Psychiatric heredity and posttraumatic stress disorder: survey study of war veterans

Aim

To explore the prevalence of psychiatric heredity (family history of psychiatric illness, alcohol dependence disorder, and suicidality) and its association with the diagnosis of stress-related disorders in Croatian war veterans established during psychiatric examination.

Methods

The study included 415 war veterans who were psychiatrically assessed and diagnosed by the same psychiatrist during an expert examination conducted for the purposes of compensation seeking. Data were collected by a structured diagnostic procedure.

Results

There was no significant correlation between psychiatric heredity of psychiatric illness, alcohol dependence, or suicidality and diagnosis of posttraumatic stress disorder (PTSD) or PTSD with psychiatric comorbidity. Diagnoses of psychosis or psychosis with comorbidity significantly correlated with psychiatric heredity (φ = 0.111; P = 0.023). There was a statistically significant correlation between maternal psychiatric illness and the patients’ diagnoses of partial PTSD or partial PTSD with comorbidity (φ = 0.104; P = 0.035) and psychosis or psychosis with comorbidity (φ = 0.113; P = 0.022); paternal psychiatric illness and the patients’ diagnoses of psychosis or psychosis with comorbidity (φ = 0.130; P = 0.008), alcohol dependence or alcohol dependence with comorbidity (φ = 0.166; P = 0.001); psychiatric illness in the primary family with the patients’ psychosis or psychosis with comorbidity (φ = 0.115; P = 0.019); alcohol dependence in the primary family with the patients’ personality disorder or personality disorder with comorbidity (φ = 0.099; P = 0.044); and suicidality in the primary family and a diagnosis of personality disorder or personality disorder with comorbidity (φ = 0.128; P = 0.009).

Conclusion

The study confirmed that parental and familial positive history of psychiatric disorders puts the individual at higher risk for developing psychiatric illness or alcohol or drug dependence disorder. Psychiatric heredity might not be necessary for the individual who was exposed to severe combat-related events to develop symptoms of PTSD.There are several risk factors associated with the development of posttraumatic stress disorder (PTSD), such as factors related to cognitive and biological systems and genetic and familial risk (1), environmental and demographic factors (2), and personality and psychiatric anamnesis (3).They are usually grouped into three categories: factors that preceded the exposure to trauma or pre-trauma factors; factors associated with trauma exposure itself; and post-trauma factors that are associated with the recovery environment (2,4).There are many studies which support the hypothesis that pre-trauma factors, such as ongoing life stress, psychiatric history, female sex (3), childhood abuse, low economic status, lack of education, low intelligence, lack of social support (5), belonging to racial and ethnic minority, previous traumatic events, psychiatric heredity, and a history of perceived life threat, influence the development of stress related disorders (6). Many findings suggest that ongoing life stress or prior trauma history sensitizes a person to a new stressor (2,7-9). The same is true for the lack of social support, particularly the loss of support from significant others (2,9-11), as well as from friends and community (12-14). If the community does not have an elaborated plan for providing socioeconomic support to the victims, then the low socioeconomic status can also be an important predictor of a psychological outcome such as PTSD (2,10,15). Unemployment was recognized as a risk factor for developing PTSD in a survey of 374 trauma survivors (16). It is known that PTSD commonly occurs in patients with a previous psychiatric history of mental disorders, such as affective disorders, other anxiety disorders, somatization, substance abuse, or dissociative disorders (17-21). Epidemiological studies showed that pre-existing psychiatric problems are one of the three factors that can predict the development of PTSD (2,22). Pre-existing anxiety disorders, somatoform disorders, and depressive disorders can significantly increase the risk of PTSD (23). Women have a higher vulnerability for PTSD than men if they experienced sexually motivated violence or had pre-existing anxiety disorders (23,24). A number of studies have examined the effects of gender differences on the predisposition for developing PTSD, with the explanation that women generally have higher rates of depression and anxiety disorders (3,25,26). War-zone stressors were described as more important for PTSD in men, whereas post-trauma resilience-recovery factors as more important for women (27).Lower levels of education and poorer cognitive abilities also appear to be risk factors (25). Golier et al (25) reported that low levels of education and low IQ were associated with poorer recall on words memorization tasks. In addition, this study found that the PTSD group with lower Wechsler Adult Intelligence Scale-Revised (WAIS-R) scores had fewer years of education (25). Nevertheless, some experts provided evidence for poorer cognitive ability in PTSD patients as a result or consequence rather than the cause of stress-related symptoms (28-31). Studies of war veterans showed that belonging to racial and ethnic minority could influence higher rates of developing PTSD even after the adjustment for combat exposure (32,33). Many findings suggest that early trauma in childhood, such as physical or sexual abuse or even neglect, can be associated with adult psychopathology and lead to the development of PTSD (2,5,26,34,35). Surveys on animal models confirm the findings of lifelong influences of early experience on stress hormone reactivity (36).Along with the reports on the effects of childhood adversity as a risk factor for the later development of PTSD, there is also evidence for the influence of previous exposure to trauma related events on PTSD (9,26,28). Breslau et al (36) reported that previous trauma experience substantially increased the risk for chronic PTSD.Perceived life threats and coping strategies carry a high risk for developing PTSD (9,26). For instance, Ozer et al (9) reported that dissociation during trauma exposure has high predictive value for later development of PTSD. Along with that, the way in which people process and interpret perceived threats has a great impact on the development or maintenance of PTSD (37,38).Brewin et al (2) reported that individual and family psychiatric history had more uniform predictive effects than other risk factors. Still, this kind of influence has not been examined yet.Keeping in mind the lack of investigation of parental psychiatric heredity on the development of stress-related disorders, the aim of our study was to explore the prevalence and correlation between the heredity of psychiatric illness, alcohol dependence, suicidality, and the established diagnosis of stress-related disorders in Croatian 1991-1995 war veterans.     

Adverse drug reactions caused by drug-drug interactions reported to Croatian Agency for Medicinal Products and Medical Devices: a retrospective observational study

Aim

To analyze potential and actual drug-drug interactions reported to the Spontaneous Reporting Database of the Croatian Agency for Medicinal Products and Medical Devices (HALMED) and determine their incidence.

Methods

In this retrospective observational study performed from March 2005 to December 2008, we detected potential and actual drug-drug interactions using interaction programs and analyzed them.

Results

HALMED received 1209 reports involving at least two drugs. There were 468 (38.7%) reports on potential drug-drug interactions, 94 of which (7.8% of total reports) were actual drug-drug interactions. Among actual drug-drug interaction reports, the proportion of serious adverse drug reactions (53 out of 94) and the number of drugs (n = 4) was significantly higher (P < 0.001) than among the remaining reports (580 out of 1982; n = 2, respectively). Actual drug-drug interactions most frequently involved nervous system agents (34.0%), and interactions caused by antiplatelet, anticoagulant, and non-steroidal anti-inflammatory drugs were in most cases serious. In only 12 out of 94 reports, actual drug-drug interactions were recognized by the reporter.

Conclusion

The study confirmed that the Spontaneous Reporting Database was a valuable resource for detecting actual drug-drug interactions. Also, it identified drugs leading to serious adverse drug reactions and deaths, thus indicating the areas which should be in the focus of health care education.Adverse drug reactions (ADR) are among the leading causes of mortality and morbidity responsible for causing additional complications (1,2) and longer hospital stays. Magnitude of ADRs and the burden they place on health care system are considerable (3-6) yet preventable public health problems (7) if we take into consideration that an important cause of ADRs are drug-drug interactions (8,9). Although there is a substantial body of literature on ADRs caused by drug-drug interactions, it is difficult to accurately estimate their incidence, mainly because of different study designs, populations, frequency measures, and classification systems (10-15).Many studies including different groups of patients found the percentage of potential drug-drug interactions resulting in ADRs to be from 0%-60% (10,11,16-25). System analysis of ADRs showed that drug-drug interactions represented 3%-5% of all in-hospital medication errors (3). The most endangered groups were elderly and polimedicated patients (22,26-28), and emergency department visits were a frequent result (29). Although the overall incidence of ADRs caused by drug-drug interactions is modest (11-13,15,29,30), they are severe and in most cases lead to hospitalization (31,32).Potential drug-drug interactions are defined on the basis of on retrospective chart reviews and actual drug-drug interactions are defined on the basis of clinical evidence, ie, they are confirmed by laboratory tests or symptoms (33). The frequency of potential interactions is higher than that of actual interactions, resulting in large discrepancies among study findings (24).A valuable resource for detecting drug-drug interactions is a spontaneous reporting database (15,34). It currently uses several methods to detect possible drug-drug interactions (15,29,35,36). However, drug-drug interactions in general are rarely reported and information about the ADRs due to drug-drug interactions is usually lacking.The aim of this study was to estimate the incidence of actual and potential drug-drug interactions in the national Spontaneous Reporting Database of ADRs in Croatia. Additionally, we assessed the clinical significance and seriousness of drug-drug interactions and their probable mechanism of action.     

Use of concentrated bone marrow aspirate and platelet rich plasma during minimally invasive decompression of the femoral head in the treatment of osteonecrosis

The aim of this paper is to describe our surgical procedure for the treatment of osteonecrosis of the femoral head using a minimally invasive technique. We have limited the use of this procedure for patients with pre-collapse osteonecrosis of the femoral head (Ficat Stage I or II). To treat osteonecrosis of the femoral head at our institution we currently use a combination of outpatient, minimally invasive iliac crest bone marrow aspirations and blood draw combined with decompressions of the femoral head. Following the decompression of the femoral head, adult mesenchymal stem cells obtained from the iliac crest and platelet rich plasma are injected into the area of osteonecrosis. Patients are then discharged from the hospital using crutches to assist with ambulation. This novel technique was utilized on 77 hips. Sixteen hips (21%) progressed to further stages of osteonecrosis, ultimately requiring total hip replacement. Significant pain relief was reported in 86% of patients (n = 60), while the rest of patients reported little or no pain relief. There were no significant complications in any patient. We found that the use of a minimally invasive decompression augmented with concentrated bone marrow and platelet rich plasma resulted in significant pain relief and halted the progression of disease in a majority of patients.Osteonecrosis of the femoral head (ONFH) occurs when the cells of the trabecular bone and marrow in the femoral head spontaneously die, leading to fracture and collapse of the articular surface (1,2). In the US, every year ONFH occurs in 10 000-20 000 adults between the ages of 20 and 60 (1,3,4). Once collapse occurs, severe pain ensues, and the disease course rarely regresses (5-8). In order to halt disease progression and provide pain relief, 80% of patients suffering from ONFH will require a total hip arthroplasty (THA); typically at a younger age than patients undergoing a THA for osteoarthritis (9-11).Although ONFH is a common indication for THA, the etiology of the disease is still unknown (12,13). ONFH is thought to be a multifactorial disease, with patients reporting a history of exposure to one or more risk factors, including trauma to the hip, alcohol abuse, corticosteroid use, hemoglobinopathies, pregnancy, coagulopathies, organ transplant, chemotherapy, Caisson disease, HIV, and autoimmune conditions; however in some patients the risk factor remains unknown, and the disease is termed “idiopathic” ONFH (12-16). Recent studies looking at the gentics risks of ONFH have resulted in identifying an autosomal dominant mutation in collagen type II gene (COL2 A1 gene) (17); which has been associated with genetic polymorphisms in alcohol metabolizing enzymes and the drug transport proteins (18,19).If the disease course is recognized before collapse of the subchondral bone and cartilage, patients can be treated with core decompression of the femoral head including Ficat Stage I or II (12,20,21). This technique has been used for over four decades, however randomized control trials have failed to show that this procedure alone halts disease progression and collapse (4). Recently, concentrated bone marrow autograft has been used to augment the decompression site to attempt to repopulate the femoral head with human mesenchymal stem cells (hMSC) (13,22,23). This aim of this paper is to describe our surgical technique and early clinical results using autologous bone marrow concentrate with platelet rich plasma and a minimally invasive decompression for the treatment of ONFH.     

Microcoagulation of junctional dorsal root entry zone is effective treatment of brachial plexus avulsion pain: long-term follow-up study

Aim

To analyze long-term clinical results of coagulation lesions of the dorsal root entry zone (DREZ) in patients with deafferentation pain due to brachial plexus avulsion and to correlate the pain relief after DREZ coagulation with pain duration before the DREZ coagulation.

Methods

Twenty-six patients with intractable deafferentation pain after brachial plexus avulsion lesion were treated for pain at the Department of Neurosurgery. Junctional coagulation lesion was made with bipolar forceps along the DREZ. The patients assessed post-operative analgesic effect using a visual analog scale at 1 week, 1 year, 3 years, and 5 years after the surgery.

Results

The greatest pain relief was reported immediately after the DREZ procedure. Over the 5-year follow-up period, the pain relief effect gradually and significantly decreased. There were no significant differences between the pain relief evaluated at 1 week and after 1 year and between the pain relief evaluated at 1 week and after 3 years. There was a correlation between the pain duration before the surgery and pain relief after the surgery, with best correlation found between pain duration before surgery and pain relief 5 years after DREZ procedure (r = 0.623, P = 0.007).

Conclusion

The long-term follow up showed that the pain relief gradually decreased over 5 years after surgery. However, the pain relief still did not significantly decrease after 3 years.There is experimental and clinical evidence that pain generators in brachial plexus avulsion are at least partially located in the deafferented dorsal horn (1-3). The term deafferentation pain has been defined as pain or dysesthesia caused by interruption of the peripheral or central afferent input in the central nervous system (4). When the large lemniscal afferents within peripheral nerves or dorsal roots are altered, the inhibitory control of the dorsal horn is reduced (5). It was suggested that dorsal horn deafferentation by cervical posterior rhizotomy in the rat provides a reliable model of chronic pain due to brachial plexus avulsion and that this deafferentation pain is successfully relieved by microsurgical dorsal root entry zone (DREZ) rhizotomy (6). Pain following brachial plexus avulsion is the most typical manifestation of the chronic deafferentation pain in humans (4). Preganglionic lesion of the dorsal horn of the cervical spinal cord due to root avulsion may lead to important pathological changes responsible for the induction of pain sensations in 90% of the patients (7). Medications, neurostimulation techniques, and various ablative surgical procedures other than DREZ surgery, including cervical anterolateral cordotomy, mesencephalic spinothalamic tractotomy, and medial thalamotomy, have not shown long-term efficacy and are not exempt from disabling side effects (8,9). On the contrary, the neurosurgical procedure of coagulation lesions in the DREZ has been shown effective in pain relief after brachial plexus avulsion (10-16). The DREZ was chosen as a possible neurosurgical target to stop abnormal firing of impulses, which most probably originate in the central portion of the dorsal nerve roots, in Lissauer’s tracts and Rexed’s laminas I-V of the dorsal horn. The idea of a DREZ lesion was put forward in 1972 (17,18) and 4 years later, it was accepted as a useful pain-relieving therapeutic procedure (7). The aim of DREZ lesioning is the treatment of neuropathic pain associated with dysfunction in the gating circuitry of the dorsal horn and generated by dorsal horn hyperactive neurons (1,5). The original procedure in the DREZ region, which includes series of focal radiofrequency heat lesions 2-3 mm apart along the line of the posterolateral fissure at the site of the avulsion of the rootlets (7,19), has been updated by Rawlings et al (20). A series of DREZ lesions may also be produced with microsurgical lasers (21-23). Dreval (24) reported on ultrasonic DREZ operation for the treatment of pain due to brachial plexus avulsion. Computer-assisted DREZ microcoagulation for posttraumatic spinal deafferentation pain is described by Edgar et al (25). In our previous study, we described our experience and clinical results of microsurgical junctional DREZ coagulation performed for pain relied in different deafferentation syndromes (26). Since the DREZ procedures are the most effective in the treatment of pain, particularly brachial plexus avulsion pain, and the good results have tendency to diminish with time, the studies to analyze the long-term effects of the procedure on pain after brachial plexus avulsion are needed.The aim of the study was to determine long-term clinical results of the DREZ coagulation lesion, primarily the duration and degree of pain relief, in patients with deafferentation pain due to brachial plexus avulsion.     

Pharmacotherapy of treatment-resistant combat-related posttraumatic stress disorder with psychotic features

Aim

To assess retrospectively the clinical effects of typical (fluphenazine) or atypical (olanzapine, risperidone, quetiapine) antipsychotics in three open clinical trials in male Croatian war veterans with chronic combat-related posttraumatic stress disorder (PTSD) with psychotic features, resistant to previous antidepressant treatment.

Methods

Inpatients with combat-related PTSD were treated for 6 weeks with fluphenazine (n = 27), olanzapine (n = 28) risperidone (n = 26), or quetiapine (n = 53), as a monotherapy. Treatment response was assessed by the reduction in total and subscales scores in the clinical scales measuring PTSD (PTSD interview and Clinician-administered PTSD Scale) and psychotic symptoms (Positive and Negative Syndrome Scale).

Results

After 6 weeks of treatment, monotherapy with fluphenazine, olanzapine, risperidone, or quetiapine in patients with PTSD significantly decreased the scores listed in trauma reexperiencing, avoidance, and hyperarousal subscales in the clinical scales measuring PTSD, and total and subscales scores listed in positive, negative, general psychopathology, and supplementary items of the Positive and negative syndrome scale subscales, respectively (P<0.001).

Conclusion

PTSD and psychotic symptoms were significantly reduced after monotherapy with typical or atypical antipsychotics. As psychotic symptoms commonly occur in combat-related PTSD, the use of antipsychotic medication seems to offer another approach to treat a psychotic subtype of combat-related PTSD resistant to previous antidepressant treatment.In a world in which terrorism and conflicts are constant threats, and these threats are becoming global, posttraumatic stress disorder (PTSD) is a serious and global illness. According to the criteria from the 4th edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (1), exposure to a life-threatening or horrifying event, such as combat trauma, rape, sexual molestation, abuse, child maltreatment, natural disasters, motor vehicle accidents, violent crimes, hostage situations, or terrorism, can lead to the development of PTSD (1,2). The disorder may also be precipitated if a person experienced, saw, or learned of an event or events that involved actual or threatened death, serious injury, or violation of the body of self or others (3,4). In such an event, a person’s response can involve intense fear, helplessness, or horror (3,4). However, not all persons who are exposed to a traumatic event will develop PTSD. Although the stress reaction is a normal response to an abnormal situation, some extremely stressful situations will in some individuals overwhelm their ability to cope with stress (5).PTSD is a chronic psychiatric illness. The essential features of PTSD are the development of three characteristic symptom clusters in the aftermath of a traumatic event: re-experiencing the trauma, avoidance and numbing, and hyperarousal (1,6). The core PTSD symptoms in the re-experiencing cluster are intrusive memories, images, or perceptions; recurring nightmares; intrusive daydreams or flashbacks; exaggerated emotional and physical reactions; and dissociative experiences (1,6,7). These symptoms intensify or re-occur upon exposure to reminders of the trauma, and various visual, auditory, or olfactory cues might trigger traumatic memories (3,4). The avoidance and numbing cluster of symptoms includes efforts to avoid thoughts, feelings, activities, or situations associated with the trauma; feelings of detachment or alienation; inability to have loving feelings; restricted range of affect; loss of interest; and avoidance of activity. The hyperarousal cluster includes exaggerated startle response, hyper-vigilance, insomnia and other sleep disturbances, difficulties in concentrating, and irritability or outbursts of anger. PTSD criteria include functional impairment, which can be seen in occupational instability, marital problems, discord with family and friends, and difficulties in parenting (3,4,8). In addition to this social and occupational dysfunction, PTSD is often accompanied by substance abuse (9) and by various comorbid diagnoses, such as major depression (10), other anxiety disorders, somatization, personality disorders, dissociative disorders (7,11), and frequently with suicidal behavior (12). Combat exposure can precipitate a more severe clinical picture of PTSD, which may be complicated with psychotic features and resistance to treatment. War veterans with PTSD have a high risk of suicide, and military experience, guilt about combat actions, survivor guilt, depression, anxiety, and severe PTSD are significantly associated with suicide attempts (12).The pharmacotherapy treatment of PTSD includes the use of antidepressants, such as selective serotonin reuptake inhibitors (fluvoxamine, fluoxetine, sertraline, or paroxetine) as a first choice of treatment, tricyclic antidepressants (desipramine, amitriptyline, imipramine), monoamine oxidase inhibitors (phenelzine, brofaromine), buspirone, and other antianxiety agents, benzodiazepines (alprazolam), and mood stabilizers (lithium) (13-16). Although the pharmacotherapy of PTSD starts with antidepressants, in treatment-refractory patients a new pharmacological approach is required to obtain a response. In treatment-resistant patients, pharmacotherapy strategies reported to be effective include anticonvulsants, such as carbamazepine, gabapentine, topiramate, tiagabine, divalproex, lamotrigine (14,17); anti-adrenergic agents, such as clonidine (although presynaptic α2-adrenoceptor agonist, clonidine blocks central noradrenergic outflow from the locus ceruleus), propranolol, and prazosin (13,14), opiate antagonists (13), and neuroleptics and antipsychotics (14,17,18).Combat exposure frequently induces PTSD, and combat-related PTSD might progress to a severe form of PTSD, which is often refractory to treatment (19-21). Combat-related PTSD is frequently associated with comorbid psychotic features (11,14,17,19-21), while psychotic features add to the severity of symptoms in combat-related PTSD patients (19,22-24). These cases of a more severe subtype of PTSD, complicated with psychotic symptoms, require the use of neuroleptics or atypical antipsychotic drugs (14,17,25-27).After the war in Croatia (1991-1995), an estimated million people were exposed to war trauma and about 10 000 of the Homeland War veterans (15% prevalence) have developed PTSD, with an alarmingly high suicide rate (28). The war in Croatia brought tremendous suffering, not only to combat-exposed veterans and prisoners of war (29), but also to different groups of traumatized civilians in the combat zones, displaced persons and refugees, victims of terrorist attacks, civilian relatives of traumatized war veterans and terrorist attacks victims, and traumatized children and adolescents (30). Among Croatian war veterans with combat-related PTSD, 57-62% of combat soldiers with PTSD met criteria for comorbid diagnoses (8-11), such as alcohol abuse, major depressive disorder, anxiety disorders, panic disorder and phobia, psychosomatic disorder, psychotic disorders, drug abuse, and dementia. In addition to different comorbid psychiatric disorders, a great proportion of war veterans with combat-related PTSD developed psychotic features (8,11,25,26), which consisted of psychotic depressive and schizophrenia-like symptoms (suggesting prominent symptoms of thought disturbances and psychosis). Psychotic symptoms were accompanied by auditory or visual hallucinations and delusional thinking in over two-thirds of patients (25,26). Delusional paranoid symptoms occurred in 32% of patients (25,26). The hallucinations were not associated exclusively with the traumatic experience, while the delusions were generally paranoid or persecutory in nature (25,26). Although psychotic PTSD and schizophrenia share some similar symptoms, there are clear differences between these two entities, since PTSD patients still retain some insight into reality and usually do not have complete disturbances of affect (eg, constricted or inappropriate) or thought disorder (eg, loose associations or disorganized responses).This proportion of veterans with combat-related PTSD refractory to treatment (18-20) and with co-occurring psychotic symptoms requires additional pharmacological strategies, such as the use of neuroleptics (25) or atypical antipsychotics (14,17,26). Studies evaluating the use of antipsychotics in combat-related PTSD with psychotic features are scarce, and antipsychotics were frequently added to existing medication in the treatment of PTSD.In this study, we compared retrospectively the clinical effects of four antipsychotic drugs – a neuroleptic drug (fluphenazine) and three atypical antipsychotics (olanzapine, risperidone and quetiapine) – in treatment-resistant male war veterans with combat-related PTSD with psychotic features.     

Blood lactate levels in patients receiving first- or second- generation antipsychotics

Aim

To compare the blood lactate levels between patients with psychotic disorder receiving first- and those receiving second-generation antipsychotics.

Methods

The study was conducted at the psychiatric inpatient and outpatient clinics of the Split Clinical Hospital from June 6, 2008 to October 10, 2009. Sixty patients with psychotic disorder who were assigned to 6-month treatment were divided in two groups: 30 received haloperidol (first generation antipsychotic) and 30 received olanzapine (second generation antipsychotic). Blood lactate levels, other metabolic parameters, and scores on the extrapyramidal symptom rating scale were assessed.

Results

Patients receiving haloperidol had significantly higher blood lactate levels than patients receiving olanzapine (P < 0.001). They also more frequently had parkinsonism, which was significantly correlated with both haloperidol treatment at 1 month (P < 0.001) and 6 months (P = 0.016) and olanzapine treatment at baseline (P = 0.016), 3 months (P = 0.019), and 6 months (P = 0.021). Also, patients receiving haloperidol had significant correlation between blood lactate and dystonia at 1 month (P < 0.001) and 6 months (P = 0.012) and tardive dyskinesia at 1 month (P = 0.032). There was a significant difference between the treatment groups in lactate levels at all points from baseline to month 6 (P < 0.001).

Conclusion

It is important to be aware of the potential effect of haloperidol treatment on increase in blood lactate levels and occurrence of extrapyramidal side effects. Therefore, alternative antipsychotics should be prescribed with lower risk of adverse side effects.

Trial identification number

NCT01139463Due to their heterogeneity, antipsychotics are difficult to classify, but they are frequently categorized as the first- and second-generation based on the incidence of extrapyramidal side effects, ie, antidopaminergic activity (1,2). First-generation antipsychotics have dominant antidopaminergic activity and pronounced extrapyramidal side effects (1), while second-generation antipsychotics have a pronounced effect on other neurotransmitter systems, as well as sporadic extrapyramidal side effects.Antipsychotics block numerous neurotransmitter receptors in a manner that induces therapeutic effects and side effects, which may vary in intensity and produce serious consequences (3-7). Extrapyramidal side effects (adverse cardiovascular, hematological, gastrointestinal, sexual, and urologic effects) are most frequently manifested in first-generation antipsychotics due to their non-selective dopaminergic block (1,8-10). The consequence of a dopaminergic effect on the tuberoinfundibular system causing dopamine to inhibit prolactin secretion is hyperprolactinemia (11,12), with possible consequences such as tissue hypoxia and mortality (13-15).Particular attention today is paid to the effects of first-generation antipsychotics on metabolic disorders. Numerous studies have shown that first-generation antipsychotic therapy may lead to metabolic changes, particularly changes in the regulation of glucose, lipid levels, and body weight (3-5,13-21). These side effects are associated with increased mortality and substantial morbidity including diabetes, hypertension, and cardiovascular disease (22,23). In many years of clinical practice, we have empirically observed that treatment with certain antipsychotics causes, along with recognized and described metabolic disorders, an increase in the blood lactate levels. Increased lactate levels are generally associated with increased morbidity and mortality in patients with chronic illnesses or critically ill patients (13,14,24-26). A review of the literature did not find any studies on the effect of antipsychotic therapy on lactate levels or such changes as a part of other antipsychotic side effects. Therefore, it is important to investigate this phenomenon in patients taking first- or second-generation antipsychotic medication.We hypothesized that a 6-month treatment with haloperidol or olanzapine would change blood lactate levels and cause extrapyramidal side effects in patients without prior antipsychotic treatment.     

Prognostic value of serum nicotinamide phosphoribosyltransferase in patients with bladder cancer

Aim

To analyze the serum nicotinamide phosphoribosyltransferase (Nampt) level and its prognostic value in bladder cancer (BC).

Methods

The study included 131 patients with transitional cell BC and 109 healthy controls from the West China Hospital of Sichuan University in the period between 2007 and 2013. Nampt concentration in serum was measured by commercial ELISA kits for human Nampt.

Results

The serum Nampt protein level in patients with BC (mean ± standard deviation, 16.02 ± 7.95 ng/mL) was significantly higher than in the control group (6.46 ± 2.08 ng/mL) (P < 0.001). Serum Nampt level was an independent prognostic marker of non-muscle-invasive BC, with a higher serum Nampt level (>14.74 ng/mL) indicating shorter recurrence-free survival rate (hazard ratio = 2.85, 95% confidence interval, 1.01-8.06; P = 0.048).

Conclusion

Our results suggest that serum Nampt level may serve as a biomarker of BC and an independent prognostic marker of non-muscle-invasive BC.Bladder cancer (BC) is the ninth most common cancer diagnosis worldwide (1) and the most expensive cancer to treat (2). Among men it is the fourth most common cancer, with incidence four times higher than in women (3). In China, BC caused 17 365 deaths in 2005, with a steady increase in mortality between 1991 and 2005 (4). Of newly diagnosed BC cases, 70%-80% will present with non-muscle-invasive disease, 50%-70% will recur despite endoscopic and intravesical treatments, and 10%-30% will progress to muscle-invasive disease (5,6). Most recurrences occur within 5 years (7). Therefore, to develop improved, more effective prevention and treatments there is a need to find new biomarkers of tumorigenesis and prognosis of BC.Nicotinamide phosphoribosyltransferase (Nampt) is a rate-limiting enzyme in the mammalian NAD⁺ biosynthesis of a salvage pathway (8). Previous studies have shown that it is significantly increased in primary colorectal cancer (9-11), lung cancer (12), breast cancer (13), prostate cancer (14) and gastric cancer (15). Thus, Nampt may be a good biomarker of malignant potential and stage progression (12,16). Our previous study revealed that genetic variants in NAMPT may predict BC risk and prognosis (17). In the present study, we analyzed the serum Nampt level and its prognostic value in BC.     

Attitudes of Slovenian family practice patients toward changing unhealthy lifestyle and the role of family physicians: cross-sectional study

Aim

To assess patients’ attitudes toward changing unhealthy lifestyle, confidence in the success, and desired involvement of their family physicians in facilitating this change.

Methods

We conducted a cross-sectional study in 15 family physicians’ practices on a consecutive sample of 472 patients (44.9% men, mean age  [± standard deviation] 49.3 ± 10.9 years) from October 2007 to May 2008. Patients were given a self-administered questionnaire on attitudes toward changing unhealthy diet, increasing physical activity, and reducing body weight. It also included questions on confidence in the success, planning lifestyle changes, and advice from family physicians.

Results

Nearly 20% of patients planned to change their eating habits, increase physical activity, and reach normal body weight. Approximately 30% of patients (more men than women) said that they wanted to receive advice on this issue from their family physicians. Younger patients and patients with higher education were more confident that they could improve their lifestyle. Patients who planned to change their lifestyle and were more confident in the success wanted to receive advice from their family physicians.

Conclusion

Family physicians should regularly ask the patients about the intention of changing their lifestyle and offer them help in carrying out this intention.Unhealthy lifestyle, including unhealthy diet and physical inactivity, is still a considerable health problem all over the world. Despite publicly available evidence about the health risks of unhealthy lifestyle, people still find it hard to improve their unhealthy diet and increase physical activity. Previous studies have shown that attitudes toward lifestyle change depended on previous health behavior, awareness of unhealthy lifestyle, demographic characteristics, personality traits, social support, family functioning, ongoing contact with health care providers, and an individual’s social ecology or network (1-4).As community-based health education approaches have had a limited effect on health risk factors reduction (3,5), the readiness-to-change approach, based on two-way communication, has become increasingly used with patients who lead an unhealthy lifestyle (3,6,7). Family physicians are in a unique position to adopt this approach, since almost every patient visits his/hers family physician at least once in five years (8). Previous studies showed that patients highly appreciated their family physicians’ advice on lifestyle changes (9,10). Moreover, patients who received such advice were also more willing to change their unhealthy habits (3,7,11). The reason for this is probably that behavioral changes are made according to the patient’s stage of the motivational circle at the moment of consultation (12), which can be determined only by individual approach.Although family physicians are convinced that it is their task to give advice on health promotion and disease prevention, in practice they are less likely to do so (13). The factors that prevent them from giving advice are time (14,15), cost, availability, practice capacity (14), lack of knowledge and guidelines, poor counseling skills (16), and personal attitudes (17). It also seems that physicians’ assessment varies considerably according to the risk factor in question. For example, information on diet and physical activity are often inferred from patients’ appearance rather than from clinical measurements (14). Also, health care professionals seldom give advice on recommended aspects of intervention that could facilitate behavioral change (18). As a large proportion of primary care patients are ready to lose weight, improve diet, and increase exercise (19), it is even more important that their family physicians provide timely advice.So far, several studies have addressed patients’ willingness to make lifestyle change (2-5,20) and the provision of professional advice (3,5,7,10,11). However, none of these studies have investigated the relation between these factors. So, the aim of our study was to assess the relation between patients’ attitudes toward changing unhealthy lifestyle, confidence in success, and the desired involvement of their family physicians in facilitating the change.     

Association between social capital,health-related quality of life,and mental health: a structural-equation modeling approach

AimTo explore the association(s) between demographic factors, socioeconomic status (SES), social capital, health-related quality of life (HRQoL), and mental health among residents of Tehran, Iran.MethodsThe pooled data (n = 31 519) were extracted from a population-based survey Urban Health Equity Assessment and Response Tool-2 (Urban HEART-2) conducted in Tehran in 2011. Mental health, social capital, and HRQoL were assessed using the 28-item General Health Questionnaire (GHQ-28), social capital questionnaire, and Short-Form Health Survey (SF-12), respectively. The study used a multistage sampling method. Social capital, HRQoL, and SES were considered as latent variables. The association between these latent variables, demographic factors, and mental health was determined by structural-equation modeling (SEM).ResultsThe mean age and mental health score were 44.48 ± 15.87 years and 23.33 ± 11.10 (range, 0-84), respectively. The prevalence of mental disorders was 41.76% (95% confidence interval 41.21-42.30). The SEM model showed that age was directly associated with social capital (P = 0.016) and mental health (P = 0.001). Sex was indirectly related to mental health through social capital (P = 0.018). SES, HRQoL, and social capital were associated both directly and indirectly with mental health status.ConclusionThis study suggests that changes in social capital and SES can lead to positive changes in mental health status and that individual and contextual determinants influence HRQoL and mental health.Mental health is defined by World Health Organization (WHO) as “a state of well-being in which every individual realizes his/her own potential, can cope with the normal pressures of life, can work productively, and is able to make a contribution to his/her community” (1,2). Mental health and associated disorders have received increasing attention worldwide, largely due to their impact on socio-economic and overall health status of patients (3). Mental health problems remain a global concern, and account for a large fraction of diseases (4,5).The overall prevalence of mental disorders in Iran between 2000 and 2008 ranged from 12.5% to 38.9% and was similar in urban (20.9%) and rural areas (21.3%) (6). Anxiety and depression were more prevalent than somatization and social dysfunction (7). The provinces with the highest prevalence of mental problems were Chaharmahal with 38.3% and Golestan with 37.3% (8).Mental health is usually determined by a complex interaction of sociocultural, psychological, environmental, and demographic factors (9). The prevalence of mental health disorders is significantly associated with age, marital status, educational level, employment, and health-related to quality of life (HRQoL) (10). HRQoL incorporates physical and socio-emotional functioning and is used to measure individual''s perception of health status, welfare, and well-being in a society (11). A frequently used psychometrical tool for the assessment of HRQoL is Short-Form Health Survey (SF-12). Its two main components are physical component summary (PCS) and mental component summary (MCS), both of which are associated with mental health (12). Previous studies have confirmed a bidirectional association between physical health and depression (as one of the main dimensions of mental health) (13). However, it is not clear whether there is a causal relationship between them (13,14).The suggested mechanisms by which depression could lead to physical disability and decreased HRQoL are poor health behaviors, increased risk of physical disease, and characteristics of depression (eg, decreased pain threshold) (15). On the other hand, physical disability can lead to depression and deterioration of mental health due to restriction of social activities and loss of social capital (15). Ultimately, this bilateral association between depression and poor physical health can lead to increasing health risks (14).Mental disorders such as depression and anxiety are also influenced by socioeconomic status (SES) (16). SES is commonly conceptualized as an individual or group’s relative social standing or class (16,17). The main predictors of SES are education level, income, and occupation (15,17,18). The correlations between SES and mental health have been explained by various mechanisms. It has been found that negative impact of low SES on mental health (19) can be reduced by the mediating effect of social capital and physical health (4,18).Social capital has been defined as individual’s social networks and social interactions, shared norms, values, and understandings that facilitate collective action within or among groups. It can act as a protective factor, promoting mental health status by reducing socioeconomic inequalities (4,20) and play an important role in reducing the prevalence of mental disorders (4). Previous studies have found that social ties and support significantly improve mental health (9). Nonetheless, the association between social capital, mental health, quality of life, and SES is not consistently reported (21,22). This population-based study aims to explore the association between demographic factors, SES, social capital, HRQoL, and mental health among Tehran residents using structural-equation modeling (SEM).     

Patients with Combat-related and War-related Posttraumatic Stress Disorder 10 Years After Diagnosis

Aim

To establish how many patients diagnosed with posttraumatic stress disorder (PTSD) in 1996 used psychiatric facilities and had psychiatric symptoms 10 years later, and assess their sociodemographic characteristics, comorbid disorders, and type of treatment.

Methods

Medical records of patients diagnosed with PTSD in 1996 were reviewed in the period 2007-2009 and the patients who contacted a psychiatrist in that period (n = 85) and those who did not (n = 158) were compared.

Results

There were 36.7% of men and 20% of women diagnosed with PTSD in 1996 who contacted a psychiatrist in the period 2007-2009. Patients who contacted a psychiatrist and those who did not did not differ in sex, age, the number of visits and hospitalizations in 1996, and employment status. The majority of patients still had PTSD and/or were enduring personality change in the period 2007-2009, and 54.8% had some comorbidity (mostly depression, alcohol-related disorders, and personality disorders). Patients were most often treated with anxiolytics and antidepressants.

Conclusion

Ten years after the traumatic experience, one third of patients with PTSD received psychiatric help, regardless of their sex, age, and employment status. Half of them had comorbid disorders and the majority of them were treated with anxiolytics and antidepressants.Posttraumatic stress disorder (PTSD) is a mental disorder that develops in 9-25% of war veterans (1-4), mainly in the first two years after the traumatic experience (5,6), but sometimes can develop years later (7,8). A similar prevalence was also found among Croatian war veterans (5-9). In the majority of cases (80-98%), PTSD is comorbid with other mental disorders: alcohol abuse, depression, anxiety disorders, and somatization (5,9-11).PTSD can also develop after a war-related trauma that is not necessarily combat-related, and the lifetime prevalence of PTSD in this population is 15-38% (12) and the prevalence of anxiety and depressive disorders is even higher (13,14).Many patients in Croatia had symptoms of PTSD and used health facilities for treatment years after the war (5-9). In the former Yugoslavia, 84% of untreated war-related PTSD patients still had PTSD symptoms years after the war (15). Resolution of PTSD is observed in 50-60% of cases (4,16).Combat-related PTSD causes more functional impairment and is less responsive to treatment than PTSD related to other traumas (17-19). It is unclear whether this happens because there is indeed a difference between the two types of PTSD or some of the patients aggravate their symptoms in order to get compensation (17,18,20). Some studies show that the use of health facilities decreases after obtaining war veteran status and compensation, but others show that the patients who had obtained the status and compensation used medical facilities more often than those who had not (20-23).The aim of this study was to establish how many patients diagnosed with PTSD in 1996 used psychiatric facilities and had psychiatric symptoms 10 years later and assess their comorbidities, sociodemographic characteristics, and type of treatment.     

Association of neural inflammation with hyperalgesia following spinal nerve ligation

Aim

To explain the variability in the behavioral response after spinal nerve ligation by investigating the relation between the development of neuropathic pain and the expression of inflammatory indicators, in dorsal root ganglia (DRG) and the spinal nerve.

Methods

Ninety-six male Sprague-Dawley rats were randomly assigned to the modified spinal nerve ligation, sham, and control group. Testing for pain-related behavior identified rats that successfully developed neuropathic pain (responders) and those which did not (non-responders). The extent of neuroinflammation in the two groups was assessed by immunohistochemical staining of dorsal root ganglions glial fibrillary acid protein (GFAP), and rat C3 complement receptor (OX-42).

Results

GFAP and OX-42 immunopositive cell density in the DRG and spinal nerve was significantly higher in hyperalgesic animals. DRG cell density was 3.96 ± 0.68 cells/2500 μm² in GFAP responders’ group, compared with 2.76 ± 0.75 cells/2500 μm² in non-responders’ group (Mann-Whitney U test, Z = -3.956, P<0.001). OX-42 density was 7.71 ± 1.03 cells/2500 μm²in responders and 4.75 ± 1.76 cells/2500 μm² in non responders (Mann-Whitney U test, Z = -2.572, P = 0.01). Hyperalgesic behavior progressively increased during the testing period, although immunopositive cell density peaked on the fourth day post-injury and progressively decreased afterwards.

Conclusion

Our study suggests that inflammation has a decisive role in initiating neuropathic pain. Also, this study confirms that, for the sake of selecting appropriate subjects for mechanistic study, it is necessary to discriminate between experimental subjects that develop pain completely and those that do not.In the last few decades, many different animal models of neuropathic pain have been developed in order to clarify the pathophysiological mechanisms of neuropathic pain (1). Most of these models are based on direct injury of sensory neurons, which in most cases leads to posttraumatic neuropathic pain, whose foremost important pathophysiological factor is immune activation (2). Therefore, when examining the potential role of immune activation in neuropathic pain, one has to take into consideration both classical immune cells such as macrophages, T lymphocytes, and immunocompetent cells (including endothelial cells, fibroblasts, and Schwann cells), which can release factors that are usually considered exclusively as immune-cell products, and immune-like spinal cord cells (astrocytes and microglia) (2).To date, studies have generally focused on the dynamics of inflammatory cell migration into nerve tissue (3) and microglial activation (4), but very few have correlated these with the process of neuropathic pain development (5,6). The majority of authors report only the average behavioral response level of all treated animals (7,8), regardless of the fact that there was substantial inconsistency in behavioral response after nerve injury (9,10). Currently, there is no explanation for these behavioral differences in animals that received the same treatment (11).The purpose of this study was to investigate the variability in the behavioral response after spinal nerve ligation. We focused on neuroinflammation in the dorsal root ganglion (DRG) and spinal nerve proximal to the injury site after spinal nerve ligation, which is characterized by activation of satellite glia cells as resident monocytic cells of the nervous system and the migration of blood circulating inflammatory cells (2,12). We compared the level of neuroinflammation between two groups of rats, one that displayed well-developed neuropathic signs (responders) and the other group that did not (non-responders). Our hypothesis was that local inflammation in the DRG and in the part of the spinal nerve proximal to the injury site differed significantly between responder and non-responder groups. If confirmed, this would suggest that inflammation has a decisive role in initiating neuropathic pain.     

Heterogeneity of posttraumatic stress disorder symptoms in Croatian war veterans: retrospective study

Aim

To determine the relationship between the intensity of combat-related posttraumatic stress disorder (PTSD) and the intensity of predominating symptoms.

Method

The study included 151 veterans from 1992-1995 war in Croatia with PTSD, aged 38.3 ± 7.3 years (mean ± standard deviation). The veterans were psychologically tested with the Mississippi Scale for Combat-related PTSD (M-PTSD), Questionnaire on Traumatic Combat and War Experiences (USTBI-M), and Minnesota Multiphasic Personality Inventory-version 201 (MMPI-201).

Results

The discriminative analysis of the data revealed that the group with lower PTSD intensity had the highest scores on MMPI scales D (depression, T-score 95.7 ± 5.6), Hs (hypochondriasis, 87.6 ± 5.1), and Hy (hysteria, 85.6 ± 4.9), whereas the group with higher PTSD intensity, besides these three scales (D = 98.3 ± 5.3; Hs = 90.1 ± 4.3; Hy = 89.5 ± 4.7), also had clinically significantly elevated Pt (psychastenia, 80.6 ± 5.6), Sc (schizophrenia, 79.6 ± 4.8), and Pa (paranoia, 85.6 ± 5.4) scales, with the highest Pa scale.

Conclusion

It was possible to differentiate study participants with different PTSD intensity on the basis of their MMPI profile. More intense PTSD was associated with externalized symptoms, such as aggression, acting-out, hostility, and mistrust, whereas less intensive PTSD was associated with mostly depressive symptoms. Our study showed that different intensity of PTSD has different symptom patterns.A person’s reaction to trauma depends on the traumatic situation itself, personality characteristics of the person exposed to trauma, and posttraumatic social environment. Most people develop some form of acute stress reaction to traumatic event, but in the majority of cases the stress-related difficulties spontaneously withdraw once the person is removed from the situation (1). Fewer people will develop chronic disorders which may evolve into a clinical picture of posttraumatic stress disorder (PTSD) (2). Symptoms that characterize PTSD include repeated re-experiencing of the trauma, emotional numbing, detachment, lack of affect, anhedonia, and avoidance of activities and situations reminiscent of the traumatic event (3).PTSD is often comorbid with other psychiatric disorders (4-7). Patients with PTSD often complain of psychosomatic disturbances, ranging from anxiety accompanied with tremor and restlessness to depressive problems with predominant cognitive aspects of depression (dark thoughts, shame, guilt, and suicidal thoughts and intentions) and to vegetative symptoms (insomnia and loss of appetite) (8). Comorbidity of PTSD with anxiety or depressive disorders is diagnosed in cases where anxiety or depressive symptoms are prevalent. Due to these psychiatric problems, patients with PTSD often resort to alcohol or drug abuse (4). Memory and concentration impairment, often present in PTSD, may seriously interfere with everyday functioning of these patients (9).Because PTSD symptoms are so heterogeneous, many researchers presume that there are different subtypes of the disorder. Previous attempts to determine different types of PTSD used different methodologic approaches (10-12). Some studies analyzed characteristics of PTSD with respect to predominant symptomatology (6,8), whereas others tried to associate PTSD symptoms with different types of stressors (12,13). Electrophysiological indicators of PTSD as well as the possibility to determine different types of PTSD on the basis of specific electrophysiological indicators were investigated (14,15).Further attempts to discern among different types of PTSD were based on personality tests, primarily Minnesota Multiphasic Personality Inventory (MMPI) (16), response to specific pharmacotherapy (17), and existing aggressive behavior (18-20). Recently, intensity of PTSD has been investigated as a factor that determines the type of the disorder (21-23).The aim of the present study was to determine the relationship between the intensity of PTSD and predominating symptoms in a sample of Croatian 1991-1995 war veterans.     

Shear-wave sonoelastographic features of invasive lobular breast cancers

AimTo evaluate shear-wave elastographic (SWE) and related gray-scale features of pure invasive lobular breast carcinoma (ILC) and compare them with invasive ductal breast cancers (IDC).MethodsQuantitative SWE features of mean (El-mean), maximum (El-max), minimum (El-min) elasticity values of the stiffest portion of the mass, and lesion-to-fat elasticity ratio (E-ratio) were measured in 40 patients with pure ILC and compared with 75 patients with IDC. Qualitative gray-scale features of lesion size, echogenicity, orientation, and presence of distal shadowing were determined and compared between the groups.ResultsILC were significantly larger than IDC (P = 0.008) and exhibited significantly higher El-max (P = 0.015) and higher El-mean (P = 0.008) than IDC. ILC were significantly more often horizontally oriented, while IDC were significantly more often vertically oriented (P < 0.001); ILC were significantly more often hyperechoic than IDC (P < 0.001). Differences in stiffness between ILC and IDC determined by quantitative SWE parameters were present only in small tumors (≤1.5 cm in size), ie, small ILC had significantly higher El-max (P = 0.030), El-mean (P = 0.014), and El-min (P = 0.045) than small IDC, while tumors larger than 1.5 cm had almost equal stiffness, without significant differences between the groups.ConclusionSpecific histopathologic features of ILC are translated into their qualitative sonographic and quantitative sonoelastographic appearance, with higher stiffness of small ILC compared to small IDC. Gray-scale and sonoelastographic features may help in diagnosing ILC.Invasive ductal cancer (IDC) is the most common breast cancer, while invasive lobular cancer (ILC) is the second most common and accounts for 6%-12% of breast cancers (1-3). ILC differs considerably from IDC by having a unique pathological growth pattern, the so called Indian-file pattern, with sheets of single-cell layers growing along the Cooper ligaments, ductuli, and other breast structures, resembling a spiderweb that diffusely spreads in the breast, producing minor desmoplastic reaction (4,5). This spiderweb-like growth is reflected in imaging features of ILC, as well as in its clinical presentation (6). IDC usually clinically manifests as a firm lump, while ILC usually manifests as a palpable thickening and skin or nipple retraction (3,5). ILC has increased tendency for multifocality and multicentricity, a higher risk of bilateral breast cancer (20%-29%), and older age at onset (7,8). Lymph node metastases are less common in ILC than in IDC of equal size, because ILC tumor cells lack cellular atypia and often have low mitotic rate (9). ILC has the propensity to metastasize to the chest, peritoneum, retroperitoneum, and pelvis (10).Because of its growth pattern of mass infiltrating surrounding tissues, IDC is much more easily detected than ILC also on mammography. ILC has higher false-negative mammographic rates than IDC, since ILC may be invisible or may have quite low mammographic density, and microcalcifications are uncommon (6,11). Due to the higher propensity for multicentric and bilateral lesions, it is generally considered that patients with ILC should be referred to preoperative breast MRI, the best imaging modality to evaluate the tumor extent, while the benefit for preoperative MRI in IDC has not yet been proven (12,13). Fine-needle aspiration is not as sensitive for the diagnosis of ILC as it is for IDC, and core-biopsy should be performed when ILC is suspected, even in cases of palpable lesions (14,15). ILC is associated more often than IDC with positive margins on surgical excision and is more often treated with mastectomy, because of the large size at diagnosis and underestimation of tumor extent with conventional imaging (16).Ultrasound of the breast is widely used in the diagnosis of breast cancer, usually after mammography, and most image-guided core biopsies of breast lesions are routinely performed under the sonographic guidance (17,18). Ultrasound is highly operator-dependent, much more than mammography or MRI. The quality of ultrasonic equipment and transducers is variable, suboptimal examinations are common, and interobserver variability is high; sensitivity of ultrasound in detection of ILC is reported in the range of 68%-88% (6,12,19).Sonoelastography is a relatively new ultrasonographic method, which may help in the detection and differentiation of benign and malignant breast lesions (18,20). Strain elastography allows qualitative estimation of the breast lesion stiffness, while shear-wave elastography (SWE) allows quantification of lesion stiffness in kilopascals (kPa) (18). Multicentric studies found that SWE features can help discriminate breast cancers and benign breast lesions, and breast cancers among themselves (20-22). It was also shown that some IDC, like triple negative breast cancers, differ in their stiffness compared to other IDC (23). Studies evaluating some SWE features of invasive cancers were done in a small number of patients with ILC, but to the best of our knowledge none so far has provided values specific for a larger, homogeneous group of patients with pure ILC (24,25).The aim of this single-center study was to evaluate and establish SWE and related conventional sonographic features of pure ILC of the breast in a group of 40 patients, and to compare these features with the most common invasive breast cancer, IDC. SWE features within ILC group were also correlated with tumor size, extent, histologic grade, and the presence of nodal metastases.     

Alcohol abuse as the strongest risk factor for violent offending in patients with paranoid schizophrenia

Aim

To determine predictive risk factors for violent offending in patients with paranoid schizophrenia in Croatia.

Method

The cross-sectional study including male in-patients with paranoid schizophrenia with (N = 104) and without (N = 102) history of physical violence and violent offending was conducted simultaneously in several hospitals in Croatia during one-year period (2010-2011). Data on their sociodemographic characteristics, duration of untreated illness phase (DUP), alcohol abuse, suicidal behavior, personality features, and insight into illness were collected and compared between the groups. Binary logistic regression model was used to determine the predictors of violent offending.

Results

Predictors of violent offending were older age, DUP before first contact with psychiatric services, and alcohol abuse. Regression model showed that the strongest positive predictive factor was harmful alcohol use, as determined by AUDIT test (odds ratio 37.01; 95% confidence interval 5.20-263.24). Psychopathy, emotional stability, and conscientiousness were significant positive predictive factors, while extroversion, pleasantness, and intellect were significant negative predictive factors for violent offending.

Conclusion

This study found an association between alcohol abuse and the risk for violent offending in paranoid schizophrenia. We hope that this finding will help improve public and mental health prevention strategies in this vulnerable patient group.Individuals with schizophrenia have an increased risk of violence (1), but different studies report different risks (1,2). Anglo-American studies commonly report higher prevalence rates than European studies (3,4). These patients have also been reported to have up to 4-6 times higher violent behavior rate than the general population (3-5). Nonetheless, less than 0.2% patients suffering from schizophrenia commit homicide (in 20-year period) and less than 10% of commit a violent act (3). Also, patients with schizophrenia contribute to 6%-11% of all homicides and homicide attempts (3-5).In general, aggressiveness is usually associated with anti-social personality features, juvenile delinquency, and psychoactive substance abuse (6). In patients with schizophrenia violence and violent offending is associated with a great number of risk factors, such as premorbid affinity to violent behavior, alcohol abuse, younger age, lower socioeconomic status (6,7), deinstitutionalization, longer duration of untreated psychosis, later onset of first episode of psychosis (1,4,8), lower social status, broken families, asocial behavior of parents, loss of father at an early age, a new marriage partner in the family, and growing up in an orphanage (9).Several studies (10-12) looked at four basic personality dimensions and their role in violence in patients with schizophrenic illness spectrum: impulse control, affect regulation, narcissism, and paranoid cognition. Impulsivity and immature affect regulation were associated with most neuropsychiatric disorders, and were particularly predictive of affinity for addictive disorders, while paranoid cognition and narcissism were predictive of violence acts (10-12).The causes of schizophrenia may be genetic, early environmental, and epigenetic risk factors (13,14), which may further modulate the risk of violent offending among individuals with this disease (1,15). Until recently, very little has been reported about the predictive factors of violence and violent offending in the patient population in Croatia. The Croatian population has during the last two decades been exposed to environmental and socio-demographic changes (eg, Croatian War 1991-1995 and post-war period), which might have had an impact on predictive risk factors. Therefore, we conducted a cross-sectional study of in-patients with paranoid schizophrenia with or without history of physical violence and violent offending (inclusive of homicide) in several hospitals in Croatia during one-year period.     

Circulating lymphocyte subsets, natural killer cell cytotoxicity, and components of hypothalamic-pituitary-adrenal axis in Croatian war veterans with posttraumatic stress disorder: cross-sectional study

Aim

To determine peripheral blood lymphocyte subsets – T cells, helper T cells, cytotoxic T cells, B cells, and natural killer cells, natural killer cell cytotoxicity, serum cortisol concentration, and lymphocyte glucocorticoid receptor expression in Croatian combat veterans diagnosed with chronic posttraumatic stress disorder (PTSD); and to examine the relationship between the assessed parameters and the time passed since the traumatic experience.

Methods

Well-characterized group of 38 PTSD patients was compared to a group of 24 healthy civilians. Simultaneous determination of lymphocyte subsets and the expression of intracellular glucocorticoid receptor was performed using three-color flow cytometry. Natural killer cell cytotoxicity was measured by ⁵¹Cr-release assay and the serum cortisol concentration was determined by radioimmunoassay.

Results

We found higher lymphocyte counts in PTSD patients than in healthy controls (2294.7 ± 678.0/μL vs 1817.2 ± 637.0/μL, P = 0.007) and a positive correlation between lymphocyte glucocorticoid receptor expression and the number of years that passed from the traumatic experience (r_s = 0.43, P = 0.008). Lymphocyte glucocorticoid receptor expression positively correlated with serum cortisol concentration both in PTSD patients (r = 0.46, P = 0.006) and healthy controls (r = 0.46, P = 0.035).

Conclusion

This study confirmed that the immune system was affected in the course of chronic PTSD. Our findings also indicated that the hypothalamic-pituitary-adrenal axis profile in PTSD was associated with the duration of the disorder. Due to the lack of power, greater sample sizes are needed to confirm the results of this study.Prolonged or frequently repeated stress response during symptomatic episodes in chronic posttraumatic stress disorder (PTSD) can result in neuroendocrine and immune alterations, posing serious threat to mental and physical health (1,2). Evidence suggests that PTSD is related to increased medical morbidity, particularly from cardiovascular and autoimmune diseases (3). With controversial findings when neurobiology of PTSD is concerned, the patophysiological mechanisms underlying increased susceptibility to disease are not clear (4,5). However, it has been implicated that the sympathetic-adrenal-medullary (SAM) and the hypothalamic-pituitary-adrenal axes are the key mediators in this process (6,7).The immune system interacts with the hypothalamic-pituitary-adrenal axis in a bidirectional fashion to maintain homeostasis. Being the primary effector of the stress response, cortisol modifies the complex cytokine network and, consequently, leukocyte function and recirculation (8). These effects are achieved through its interaction with the specific intracellular glucocorticoid receptors (9).Studies of the leukocyte recirculation (10,11), immune cells function (12), and hypothalamic-pituitary-adrenal axis activity (5) in PTSD yielded controversial results. Overall findings support the hypothesis that immune activation in PTSD may be associated with Th2 cytokine shift and alterations in the proinflammatory cytokine system (4). Besides, it is believed that PTSD is linked with low plasma cortisol levels and higher glucocorticoid receptor expression, suggesting enhanced feedback sensitivity to cortisol (13). In contrast to these findings, Gotovac et al (14) showed that Croatian combat veterans with PTSD, approximately 6 years after traumatic event, had lower expression of glucocorticoid receptor in lymphocyte subsets, with higher serum cortisol concentration than healthy subjects. Majority of other studies did not take into account the time passed since the trauma and their samples mainly included Vietnam veterans (15) or Holocaust survivors (16), who had greater time gap since the traumatic experience than Croatian war veterans.Considering the strong discrepancies in the results published to date, we performed a cross-sectional study to evaluate the correlation between PTSD in Croatian combat war veterans and the percentages of circulating lymphocyte subsets, natural killer cell cytotoxicity as a measure of immune function, and the serum cortisol concentration with lymphocyte glucocorticoid receptor expression as components of hypothalamic-pituitary-adrenal axis. The emphasis was put on the relationship between the assessed parameters and the time passed since the traumatic experience.     

Regional differences in incidence and clinical presentation of type 1 diabetes in children aged under 15 years in Croatia

Aim

To determine regional differences in the incidence, incidence trends, and clinical presentation of type 1 diabetes in children under the age of 15 years in Croatia in a 9-year period (1995-2003).

Methods

We included the patients who had been diagnosed with the disease and had started the insulin treatment before they were 15 years old. Regional differences between eastern, central, and southern Croatia were observed. The gross incidence was expressed by the number of newly diagnosed type 1 diabetes patients in 100 000 children of the same age and sex per year, ie, for the 0-14 age group, and for the 0-4, 5-9, and 10-14 subgroups.

Results

The highest incidence was observed in southern Croatia (10.91 per 100 000/y) and the lowest in central Croatia (8.64 per 100 000/y), and in eastern Croatia the incidence was 8.93 per 100 000/y. All three regions showed a growing incidence trend, which was significant only in eastern and southern Croatia. There was 35.9% of patients with diabetic ketoacidosis in eastern Croatia, 41.7% in central Croatia, and 31.3% in southern Croatia.

Conclusion

Croatian regions show differences in the incidence, incidence trends, and disease presentation of type 1 diabetes. A further follow-up is needed to establish whether the regional differences are a consequence of the population dynamics in the observed period or they will continue to exist, pointing to differences in environmental risk factors.The incidence of type 1 diabetes is highest in Finland, amounting to 40.9/100 000/y, and lowest in China and Venezuela, amounting to 0.1/100 000/y (1). It varies up to by 10 times among European countries, and as much as by 400 times globally (2). These variations are mainly caused by differences in the genetic makeup of specific ethnic groups and diverse environmental factors (3,4).Sometimes countries of a certain region have similar incidence patterns despite their genetic and long-standing socio-economic differences. A good example are Hungary (7.87/100 000/y), Austria (9.5/100 000/y), the Czech Republic (9.8/100 000/y), and Slovakia (9.2/100 000/y) (5,6). In contrast to this, certain bordering countries sharing the same genetic pool show considerable differences in their incidence rates, ie, Spain and Portugal, and Finland and the Russian province Karelia (7,8). Such cases have not only been recorded in Europe, but also in America. While the incidence for Puerto Rico is the same as for the majority of the US states (17/100 000/y), the neighboring Cuba has a considerably lower incidence, with fewer than 3 patients per 100 000/y (9).Differences in the incidence rates have been recorded even among the regions of the same country (5,10-14). In some cases, this may be explained by the presence of a certain ethnic minority (14) with a different genetic base than the majority population. However, variations are sometimes noted in genetically more homogeneous populations, which points to environmental factors as the possible cause of the differences (10,11). Some studies have shown that changes in the incidence in different regions do not necessarily follow the same pattern over a course of time (15).Establishing the regional distribution of a disease is an important epidemiological method, which may lead to certain etiological hypotheses (10). Since the national incidence and clinical presentation patterns of type 1 diabetes in Croatia had already been established (16,17), the aim of this study was to determine regional differences in the incidence, incidence trends, and clinical presentation of type 1 diabetes in children under the age of 15 years within a 9-year period.     

Sex-specific chronic stress response at the level of adrenal gland modifies sexual hormone and leptin receptors

Aim

To compare cardiometabolic risk-related biochemical markers and sexual hormone and leptin receptors in the adrenal gland of rat males, non-ovariectomized females (NON-OVX), and ovariectomized females (OVX) under chronic stress.

Methods

Forty six 16-week-old Sprague-Dawley rats were divided into male, NON-OVX, and OVX group and exposed to chronic stress or kept as controls. Weight, glucose tolerance test (GTT), serum concentration of glucose, and cholesterol were measured. Adrenal glands were collected at the age of 28 weeks and immunohistochemical staining against estrogen beta (ERβ), progesterone (PR), testosterone (AR), and leptin (Ob-R) receptors was performed.

Results

Body weight, GTT, serum cholesterol, and glucose changed in response to stress as expected and validated the applied stress protocol. Stressed males had significantly higher number of ERβ receptors in comparison to control group (P = 0.028). Stressed NON-OVX group had significantly decreased AR in comparison to control group (P = 0.007). The levels of PR did not change in any consistent pattern. The levels of Ob-R increased upon stress in all groups, but the significant difference was reached only in the case of stressed OVX group compared to control (P = 0.033).

Conclusion

Chronic stress response was sex specific. OVX females had similar biochemical parameters as males. Changes upon chronic stress in adrenal gland were related to a decrease in testosterone receptor in females and increase in estrogen receptor in males.Maintaining homeostasis is often challenged by different types of stressors (1). Homeostasis is regulated by a complex endocrine processes engaging the hypothalamic-pituitary-adrenal axis (HPA) and sympathetic autonomic system (2-4). Stress can occur either in acute or chronic form with different consequences – the acute stress mostly induces the ˝fight or flight˝ response, while chronic stress promotes long term changes, which can lead to a variety of diseases (5,6). If stress is of sufficient magnitude and duration, the action of HPA is unsuppressed and results in prolonged elevation of cortisol (7), induced production of energy, vasoconstriction, lipolysis, proteolysis, immunosuppression, and suppression of reproductive function to save energy and retain overall homeostasis (8). Women are generally less susceptible to chronic stress up to the period of menopause, when the loss of protective hormones, estrogen and progesterone, occurs and thus they become prone to development of depression, anxiety, or schizophrenia (9). In contrast, men are generally more susceptible and sensitive to chronic stress, showing changes in feeding habits and decreased body weight (10,11).Chronic stress can cause the development of cardiovascular disorder, obesity, and diabetes, which can be reflected in serum cholesterol, glucose, and decreased glucose tolerance (12-14). There is a strong correlation between stress and sexual hormones, but the mechanisms by which estrogen, testosterone, and progesterone exert their possible protective role under stress conditions are not fully explored. Sexual hormones affect stress outcome and stress hormones affect the levels of sexual hormones (15-17). Testosterone is activated during stress response in rats and humans (18,19) and tends to increase more in men than women (20). Estrogen lowers the stress-induced response in women and men (9,21). Estrogens and progesterone are produced even after ovariectomy by adrenal glands (22) but it is not known if such compensation can withstand additional challenge like stress. Another possible player in stress response is leptin (Ob), hormone responsible for maintaining body weight, which is synthesized and secreted by adipose tissue (23), exerting its effects through the leptin receptor (Ob-R) (24). Chronic stress models imply a direct link between stress response and leptin (25,26). Receptors for leptin are present in the adrenal gland (27). The aim of this study was to investigate cardiovascular risk parameters and changes in leptin and sexual hormone receptors in adrenal gland during chronic stress. There is a clinically relevant change in the onset of cardiometabolic risk between healthy women and women with premature ovarian failure (28) and because of that ovariectomized female rats were included in the study.     

The involvement of noradrenergic mechanisms in the suppressive effects of diazepam on the hypothalamic-pituitary-adrenal axis activity in female rats

Aim

To elucidate the involvement of noradrenergic system in the mechanism by which diazepam suppresses basal hypothalamic-pituitary-adrenal (HPA) axis activity.

Methods

Plasma corticosterone and adrenocorticotropic hormone (ACTH) levels were determined in female rats treated with diazepam alone, as well as with diazepam in combination with clonidine (α₂-adrenoreceptor agonist), yohimbine (α₂-adrenoreceptor antagonist), alpha-methyl-p-tyrosine (α-MPT, an inhibitor of catecholamine synthesis), or reserpine (a catecholamine depleting drug) and yohimbine.

Results

Diazepam administered in a dose of 2.0 mg/kg suppressed basal HPA axis activity, ie, decreased plasma corticosterone and ACTH levels. Pretreatment with clonidine or yohimbine failed to affect basal plasma corticosterone and ACTH concentrations, but abolished diazepam-induced inhibition of the HPA axis activity. Pretreatment with α-MPT, or with a combination of reserpine and yohimbine, increased plasma corticosterone and ACTH levels and prevented diazepam-induced inhibition of the HPA axis activity.

Conclusion

The results suggest that α₂-adrenoreceptors activity, as well as intact presynaptic noradrenergic function, are required for the suppressive effect of diazepam on the HPA axis activity.Benzodiazepines are used for their anxiolytic, sedative-hypnotic, muscle relaxant, and anticonvulsant properties in the treatment of a variety of neuropsychiatric disorders (1,2), including anxiety and depression, which are often related to disturbances in the activity of hypothalamic-pituitary-adrenal (HPA) axis (3,4). Although these drugs exert most of their pharmacological effects via γ-aminobutyric acid_A (GABA_A) receptors (5,6), benzodiazepine administration has been associated with alterations in neuroendocrine function both in experimental animals and humans (7-9). However, even after years of extensive studies, the complex mechanisms by which these widely used drugs produce their effects on the HPA axis are still not known.Although most of the previous studies have demonstrated that classical benzodiazepines such as diazepam decrease the HPA axis activity in stressful contexts (10-14), under basal conditions they have been shown to stimulate (9,11,15-18), inhibit (15,19-22), and not affect (17,23-25) the HPA axis activity. Such diverse results might be related to several factors such as the dose and gender (15,16,20,21,26-28), or may also be a consequence of the net effect of non-selective benzodiazepines on the various GABA_A receptor isoforms (9).Our previous studies demonstrated that while diazepam (1 mg/kg) produced no change in plasma corticosterone levels in male rats (15,20), it decreased basal levels of corticosterone in female rats (15,26). However, although diazepam inhibited the HPA axis activity of female rats following administration of lower doses (1 or 2 mg/kg) (15,20,21,26), it stimulated the HPA axis activity following administration of high doses (10 mg/kg) (15,16,26). Moreover, whereas the suppressive effect of the lower doses of diazepam (2.0 mg/kg) on the HPA axis activity in female rats involves the GABA_A receptor complex (21), increases in corticosterone levels by a higher dose of diazepam (10 mg/kg) do not involve the stimulation of GABA_A receptors (16). In addition, stimulatory effect of 10 mg/kg diazepam on the HPA axis activity in rats seems not to be mediated by the benzodiazepine/GABA/channel chloride complex or by peripheral benzodiazepine receptors, but rather by a cyclic adenosine monophosphate (AMP)-dependent mechanism (18).Since our previous results suggested that the effect of a high dose of diazepam on the activity of the HPA axis in female rats might be due to a blockade of α₂-adrenergic receptors (16), the aim of this study was to elucidate whether noradrenergic system also has a modulatory role in the inhibitory effect of 2.0 mg/kg diazepam on basal plasma adrenocorticotropic hormone (ACTH) and corticosterone levels in female rats.