to study cells with therapeutic resistance and CSC-like properties for the future purpose of developing new strategies for the treatment of metastatic cancer., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aim: The aim of this study was to assess adherence to the 2014 Ministry of Health (MoH) screening guidelines for diabetes in pregnancy (DiP) by Māori and non-Māori in the Waikato region., Methods: Clinical records were reviewed for women without known diabetes before pregnancy who delivered in hospitals or community birth centres in the Waikato region during June-August 2017. Screening rates for DiP were assessed using HbA1c, glucose challenge and/or glucose tolerance tests., Results: Of a total of 807 women, 94% received some form of screening for DiP; 527 (65.3%) underwent HbA1c screening at <20 weeks and 267 (33.1%) underwent testing for gestational diabetes at 24-28 weeks' gestation. However, only 213 (26.4%) received all screening as per the MoH guideline. HbA1c testing was the most common screening performed (83.9% of all pregnancies), and three quarters of women had a glucose load screen at some point during pregnancy. In all measures, screening rates were lower in Māori, with only 17.5% (46 of 263 women) receiving both HbA1c and further glucose load screening in the recommended gestation windows (versus 31.6% (171 of 541) for non-Māori; P<0.0005)., Conclusions: Adherence to screening guidelines for DiP was poor with a marked ethnic inequity. Further work is needed to investigate the barriers to care that drive these differences., Competing Interests: Nil.

This prospective service evaluation aimed to determine if integrated psychological support for patients with inflammatory bowel disease (IBD) enhanced outcomes. 75 patients were assessed and treated by a specialist liaison psychiatric service between 2015 and 2017; 43 received psychiatric intervention alone, 32 were referred for psychological intervention by clinical health psychologist; 26 completed this. Pre-post data (n=15 available) included global impression, quality of life, and psychiatric and IBD symptom scores. Referrer/patient satisfaction and cost-effectiveness were retrospectively calculated. Psychological intervention led to reductions in IBD symptoms (ΔSIBD; p=0.003), alongside improvements in depression scores (ΔPHQ-9, p=0.006) and global impression (ΔCGI; p=0.046). Patient/referrer satisfaction was very high. Indicative data comparing service utilisation 1 year before and after engagement found reductions in outpatient appointments and in imaging. This small study suggests consideration of increased access to integrated psychological support services to improve outcomes and gather further evidence of efficacy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In the present study we investigate neural network changes after moderate and severe traumatic brain injury (TBI) through the use of resting state functional connectivity (RSFC) methods. Using blood oxygen level dependent functional MRI, we examined RSFC at 3 and 6 months following resolution of posttraumatic amnesia. The goal of this study was to examine how regional off-task connectivity changes during a critical period of recovery from significant neurological disruption. This was achieved by examining regional changes in the intrinsic, or "resting", BOLD fMRI signal in separate networks: 1) regions linked to goal-directed (or external-state) networks and 2) default mode (or internal-state) networks. Findings here demonstrate significantly increased resting connectivity internal-state networks in the TBI sample during the first 6 months following recovery. The most consistent finding was increased connectivity in both internal and external state networks to the insula and medial temporal regions during recovery. These findings were dissociable from repeat measurements in a matched healthy control sample., (Copyright © 2011 Elsevier B.V. All rights reserved.)

We report a case of spontaneous tumour lysis syndrome that developed postoperatively in a patient with undiagnosed Burkitt's lymphoma. The former diagnosis was made, unusually, following the development of white emulsion-like urine in the catheter bag whilst the patient was being managed in the intensive care unit. After laboratory analysis, the urine was found to contain large quantities of uric acid crystals which were the key to the prompt diagnosis. Spontaneous tumour lysis syndrome is rare and this case highlights the difficulties in making an early diagnosis when the presence of a predisposing tumour has not yet been identified. Untreated tumour lysis syndrome can be fatal due to severe biochemical disturbances causing cardiac dysfunction and multi-organ failure. Early recognition and treatment are crucial to prevent morbidity and mortality. The unusual presentation of this case in association with an undiagnosed Burkitt's lymphoma emphasises how vigilant anaesthetists and intensivists must be in recognising this potentially life-threatening condition. We believe that the triggering factor in this case was laparotomy and handling of the tumour., (© 2010 The Authors. Journal compilation © 2010 The Association of Anaesthetists of Great Britain and Ireland.)

Antibody levels to measles were evaluated in 16 HIV-seropositive and 34 seronegative pregnant women and in cord blood samples of their infants. Infants were followed prospectively, and a second blood sample was taken at 3-7 months of age. Antibody levels were significantly lower in HIV-seropositive pregnant women and HIV-exposed cord bloods at birth (p=0.01 and 0.04, respectively) compared to controls. The prevalence of protective immunity (> or =1.09 optical density ratio) was also significantly lower (p=0.02) in HIV-seropositive pregnant women. T-cell counts were lower in HIV-seropositive women who were nonimmune (268/mm3) to measles compared to those who were immune (618/mm3), but the difference did not reach significance (p=0.07). Immunity to measles declined significantly to nonprotective levels in all infant samples obtained at 3-7 months of age. A secondary analysis determined the impact of mother's place of birth. Antibody levels were significantly higher (p=0.03) in foreign-born HIV-seronegative pregnant women and cord blood samples (p=0.01) compared to U.S.-born HIV-seronegative pregnant women seen in our inner-city clinic. Thus, HIV-seropositive and even some seronegative U.S.-born women may need a booster vaccine to ensure passage of adequate levels of passive immunity.

Objectives: We studied trends of hypertensive disorders of pregnancy by residential socioeconomic status (SES) and racial/ethnic subgroups in New York State over a 10-year period., Methods: We merged New York State discharge data for 2.5 million women hospitalized with delivery from 1993 through 2002 with 2000 US Census data., Results: Rates of diagnoses for all hypertensive disorders combined and for preeclampsia individually were highest among Black women across all regions and neighborhood poverty levels. Although hospitalization rates for preeclampsia decreased over time for most groups, differences in rates between White and Black women increased over the 10-year period. The proportion of women living in poor areas remained relatively constant over the same period. Black and Hispanic women were more likely than White women to have a form of diabetes and were at higher risk of preeclampsia; preeclampsia rates were higher in these groups both with and without diabetes than in corresponding groups of White women., Conclusions: An increasing trend of racial/ethnic disparity in maternal hypertension rates occurred in New York State during the past decade. This trend was persistent after stratification according to SES and other risk factors. Additional research is needed to understand the factors contributing to this growing disparity.

Background: In Alabama, low birth weight (LBW) infants are about 20 times more likely to die before their first birthday compared to normal birth weight infants. While the rate of LBW has been consistently higher among African Americans compared to whites, there has been a gradual increase in LBW for both African Americans and whites over the last 15 years. In an attempt to identify modifiable risk factors for LBW, we have previously reported that a pregnant woman's poor periodontal health may be an independent risk factor for low birth weight., Methods: A predominantly African American and socioeconomically homogeneous group of 448 women was followed from the second trimester of their first pregnancy. Thirty-nine LBW cases were observed at the end of follow-up. Using 17 preterm LBW cases and 63 randomly selected controls from the above cohort, the periodontal pathogen-specific maternal serum IgG levels during the second trimester of pregnancy were evaluated in relation to birth weight of the infant, while controlling for known risk factors for LBW., Results: Porphyromonas gingivalis (P.g.)-specific maternal serum IgG levels were higher in the LBW group (mean 58.05, SE = 20.00 microg/ml) compared to the normal birth weight (NBW) group (mean 13.45, SE = 3.92 microg/ml; P= 0.004). Women with higher levels of P.g.-specific IgG had higher odds of giving birth to LBW infants (odds ratio [OR] = 4.1; 95% confidence interval [CI] for odds ratio = 1.3 to 12.8). This association remained significant after controlling for smoking, age, IgG levels against other selected periodontal pathogens, and race., Conclusions: Low birth weight deliveries were associated with a higher maternal serum antibody level against P. gingivalis at mid-trimester.

Background: Resistance to the affordable malaria treatments chloroquine and pyrimethamine-sulfadoxine is seriously impeding malaria control through treatment in east Africa. We did an open, alternate drug allocation study to assess the efficacy of chlorproguanil-dapsone in the treatment of falciparum malaria clinically resistant to pyrimethamine-sulfadoxine., Methods: Children younger than 5 years with non-severe falciparum malaria, attending Muheza district hospital in Tanzania, were treated with the standard regimen of pyrimethamine-sulfadoxine. Patients whose clinical symptoms resolved but who remained parasitaemic 7 days after pyrimethamine-sulfadoxine were followed up for 1 month. Clinical malaria episodes were retreated with either single dose pyrimethamine-sulfadoxine or a 3-day regimen of chlorproguanil-dapsone. Those with parasitaemia after 7 days were treated with chlorproguanil-dapsone. Parasite DNA was collected on day 7 after first treatment with pyrimethamine-sulfadoxine and we looked for point mutations in the genes encoding dihydrofolate reductase (dhfr) and dyhydropteroate synthetase (dhps)., Findings: 360 children were enrolled and treated with pyrimethamine-sulfadoxine. On day 7, 192 (55%) of 348 had cleared parasitaemia. Of the remaining 156 parasitaemic children, 140 (90%) were followed up to day 28, and 92 (66%) of 140 developed clinical malaria. These 92 patients were alternately retreated with either pyrimethamine-sulfadoxine (46) or chlorproguanil-dapsone (46). 28 (61%) of 46 children retreated with pyrimethamine-sulfadoxine were still parasitaemic at day 7, compared with three (7%) of 44 [corrected] children retreated with chlorproguanil-dapsone. Resistance to pyrimethamine-sulfadoxine increased from 45% (156/348) at the first treatment to 61% (28/46) after retreatment. 83 of 85 parasite isolates collected after the first pyrimethamine-sulfadoxine treatment, and before and after the second treatments with pyrimethamine-sulfadoxine and chlorproguanil-dapsone showed triple-mutant dhfr alleles, associated with a variety of dhps mutations., Interpretation: Most patients treated with pyrimethamine-sulfadoxine, who remain parasitaemic at day 7, develop new malaria symptoms within 1 month. Chlorproguanil-dapsone was a practicable therapy under these circumstances. Analysis of parasite dhfr and dhps before and after treatment supports the view that pyrimethamine-sulfadoxine resistance in this part of Africa is primarily due to parasites with three mutations in the dhfr domain.

We describe a child who developed acidosis, hyperkalaemia and cyanosis while emerging from an otherwise uneventful anaesthetic. A diagnosis of tumour lysis syndrome was suspected and confirmed biochemically. Although this syndrome is usually associated with chemotherapy and has been described to occur spontaneously, it has not previously been reported as being associated with anaesthesia.

Object: This study was conducted to determine whether proton magnetic resonance spectroscopy (MRS) is a sensitive method for detecting diffuse axonal injury, which is a primary sequela of traumatic brain injury (TBI). Diffuse axonal injury is characterized by selective damage to white matter tracts that is caused in part by the severe inertial strain created by rotational acceleration and deceleration, which is often associated with motor vehicle accidents. This axonal injury is typically difficult to detect by using conventional imaging techniques because it is microscopic in nature. The splenium was selected because it is a site vulnerable to shearing forces that produce diffuse axonal injury., Methods: The authors used proton MRS to evaluate the splenium, the posterior commissure of the corpus callosum, in normal control volunteers and in patients with TBI. Proton MRS provided an index of neuronal and axonal viability by measuring levels of N-acetyl aspartate (NAA)., Conclusions: A majority of mildly brain injured patients, as well as those more severely injured, showed diminished NAA/creatine (Cr) levels in the splenium compared with normal control volunteers. The patients displaying lowered NAA/Cr in the splenium were also likely to exhibit lowered NAA/Cr in lobar white matter. Also, the levels of NAA/Cr in the splenium of normal volunteers were higher compared with those found in lobar white matter. Decreases in NAA/Cr levels in the splenium may be a marker for diffuse injury. A proton MRS examination may be particularly useful in evaluating mildly injured patients with unexplained neurological and cognitive deficits. It is concluded that MRS is a sensitive tool in detecting axonal injury.

Disorders of visuomotor function are common following traumatic brain injury (TBI), but spatially directed visual attention has received little study in this population. 'Cancellation' testing is a common bedside method for assessing directed attention, which can provide information on how task properties influence visual scanning and search following severe TBI. Groups of 20 individuals after severe TBI and 21 healthy control subjects were matched for age and education. Participants performed finger tapping tests to assess motor speed as well as four cancellation tests employing letter and geometric figure stimuli in random and structured arrays. Control and TBI groups differed significantly on measures of accuracy, task completion time, and search quality. There was no significant effect of stimulus or array type on accuracy or time. Figure targets in a higher search quality, suggesting a right hemispheric dominance effect on these tasks. The findings support a deficit in visuomotor scanning performance in TBI beyond a purely motor effect. Interactions between stimulus and array types suggest that hemispheric cooperation is required for the optimal performance of these tasks, and that interhemispheric communication may be preferentially compromised by TBI.

The object of this study was to investigate stimulus effects and motor limitations on visuospatial performance after traumatic brain injury (TBI). Previous findings have not fully explained the basis of attentional impairments after TBI. There has been little study of the spatial aspects of attention and information processing in this group. We studied 20 patients after severe TBI and 21 healthy controls. Four random-array letter cancellation tasks, varying in number of stimuli (50 and 100) and target-to-distractor ratio (1:4 and 1:9) were employed. Performance was calculated from the number and proportion of cancelled targets, as well as time to completion. TBI subjects were slower on finger tapping and achieved lower cancellation performance scores. Both TBI subjects and controls performed better on tasks with target-to-distractor (T/D) ratios of 1:4 than on those with 1:9. There was no effect of stimulus number. We conclude that there are both quantitative (speed) and qualitative contributors to impaired visuospatial ability following TBI. Motor impairments may slow the overall cancellation performance, but the differential effect of T/D ratio in the two populations suggests that TBI impairs quality of research. Accounting for both speed and accuracy suggests increased utility for the cancellation paradigm in clinical and research assessment of visuospatial attention.

Ivermectin 150mcg/kg was given orally to 743 patients with positive skin snips for Onchocerca volvulus and to 697 residents in two villages in the Usambara mountains. 620 villagers attended for a second dose. On direct questioning, 98.7% patients with +ve skin snips and 91.8% villagers given mass chemotherapy admitted to adverse reactions. After a second dose, 16.6% had mild reactions. No serious problems were encountered. 167 of 170 repeat skin snips were negative. Repeated administration of ivermectin is well tolerated and offers a chance of reducing the burden of onchocerciasis in the Usambara mountains.

Short elective sabbatical visits have been arranged between Herefordshire Health Authority in England and Muheza Health District in Tanzania over the past eight years. Any employee can apply, and the 64 who have participated include midwives, physiotherapists, engineers, and nurse tutors. The possibility of being chosen adds to the attractiveness of working in both districts, and costs have been small. The visits are believed to have led to new ideas and a willingness and confidence to consider change.

Education of medical students is an important component of physical medicine and rehabilitation training programs. A one-day combined lectures/rotating stations conference was designed to introduce physical medicine and rehabilitation to third year medical students during the academic years 1991 through 1993. Pre- and post-testing allowed objective measurement of student knowledge of physical medicine and rehabilitation. The lectures and rotating stations were evaluated, and the feedback was used to improve subsequent conferences. Pre- and post-tests indicated increased student knowledge, and interest in physical medicine and rehabilitation doubled in each class that participated. This instructional method increases third year medical student exposure to physical medicine and rehabilitation in a cost-effective and efficient manner.

Patients with kidney stones (n = 59) and healthy controls (n = 31) collected a 24-hour urine sample and later underwent a 6-hour 'fast and load' test in which an oral calcium load was taken after 2 hours. In the 24-hour urine sample, mean calcium excretion was higher in patients than controls, while mean urate, oxalate and citrate levels were similar. The patients had higher levels of fasting plasma calcium, serum calcitriol and fasting urinary calcium, and lower levels of plasma phosphate than did the controls. Following the calcium load, plasma and urinary calcium increased similarly in both groups. Serum parathyroid hormone (PTH) levels were similar in both groups and decreased similarly following the calcium load. Multiple linear regression, relating the presence or absence of stone formation to all variables, found the only variables significantly related to stone formation to be plasma levels of calcium (p less than 0.001) and phosphate (p = 0.001) and fasting urinary urea (p less than 0.001), and 24-hour urinary calcium excretion (p less than 0.05). Urinary oxalate and citrate were not related to stone formation. The data do not support the hypothesis that primary stimulation by calcitriol produces a normal fasting plasma calcium level, with an exaggerated increase after an oral calcium load. The findings instead suggest an abnormality of parathyroid cell 'set point', such that PTH secretion continues until the plasma calcium level is a little higher and the phosphate a little lower than in controls.

The purpose of this study was to establish the smallest dose of nasally administered salmon calcitonin (SCT) which, if given in conjunction with a previously published calcium/thiazide treatment, would be as effective as parenteral SCT in the treatment of Paget's disease of bone. Forty patients suffering from symptomatic Paget's disease were treated with 0.5 g calcium three times daily, 10 mg/day clopamide, and 400 IU nasally administered salmon calcitonin given once or twice weekly. This regimen was given for 5 months, after which all treatment was ceased for 4 months. Parenteral SCT (100 IU) was then given three times weekly for 5 months to 25 of the patients. With the oral/nasal treatment, the plasma alkaline phosphatase level (AP) decreased by 30 +/- 15 (SD)% when the SCT was given once weekly and by 39 +/- 11% (P less than 0.05) when the SCT was given twice weekly. There were similar decreases in the fasting urinary hydroxyproline:creatinine ratios. The parenteral SCT reduced the AP by 33 +/- 23%. Though reduction in bone pain was similar with both treatments, most patients preferred the oral/nasal treatment. It is concluded that the oral/nasal treatment, when the SCT is given twice weekly, has similar efficacy to parenteral SCT, and is a well tolerated, effective initial treatment for Paget's disease of bone.

We examined femoral head bone from 50 cadavers and from 21 patients who had suffered pathologic fracture of the femoral neck. We used a histochemical technique for lactate dehydrogenase (LDH) activity to demonstrate osteocyte viability. The femoral heads were removed within 36 hours of death or fracture, as LDH activity persists in the cytoplasm of viable cells for this time at 37 degrees after interruption of the blood supply. In the controls, there was an age-related reduction in mean osteocyte viability, from 88 +/- 7% (mean +/- SD) at age 10-29 years to 58 +/- 12% at age 70-89 years. In the hip fracture patients, mean osteocyte viability was 58 +/- 21% but there was much variability in both osteocyte viability and bone mass. In 5 fracture patients, there was extensive osteocyte death, suggesting that most of the femoral head bone was nonviable; these patients had little microfracture callus. Others had predominantly viable bone which was usually osteoporotic, and their bone frequently showed microfracture callus. Osteomalacia was not seen in any patient. It is suggested that bone death, in addition to osteoporosis, may sometimes contribute to hip fracture in the elderly.

We studied 5 patients with immobilisation hypercalcemia. Plasma calcium was 3.28 +/- (SD) 0.26 mmol/l. Plasma parathyroid hormone (PTH) level was elevated in 3 patients and inappropriately detectable in 1. Nephrogenous cAMP, measured in 3 patients, was low-normal in 1 who had a normal PTH and zero in 2 who had elevated PTH. Quantitative bone histology was performed in 3 patients. 1 had evidence of increased resorption (osteoclast count 7.1/mm2 section area, normal 1.0 +/- 0.5) and had a high-normal bone formation rate. Another had a normal osteoclast count but no evidence of bone formation. The third had normal bone histology. We conclude that (a) the PTH appears to be biologically inactive and its elevation may be due, in some patients, to renal retention of carboxyterminal fragments; (b) the histologic pattern in bone is variable and not predictable from the duration of illness; (c) the mechanism by which immobilisation induces these changes is obscure, and (d) careful clinical assessment may be necessary to avoid misdiagnosing the condition as primary hyperparathyroidism.

Height, expressed as standard deviation scores for chronological age and for bone age, was studied in relation to glomerular filtration rate, bone age delay, and bone histology in 47 children with chronic renal disease and GFR less than 80 ml/min/1.73 m2. In multiple regression in all 47 patients, only GFR and bone age delay significantly affected height; 40% of children were short (height standard deviation score less than -2) for chronological age, and 9% were short for bone age. Renal osteodystrophy, which only occurred at GFR less than 30 ml/min/1.73 m2, significantly affected height only in children with congenital renal disease and GFR less than 20 ml/min/1.73 m2. Although radiological and biochemical changes of renal osteodystrophy were seen more often in short children, histological bone disease occurred just as frequently in tall children as in short children. Thus much of the observed height retardation in chronic renal failure is associated with delayed skeletal maturation. In addition, although severe renal osteodystrophy may contribute to growth retardation in advanced renal failure, our data suggest that milder degrees of bone disease evident only on histological study cannot be implicated in the etiology of growth failure in chronic renal impairment.

In some patients with rheumatoid disease gas transfer across the lungs is abnormal. We measured the membrane component of gas transfer (Dm) and pulmonary capillary volume (Vc) in 48 patients with rheumatoid arthritis and in 48 normal volunteers matched for age, sex, and smoking habits. Volunteers had normal chest radiographs and normal forced expiratory volume in one second and vital capacity. There were no significant differences between the rheumatoid and control groups for Dm. Mean Vc in rheumatoid male smokers (64.0 ml, SD 16.5) was significantly lower than in control male smokers (76.3 ml, SD 18.0 p less than 0.05). In rheumatoid female smokers mean Vc (43.4 ml, SD 13.3) was significantly lower than in rheumatoid female non-smokers (58.4 ml, SD 15.4 p less than 0.01). There was no significant difference between rheumatoid and control female non-smokers (mean Vc 58.4 ml and 60.7 ml respectively). Significant differences in Vc in terms of per cent predicted normal were found between patients receiving corticosteroids and those not receiving corticosteroids or penicillamine (p less than 0.02) and between patients with nodules and those without (p less than 0.05). Patients with persistently low transfer factor for five years had a significantly lower Vc (p less than 0.02). There was no consistent correlation between Dm and Vc and dynamic compliance or static recoil pressure. It appears that the abnormality of transfer factor in rheumatoid disease previously demonstrated is caused by reduction of Vc. It seems that involvement of pulmonary blood vessels occurs in patients with nodules and is suppressed by treatment with corticosteroids.

A feasibility demonstration with a gas chromatograph/mass spectrometer/computer system (GC/MS) was initiated to provide a 24-hour (seven days/week) adjunct emergency toxicology service to the hospitals in the tricounty area comprising Metropolitan Detroit. During June 1, 1974, to April 1, 1975, more than 85 different drugs and other agents were identified in the body fluids of approximately 1,000 victims of accidental or deliberate poisonings. At least one toxic substance was identified in 57% of the cases, and the presence of two or more drugs was established in one of five (19%) of the victims. This study indicates that a centrally located GC/MS/computer system can provide an effective adjunct emergency toxicology service for an entire metropolitan community and thereby provide guidelines for a prompt and rational therapy.

Quantitative bone histology was carried out in five osteosclerotic adults. The bone was extremely hard in all patients, and open biopsy was usually required. One patient, aged 18 years, presented with hypoplastic anemia, and the most probable explanation for the osteosclerosis is a marrow stem cell defect leading to defective osteoclasts. Another had the dominant form of osteopetrosis. Her bone contained cartilage remnants, and there were many large, morphologically abnormal osteoclasts, which lacked normal cytoplasmic acid phosphatase activity. The third patient had chronic renal failure and osteomalacia; here the increased bone mass might have resulted from an inability of normal osteoclasts to resorb bone, due to the surface coating of osteoid, though an earlier increase of bone formation cannot be excluded. The fourth patient, who suffered from systemic mastocytosis, had high turnover bone, with greatly increased bone formation. The fifth patient, with fluorosis of bone, also had increased bone formation and resorption, the process being much more pronounced in the head of her pathologically fractured femur than it was in the iliac crest. In this patient some osteoclasts had reduced acid phosphatase activity and long cytoplasmic extensions, both changes similar to those observed in diphosphonate-treated animals. Very diverse processes can result in the increased cancellous bone mass producing the radiographic appearance of diffuse osteosclerosis.

We studied the effect of calcium deprivation and loading in 17 healthy subjects and 76 patients with renal calculi. Five had primary hyperparathyroidism with an elevated plasma ionised calcium and detectable plasma parathyroid hormone. Forty-nine had idiopathic hypercalciuria, defined by a urine calcium greater than 7 mmol/day on a free diet. Twenty-two were normocalciuric. Fasting plasma calcium, corrected for albumin, was higher in the patients with idiopathic hypercalciuria (2.40 +/- 0.10 mmol/l) than in controls (2.28 +/- 0.05 mmol/l, p less than 0.005). Plasma calcium was intermediate in the normocalciuric stone formers (2.35 +/- 0.08 mmol/l) and elevated in the patients with primary hyperparathyroidism (2.62 +/- 0.07 mmol/l). Nephrogenous cyclic adenosine monophosphate (cAMP) and parathyroid hormone levels were highest in the primary hyperparathyroid group and did not differ significantly within the other groups. Nephrogenous cAMP correlated positively with plasma calcium in the patients with primary hyperparathyroidism and negatively in controls; there was no correlation in the idiopathic hypercalciuria group. Following an oral calcium load, plasma calcium rose and nephrogenous cAMP fell similarly in all groups. Fasting urinary calcium and its increase after load were greatest in the idiopathic hypercalciuria and primary hyperparathyroid groups, with intermediate results in the normocalciuric patients. Neither the initial metabolic patterns nor the response to thiazide fitted with the previously described patterns of absorptive and renal hypercalciuria. Increased parathyroid gland activity is the most probable cause of idiopathic hypercalciuria.

We studied the effects of vitamin D metabolites in 29 patients established on chronic hemodialysis. The patients were divided into four groups; one was treated with 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] 0.5 microgram/day, one with 24R,25-dihydroxyvitamin D3 [24,25-(OH)2D3] 10 micrograms/day, and one with both metabolites. The control group was not given vitamin D. Plasma levels of both metabolites were low before treatment. 1,25-(OH)2D3 levels became normal, and 24,25-(OH)2D3 increased to supranormal levels after administration of the corresponding metabolite. Combined treatment produced still higher plasma levels of 24,25-(OH)2D3, suggesting an interaction between the two metabolites. Patients receiving 1,25-(OH)2D3 alone had a greater increase in plasma calcium than those receiving both metabolites. In control patients, hyperparathyroid bone disease worsened over the 10-month observation period. 1,25-(OH)2D3 improved hyperparathyroid bone disease in most patients, as reflected by a reduction in osteoclast and osteoblast numbers, but had no demonstrable effect on mild osteomalacia. 24,25-(OH)2D3 had no significant effect on plasma biochemistry or bone histology, and the effect of combined treatment on histology was similar to that of 1,25-(OH)2D3 alone. Stainable bone aluminum increased slightly in patients given 1,25-(OH)2D3, but aluminum did not affect the response to treatment. We conclude that 1,25-(OH)2D3 is a useful agent in the treatment of renal bone disease, but no therapeutic role is apparent for 24,25-(OH)2D3.

The effects of intraperitoneal aluminum chloride (1.5 mg aluminum/kg/day for 9 weeks) were studied in normal and uremic rats. Parameters measured included tissue aluminum, serum vitamin D metabolites, and quantitative bone histology. Aluminum administration increased tissue concentrations of this metal in uremic and nonuremic animals. Bone aluminum concentrations were higher in uremic rats (121 +/- 27 mg/kg compared to 47 +/- 4), whereas liver values were higher in the nonuremic group (175 +/- 47 mg/kg compared to 100 +/- 36). Serum concentrations of 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D were reduced in uremia, but aluminum was without apparent effect on any vitamin D metabolite. Aluminum, in the doses administered, caused no skeletal changes in nonuremic animals. Some uremic, non-aluminum-treated rats developed osteomalacia and marrow fibrosis. However, osteomalacia was more severe and the osteoclast count was higher in the uremic, aluminum-treated rats. In this group of animals the mineral apposition rate was reduced at the metaphyseal endosteum but increased at the periosteum, indicating different control mechanisms at the two sites.

Weaning, male rats were given ethane-1-hydroxy 1,1-diphosphonate (EHDP) or dichloromethylene diphosphonate (Cl2MDP) 0.5 mgP/kg/day for 140 days. Samples prepared after sacrifice were: (1) thin ground (30 micrometers) transverse tibial sections, (2) methacrylate-embedded 5 micrometers sections of the proximal tibial metaphysis, and (3) ultrathin calcified metaphyseal sections for electron microscopy. Cl2MDP reduced the diaphyseal medullary cavity, and EHDP increased the osteoid width. Both drugs increased endosteal bone apposition (possible secondarily to the impaired resorption) and, perhaps as a result, periosteal apposition was increased. Consequently, diaphyseal bone area was unchanged. Metaphyseal bone area was increased and osteoclast numbers reduced, in contrast to the increased osteoclast numbers reported previously in animal experiments with diphosphonates. Acid phosphatase activity within osteoclasts was markedly reduced with EDHP and unchanged with Cl2MDP. The ultrastructural changes in osteoclasts, i.e., a deficiency of ruffled borders, reduced numbers of cytoplasmic vacuoles and the presence of crystals between bone and the osteoclastic plasmalemma, were more marked with EHDP than Cl2MDP.

We have investigated and treated 176 patients who were suffering from renal calculi. The stones contained calcium in 87% of patients, predominantly urate in 11%, and rarely contained magnesium ammonium phosphate or cystine. Of the patients with calcium stones, hypercalciuria was present in 75% and was identified in 57% by the measurement of the 24-hour urinary calcium excretion, and in a further 18% by a standardization calcium "fast-and-load" test. Nine patients were found to have primary hyperparathyroidism and were treated surgically. A further 21% were suspected to have normocalcaemic hyperparathyroidism, and metabolic studies are being developed to clarify this. The treatment of hypercalciuria included a low-calcium diet, and various combinations of a thiazide diuretic, phosphate supplements and sodium cellulose phosphate. Hypercalciuria was controlled in all compliant patients, and only two developed further stones. Hyperuricosuria was rarely the sole metabolic abnormality in patients with calcium stones, though this might reflect the referral pattern of the Unit. Uric acid stones were frequently, but not invariably, associated with hyperuricosuria and acid urine, and even large uric acid calculi dissolved with a combined therapy of high fluid intake, allopurinol and an alkalinizing agent. Surgical treatment was rarely required in these patients. A stone in the renal pelvis of one patient was removed percutaneously and did not require ultrasonic fragmentation. Modern methods of investigation and treatment have greatly improved the outlook for patients with recurrent renal calculi.

Quantitative bone histology (on undecalcified sections following double tetracycline labeling), radiographs, and biochemistry were studied in 47 children, ages 1 to 17 years, with glomerular filtration rates (GFR) below 80 ml/min/1.73m2. The earliest histologic change was an increased osteoid surface accompanied by increased osteoblast and tetracycline surfaces. However, significant bone disease (increased osteoclastic surface, fibrosis, increased osteoid area, increased mineralization lag time, and reduced tetracycline uptake at osteoid surfaces) occurred only at GFR below 30 ml/min/1.73m2. Radiographs and alkaline phosphatase were normal in 25% of children with significant bone disease; parathyroid hormone was increased in 48% of children without bone disease. Thus, these noninvasive investigations were poor predictors of disease presence. GFR was the most sensitive indicator because bone disease occurred only at GFR below 30 ml/min/1.73m2 and was present in all children with GFR below 20 ml/min/1.73m2. It was concluded that bone histology is required for early detection of bone disease and is an essential tool in experimental studies of renal osteodystrophy. However, because the level of GFR will indicate the presence or absence of bone disease in most children, bone biopsy can be avoided generally in clinical practice.