Studies on the interaction between GP-18-0-deficient neutrophils and vascular endothelium

A patient whose neutrophils lack the glycoprotein gp-180 shows an increased susceptibility to bacterial infections. Neutrophils from this patient migrate abnormally both in vivo and in vitro. To examine the basis for this abnormality in migration, a study was carried out on the interaction of gp-180-deficient neutrophils with artificial surfaces and with human endothelial cell cultures. Compared with normal neutrophils. gp-180-deficient neutrophils showed decreased adhesion to cold-insoluble globulin-coated plastic surfaces, and their ability to spread on this substratum was greatly impaired. In contrast, gp-180- deficient neutrophils interacted in a normal fashion with endothelial monolayers, attaching to their surfaces and migrating between cell junctions to spread between the monolayers and the subjacent plastic. A normal interaction with endothelium in vivo was implied by the finding that the rise in the neutrophil count in response to epinephrine, an index of the marginated pool, was normal in the gp-180-deficient patient. We conclude that the abnormal function of gp-180-deficient cells is unlikely to be caused by a faulty interaction with the vascular endothelium. We postulate instead that these cells migrate poorly in vivo because of an abnormal interaction with extravascular connective tissue matrix constituents.     

A combination of the effects of rare genotypes at the XK and KEL blood group loci results in absence of Kell system antigens from the red blood cells

The 22 antigens of the Kell blood group system are located on a red blood cell (RBC) membrane glycoprotein that shows sequence homology with a family of metalloendopeptidases. Expression of the Kell system antigens is partially governed by XK, an X-linked gene that encodes the Kx protein; absence of Kx results in reduced Kell antigen expression. Almost total absence of Kell antigens from the RBCs of a German man with no symptoms of neuroacanthocytosis could not be due to the Kell- null phenotype, Ko, because his RBCs had very weak expression of Kx antigen and his three children were Kp(a + b+). Kell antigens were normal on the RBCs of his son but weak on those of his two daughters. An Nla III restriction fragment-length polymorphism within the KEL gene showed the Kpa/Kpa genotype in the propositus. Sequencing of his XK gene showed a single base change within the donor splice consensus sequence of intron 2. A BsaAl restriction fragment-length polymorphism showed the mutation in both of his daughters but not in his son. The extreme depression of the Kell antigens of the propositus must be due to a combination of effects, ie, homozygosity for Kpa and deficiency of Kx protein, each of which is capable of causing some degree of weakening of Kell antigens.     

Major depressive disorder: reification and (maybe) rheostasis

The heterogeneity of clinical syndromes subsumed by diagnostic criteria for major depressive disorder (MDD) is regarded by some as a reason to abandon or modify the criteria. However, heterogeneity may be unavoidable because of the biopsychosocial complexity of depression. MDD may be characterised by complexities that cannot be distilled down to any brief set of diagnostic criteria. Psychiatrists and psychiatric epidemiologists may need to revise their expectations of this diagnosis in order to avoid over-estimating its ability to guide the selection of treatments and prediction of prognosis. An opposing perspective is that of reification, in which the diagnosis is viewed as being more real than it really is. The concept of rheostasis may help to explain some features of this condition, such as why major depressive episodes sometimes seem understandable or even adaptive (e.g. in the context of bereavement) whereas at other times such episodes are inexplicable and maladaptive.Key words: classification, clinical utility, conceptual validity, depression, diagnosis, major depressive disorder

In this issue of Epidemiology and Psychiatric Sciences, Lorenzo-Luaces (2015) seeks to reconcile divergent opinions about the fundamental nature of major depressive disorder (MDD). The Lorenzo-Luaces review asks a question: is MDD the ‘common cold’ of psychiatry or is it a highly debilitating chronic illness? The author concludes that MDD is a heterogeneous condition that can be both of these things. Several additional arguments are presented in this commentary, with the goal of augmenting this discussion. First, there is a need to differentiate major depressive episodes (MDE) from MDD in any critique of the diagnostic validity of MDD. Second, it is important to challenge the idea that threshold-setting is the logical solution to these problems. Third, while the heterogeneity of MDD is clear, what are the implications of this? Should the category be abandoned or can it be used differently? Finally, the infrequently discussed concept of rheostasis deserves mention as it offers an interesting alternative perspective on these diagnostic problems.In a highly referenced paper, Regier et al. (1998) noted that some people meeting diagnostic criteria for MDE do not display characteristics usually associated with illness (e.g., a clear need for treatment). This does not necessarily mean, however, that such episodes are devoid of clinical significance. In examining longitudinal data from Canada, we found that brief and mild episodes (including subthreshold episodes, those lasting only a few weeks and those not associated with suicidal ideation or marked functional impairment) nevertheless strongly predicted the subsequent course of major depression (Patten et al. 2010b). Since MDD is characterised by episodes that may have various levels of severity and persistence, it would be a mistake to confound the characteristics of specific episodes with the broader question of the conceptual validity of MDD. As a diagnostic category, MDD would seem most useful in situations where it identifies people who, without treatment, will be at risk of experiencing recurrent severe and/or persistent episodes of depression. It does not follow that every episode they experience must be particularly severe or persistent.While it is often asserted that the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) sets its threshold for a diagnosis of MDD too low, the problem of discerning a heterogeneous condition such as MDD from the inevitable diversity of emotional experience is not merely a question of threshold setting (Wakefield, 1992; Zimmerman et al. 2004). This is true irrespective of whether diagnostic thresholds are defined in terms of the number of required symptoms, symptom severity, persistence, impact of the syndrome on functioning and safety, or some combination of these factors. A higher threshold for diagnosis will predictably increase specificity at the expense of sensitivity while setting the bar lower can be expected to increase sensitivity at the cost of decreased specificity. Of course, invoking terminology such as sensitivity and specificity implies a gold standard. While it is true that there is currently no available gold standard instrument, there is nevertheless an unarticulated gold standard: strong predictive validity for prognosis and treatment response. The Lorenzo-Luaces review emphasises that current criteria for MDD fall short of this ideal but the author does not advocate abandonment of diagnostic criteria altogether. Indeed, to do so could reduce reliability, rob psychiatry of an empirical ‘common language’ and might potentially impede the translation of research evidence into clinical practice.The Lorenzo-Luaces review ultimately concludes that more research is needed to refine this diagnosis and to better understand its implications. This is certainly true, but scientific advances of this sort are likely to be incremental and have thus far been slow in coming. Until an enhanced definition surfaces the best interim solution may actually be greater acceptance of the heterogeneity of this condition. This would involve invoking a more flexible range of clinical responses to MDD, acknowledging the limitations of its crude categorisation. As pointed out in the review, this approach demands a better evidence-base than currently exists. A goal of research should be to generate knowledge capable of guiding management, including identification of situations (falling under the broad umbrella of MDD) in which: no intervention is needed; where monitoring (such as ‘watchful waiting’) is helpful; when unobtrusive interventions (education, exercise) are most suitable; and when more formal treatments are needed.The idea that MDD must or should be a real illness (‘truly ill’ to use the words of Lorenzo-Luaces) involves a degree of reification of the syndromal definition of MDD. Many apparently mentally healthy people experience similar syndromes in relation to major losses or threatening life events, bereavement being a classical example (Wakefield et al. 2007). Sensitivity to distress, ability to function in spite of symptoms and vulnerability to suicide are clinically important aspects of the syndrome of depression, but it is unrealistic to expect that a diagnostic definition could subsume all of the implications of such factors. To do so would require excessive definitional complexity; which would likely come at a cost of diminished clinical utility. MDD is inevitably intertwined with the personal and social contexts in which it occurs. The common tendency to reify this diagnosis may explain a tendency to over-estimate the extent to which it can be used as a predictor of prognosis or treatment response. This error, in turn, leads to many of the problems highlighted in the Lorenzo-Luaces review.One of the most troubling findings in psychiatric epidemiology is the tendency for the lifetime prevalence of many of the common mental disorders, MDD included, to decline with age. Lorenzo-Luaces takes this phenomenon as an indication that ‘forgotten’ episodes must have been trivial ones. This is not necessarily correct. The apparent decline in recall of past episodes starts long before ‘old age’ with peak lifetime prevalence occurring in middle age (Patten et al. 2010a). Autobiographical memory is far from perfect. One study reported that only about half of people hospitalised for depression were able to recall their symptoms in a way that could confirm a diagnosis 25 years later (Andrews et al. 1999). These measurement problems do not necessarily mean that past episodes were trivial or unimportant at the time of their occurrence.Lorenzo-Luaces adopts Regier''s use of the term ‘homeostatic’ to describe episodes that are adaptive rather than maladaptive (Regier et al. 1998). The term ‘allostatic’ may be more appropriate since the issue is that of adaptation to an external environment rather than maintenance of internal balance (McEwen, 2003). The term ‘rheostasis’ may be even more fitting since depressive disorders may reflect problems with calibration of otherwise adaptive mechanisms. A potential example may be found in Meaney''s work on epigenetic programming of stress responses (Meaney et al. 2007). Epigenetic regulation may be an example of a strategy for calibrating stress responses to environmental conditions. Nesse (2005) has pointed out that evolutionarily adaptive rheostatic mechanisms can produce false positive ‘all or nothing reactions’ (both depression and panic attacks may be examples) while reacting to an environment that contains both signal and noise (Nesse, 2005). Nesse''s ideas provide an interesting contrast to discussions of sensitivity and specificity, e.g. of DSM-5 criteria as in the third paragraph of this commentary. These ideas posit that sensitivity and specificity are parameters quantifying ways in which the brain itself responds to its environment. Rather than a dichotomy between adaptive and maladaptive types of depression, this framework suggests that a depressive episode might be a true positive (a ‘hit’), a false positive (false alarm), true negative or false negative. According to Nesse (2005), even an optimally calibrated system can produce false alarms, a so-called ‘fire alarm effect.’ Through the lens of rheostasis, strong clinical evidence of psychopathology is more likely to be found in maladaptive patterns of symptoms and episodes over time rather than by examination of the clinical characteristics of specific episodes, or refined definitions of such episodes. DSM-5, unfortunately, does not support such an approach since even a single MDE can support a diagnosis of MDD.Lorenzo-Luaces asserts that most episodes of major depression are brief, a statement supported by epidemiological data. However, this statement deserves further epidemiological refinement. Most new-onset episodes are brief but, since prevalence is proportional to incidence and duration, longer-lasting episodes accumulate in the population, such that the assertion has more veracity when it is applied to incident cases in the community than cases presenting in clinical settings, for an animated depiction of this phenomenon, see additional file 2 in Patten (2006). Delays in reaching clinical services will result in selection of more persistently ill patients. The rate of recovery from MDE declines as duration of an episode increases, leading to a characteristic pattern of cumulative recovery (Vos et al. 2004; Patten, 2006) and secondarily to a mean duration that is typically much longer than the median duration. Also caution is needed in referring to ‘placebo response rates’ in an episodic condition, since regression to the mean is important too. A person experiencing recurrent episodes may have a high rate of improvement while being treated with placebo, but this does not mean that the placebo treatment caused the improvement, nor that the patient''s episode was a trivial one.MDD is best treated as a label to enhance communication and increase reliability of diagnosis. It should not be regarded as an effective direct guide for clinical action.     

Influence of somatic symptoms on patient health questionnaire‐9 depression scores among patients with systemic sclerosis compared to a healthy general population sample

Objective

Depression symptom measures that include somatic symptoms may inflate severity estimates among medically ill patients, including patients with systemic sclerosis (SSc; scleroderma). The 9‐item Patient Health Questionnaire (PHQ‐9) is increasingly used to assess depressive symptoms in medical settings, but it is not known whether PHQ‐9 scores are influenced by somatic symptoms common in medical illness. The objective was to assess whether SSc patients had higher somatic symptom scores on the PHQ‐9 than non–medically ill respondents from the general population matched on cognitive/affective scores.

Methods

SSc patients from the Canadian Scleroderma Research Group Registry were matched with respondents from a random population survey of Alberta, Canada residents who were without chronic disease on total PHQ‐9 cognitive/affective scores (5 items), sex, and, as close as possible, age. PHQ‐9 somatic scores (4 items) were compared between SSc patients and healthy Alberta survey respondents using t‐tests for unadjusted analyses and analysis of covariance to adjust for age differences that remained after matching.

Results

Somatic symptoms accounted for 64% of the total PHQ‐9 scores for 762 matched SSc patients (n = 837 total) compared to 56% for 762 matched Alberta population survey respondents (n = 3,304 total), a mean difference of 1.0 point, or 19% of the total scores for the SSc patients (Hedges's g = 0.38). After adjusting for age, the mean difference increased to 1.4 points, reflecting 25% of the SSc patients' total scores (Hedges's g = 0.55).

Conclusion

PHQ‐9 scores among patients with SSc may include a small to moderate amount of variance from somatic symptoms that are not necessarily related to depression.     

Impact on ART initiation of point-of-care CD4 testing at HIV diagnosis among HIV-positive youth in Khayelitsha,South Africa

Introduction

Despite the rapid expansion of antiretroviral therapy (ART) programmes in developing countries, pre-treatment losses from care remain a challenge to improving access to treatment. Youth and adolescents have been identified as a particularly vulnerable group, at greater risk of loss from both pre-ART and ART care. Point-of-care (POC) CD4 testing has shown promising results in improving linkage to ART care. In Khayelitsha township, South Africa, POC CD4 testing was implemented at a clinic designated for youth aged 12–25 years. We assessed whether there was an associated reduction in attrition between HIV testing, assessment for eligibility and ART initiation.

Methods

A before-and-after observational study was conducted using routinely collected data. These were collected on patients from May 2010 to April 2011 (Group A) when baseline CD4 count testing was performed in a laboratory and results were returned to the clinic within two weeks. Same-day POC CD4 testing was implemented in June 2011, and data were collected on patients from August 2011 to July 2012 (Group B).

Results

A total of 272 and 304 youth tested HIV-positive in Group A and Group B, respectively. Group B patients were twice as likely to have their ART eligibility assessed compared to Group A patients: 275 (90%) vs. 183 (67%) [relative risk (RR)=2.4, 95% CI: 1.8–3.4, p<0.0001]. More patients in World Health Organization (WHO) Stage 1 disease (85% vs. 69%), with CD4 counts≥350 cells/µL (58% vs. 35%) and more males (13% vs. 7%) were detected in Group B. The proportion of eligible patients who initiated ART was 50% and 44% (p=0.6) in Groups B and A, respectively; and 50% and 43% (p=0.5) when restricted to patients with baseline CD4 count≤250 cells/µL. Time between HIV-testing and ART initiation was reduced from 36 to 28 days (p=0.6).

Discussion

POC CD4 testing significantly improved assessment for ART eligibility. The improvement in the proportion initiating ART and the reduction in time to initiation was not significant due to sample size limitations.

Conclusions

POC CD4 testing reduced attrition between HIV-testing and assessment of ART eligibility. Strategies to improve uptake of ART are needed, possibly by improving patient support for HIV-positive youth immediately after diagnosis.     

阿托伐他汀联合降压治疗对老年高血压患者平滑指数的影响

目的 观察应用阿托伐他汀调脂联合贝那普利和氨氯地平对老年高血压患者平滑指数的影响.方法 选取2013年10月至2014年2月上海市嘉定区南翔医院≥2级老年高血压患者120例,随机分为单纯降压组及调脂联合降压组,各60例.单纯降压组患者接受贝那普利和氨氯地平治疗,调脂联合降压组在此基础上加用阿托伐他汀（10mgqn po）调脂治疗.治疗3个月和6个月后随访,两组分别进行血脂及24 h动态血压监测,记录24 h平均收缩压（24 h SBP）和平均舒张压（24 h DBP）,计算24h收缩、舒张压平滑指数（SISBP和SIDBP）及脉压（PP）、脉压指数（PPI）,分别比较两组患者治疗前后血脂、动态血压值及稳定性的变化.结果 治疗3个月及个6月后,两组患者血压均控制良好.与单纯降压组相比,调脂联合降压组患者的总胆固醇及甘油三酯水平明显降低,PP及PPI明显降低（P＜0.05）,而SISBP和SIDBP明显升高（P＜0.05,P＜0.01）.结论 阿托伐他汀调脂联合降压治疗能更加有效降低≥2级高血压患者动态血压的PP及PPI,并且明显提高血压平滑指数,能有效减轻老年高血压患者靶器官损害.     

Clinical characteristics and outcome of intracerebral hemorrhage in young adults

Data on determinants of prognosis after intracerebral hemorrhage (ICH) in young adults are scarce. Our aim was to identify clinical determinants of prognosis after ICH in adults aged 18–50. We investigated 98 consecutive patients with an ICH, aged 18–50 years, admitted to our hospital between 1980 and 2010. Collected ICH characteristics included presenting symptoms, etiology, location, severity and Glasgow Coma Scale (GCS). Outcomes were case-fatality (death within 30 days), poor functional outcome (modified Rankin Scale >2), long-term mortality and recurrent ICH. We assessed discriminatory power of factors associated with case-fatality [area under receiver operating curve (AUC)]. Case-fatality was 20.4 % (n = 20) and well predicted by the GCS (AUC 0.83). Among 30-day survivors, a poor functional outcome at discharge was present in 51.3 %. During a mean follow-up of 11.3 years mortality was only increased in patients aged 40–50 years [standardized mortality ratio 4.8 (95 % CI 2.3–8.6)], but not in patients aged 18–40 years. Recurrent ICH occurred in 6 patients [10-year cumulative incidence 12.2 % (95 % CI 1.5–22.9 %)], all with the index ICH attributable to structural vascular malformations. Prognosis after ICH in young adults is poor, mainly due to high case-fatality, that is well predicted by the GCS. An exception is 30-day survivors <40 years, who have a similar risk of dying as the general population. Recurrence risk is especially present in patients with structural vascular malformations, whereas risk seems to be very low in other patients.