Mutations in the tail and rod domains of the neurofilament heavy-chain gene increase the risk of ALS.

OBJECTIVE: Neurofilament heavy-chain gene (NEFH) variants are associated with multiple neurodegenerative diseases, however, their relationship with ALS has not been robustly explored. Still, NEFH is commonly included in genetic screening panels worldwide. We therefore aimed to determine if NEFH variants modify ALS risk. METHODS: Genetic data of 11,130 people with ALS and 7,416 controls from the literature and Project MinE were analysed. We performed meta-analyses of published case-control studies reporting NEFH variants, and variant analysis of NEFH in Project MinE whole-genome sequencing data. RESULTS: Fixed-effects meta-analysis found that rare (MAF <1%) missense variants in the tail domain of NEFH increase ALS risk (OR 4.55, 95% CI 2.13-9.71, p < 0.0001). In Project MinE, ultrarare NEFH variants increased ALS risk (OR 1.37 95% CI 1.14-1.63, p = 0.0007), with rod domain variants (mostly intronic) appearing to drive the association (OR 1.45 95% CI 1.18-1.77, pMadsen-Browning = 0.0007, pSKAT-O = 0.003). While in the tail domain, ultrarare (MAF <0.1%) pathogenic missense variants were also associated with higher risk of ALS (OR 1.94, 95% CI 0.86-4.37, pMadsen-Browning = 0.039), supporting the meta-analysis results. Finally, several tail in-frame deletions were also found to affect disease risk, however, both protective and pathogenic deletions were found in this domain, highlighting an intricated architecture that requires further investigation. INTERPRETATION: We showed that NEFH tail missense and in-frame deletion variants, and intronic rod variants are risk factors for ALS. However, they are not variants of large effect, and their functional impact needs to be clarified in further studies. Therefore, their inclusion in routine genetic screening panels should be reconsidered.

Genetic variability in sporadic amyotrophic lateral sclerosis.

With the advent of gene therapies for amyotrophic lateral sclerosis (ALS), there is a surge in gene testing for this disease. Although there is ample experience with gene testing for C9orf72, SOD1, FUS and TARDBP in familial ALS, large studies exploring genetic variation in all ALS-associated genes in sporadic ALS (sALS) are still scarce. Gene testing in a diagnostic setting is challenging, given the complex genetic architecture of sALS, for which there are genetic variants with large and small effect sizes. Guidelines for the interpretation of genetic variants in gene panels and for counselling of patients are lacking. We aimed to provide a thorough characterization of genetic variability in ALS genes by applying the American College of Medical Genetics and Genomics (ACMG) criteria on whole genome sequencing data from a large cohort of 6013 sporadic ALS patients and 2411 matched controls from Project MinE. We studied genetic variation in 90 ALS-associated genes and applied customized ACMG-criteria to identify pathogenic and likely pathogenic variants. Variants of unknown significance were collected as well. In addition, we determined the length of repeat expansions in C9orf72, ATXN1, ATXN2 and NIPA1 using the ExpansionHunter tool. We found C9orf72 repeat expansions in 5.21% of sALS patients. In 50 ALS-associated genes, we did not identify any pathogenic or likely pathogenic variants. In 5.89%, a pathogenic or likely pathogenic variant was found, most commonly in SOD1, TARDBP, FUS, NEK1, OPTN or TBK1. Significantly more cases carried at least one pathogenic or likely pathogenic variant compared to controls (odds ratio 1.75; P-value 1.64 × 10-5). Isolated risk factors in ATXN1, ATXN2, NIPA1 and/or UNC13A were detected in 17.33% of cases. In 71.83%, we did not find any genetic clues. A combination of variants was found in 2.88%. This study provides an inventory of pathogenic and likely pathogenic genetic variation in a large cohort of sALS patients. Overall, we identified pathogenic and likely pathogenic variants in 11.13% of ALS patients in 38 known ALS genes. In line with the oligogenic hypothesis, we found significantly more combinations of variants in cases compared to controls. Many variants of unknown significance may contribute to ALS risk, but diagnostic algorithms to reliably identify and weigh them are lacking. This work can serve as a resource for counselling and for the assembly of gene panels for ALS. Further characterization of the genetic architecture of sALS is necessary given the growing interest in gene testing in ALS.

Large-scale analyses of CAV1 and CAV2 suggest their expression is higher in post-mortem ALS brain tissue and affects survival.

Introduction: Caveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role in amyotrophic lateral sclerosis (ALS). Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead to disruption of membrane lipid rafts. Methods: Using large ALS whole-genome sequencing and post-mortem RNA sequencing datasets (5,987 and 365 tissue samples, respectively), and iPSC-derived motor neurons from 55 individuals, we investigated the role of CAV1/2 expression and enhancer variants in the ALS phenotype. Results: We report a differential expression analysis between ALS cases and controls for CAV1 and CAV2 genes across various post-mortem brain tissues and three independent datasets. CAV1 and CAV2 expression was consistently higher in ALS patients compared to controls, with significant results across the primary motor cortex, lateral motor cortex, and cerebellum. We also identify increased survival among carriers of CAV1/2 enhancer mutations compared to non-carriers within Project MinE and slower progression as measured by the ALSFRS. Carriers showed a median increase in survival of 345 days. Discussion: These results add to an increasing body of evidence linking CAV1 and CAV2 genes to ALS. We propose that carriers of CAV1/2 enhancer mutations may be conceptualised as an ALS subtype who present a less severe ALS phenotype with a longer survival duration and slower progression. Upregulation of CAV1/2 genes in ALS cases may indicate a causal pathway or a compensatory mechanism. Given prior research supporting the beneficial role of CAV1/2 expression in ALS patients, we consider a compensatory mechanism to better fit the available evidence, although further investigation into the biological pathways associated with CAV1/2 is needed to support this conclusion.

The SOD1-mediated ALS phenotype shows a decoupling between age of symptom onset and disease duration.

Superoxide dismutase (SOD1) gene variants may cause amyotrophic lateral sclerosis, some of which are associated with a distinct phenotype. Most studies assess limited variants or sample sizes. In this international, retrospective observational study, we compare phenotypic and demographic characteristics between people with SOD1-ALS and people with ALS and no recorded SOD1 variant. We investigate which variants are associated with age at symptom onset and time from onset to death or censoring using Cox proportional-hazards regression. The SOD1-ALS dataset reports age of onset for 1122 and disease duration for 883 people; the comparator population includes 10,214 and 9010 people respectively. Eight variants are associated with younger age of onset and distinct survival trajectories; a further eight associated with younger onset only and one with distinct survival only. Here we show that onset and survival are decoupled in SOD1-ALS. Future research should characterise rarer variants and molecular mechanisms causing the observed variability.

The Effect of SMN Gene Dosage on ALS Risk and Disease Severity.

OBJECTIVE: The role of the survival of motor neuron (SMN) gene in amyotrophic lateral sclerosis (ALS) is unclear, with several conflicting reports. A decisive result on this topic is needed, given that treatment options are available now for SMN deficiency. METHODS: In this largest multicenter case control study to evaluate the effect of SMN1 and SMN2 copy numbers in ALS, we used whole genome sequencing data from Project MinE data freeze 2. SMN copy numbers of 6,375 patients with ALS and 2,412 controls were called from whole genome sequencing data, and the reliability of the calls was tested with multiplex ligation-dependent probe amplification data. RESULTS: The copy number distribution of SMN1 and SMN2 between cases and controls did not show any statistical differences (binomial multivariate logistic regression SMN1 p = 0.54 and SMN2 p = 0.49). In addition, the copy number of SMN did not associate with patient survival (Royston-Parmar; SMN1 p = 0.78 and SMN2 p = 0.23) or age at onset (Royston-Parmar; SMN1 p = 0.75 and SMN2 p = 0.63). INTERPRETATION: In our well-powered study, there was no association of SMN1 or SMN2 copy numbers with the risk of ALS or ALS disease severity. This suggests that changing SMN protein levels in the physiological range may not modify ALS disease course. This is an important finding in the light of emerging therapies targeted at SMN deficiencies. ANN NEUROL 2021;89:686-697.

Changes in Neuroendovascular Procedural Volume During the COVID-19 Pandemic: An International Multicenter Study.

BACKGROUND AND PURPOSE: The effect of coronavirus disease 2019 (COVID-19) pandemic on performance of neuroendovascular procedures has not been quantified. METHODS: We performed an audit of performance of neuroendovascular procedures at 18 institutions (seven countries) for two periods; January-April 2019 and 2020, to identify changes in various core procedures. We divided the region where the hospital was located based on the median value of total number of COVID-19 cases per 100,00 population-into high and low prevalent regions. RESULTS: Between 2019 and 2020, there was a reduction in number of cerebral angiograms (30.9% reduction), mechanical thrombectomy (8% reduction), carotid artery stent placement for symptomatic (22.7% reduction) and asymptomatic (43.4% reduction) stenoses, intracranial angioplasty and/or stent placement (45% reduction), and endovascular treatment of unruptured intracranial aneurysms (44.6% reduction) and ruptured (22.9% reduction) and unruptured brain arteriovenous malformations (66.4% reduction). There was an increase in the treatment of ruptured intracranial aneurysms (10% increase) and other neuroendovascular procedures (34.9% increase). There was no relationship between procedural volume change and intuitional location in high or low COVID-19 prevalent regions. The procedural volume reduction was mainly observed in March-April 2020. CONCLUSIONS: We provided an international multicenter view of changes in neuroendovascular practices to better understand the gaps in provision of care and identify individual procedures, which are susceptible to change.

Native High-Density Lipoprotein and Melatonin Improve Platelet Response Induced by Glycated Lipoproteins.

Activated platelets and glycated lipoproteins are responsible for atherothrombosis in diabetics. Melatonin and native high-density lipoproteins are crucial in the preservation of pro/oxidant-antioxidant balance. The aim of the present study was to investigate the in vitro effects of native high-density lipoproteins and melatonin on altering the platelet response induced by glycated lipoproteins. Low-density lipoproteins and high-density lipoproteins were purified from plasma by ultracentrifugation and were glycated with glucose for three weeks. After incubation with or without melatonin/or native highdensity lipoproteins, low-density lipoproteins, glycated low-density lipoproteins/glycated high-density lipoproteins were added to ADP-induced platelets. Oxidative parameters, caspase-3/9 and nitric oxide levels were measured spectrophotometrically; CD62-P/ annexin-V expression was determined by flow cytometry. In glycated low-density lipoprotein/glycated high-density lipoprotein-treated groups, platelet malondialdehyde/ protein carbonyl, P-selectin, annexin-V, caspase-3/9 levels were increased (ranging from P < 0.001 to P < 0.01); glutathione and nitric oxide levels were reduced (ranging from P < 0.001 to P < 0.01). In glycated low-density lipoprotein/glycated high-density lipoprotein-treated groups, melatonin treatment reduced malondialdehyde, protein carbonyl, CD62-P, annexin-V and caspase-3/9 (P < 0.001, P < 0.01) levels and elevated nitric oxide (only glycated low-density lipoproteins). In glycated low-density lipoprotein/glycated high-density lipoprotein-treated groups, native high-density lipoprotein treatment reduced malondialdehyde, protein carbonyl, annexin-V, caspase-3/9 levels (P < 0.001, P < 0.01) and increased glutathione; nitric oxide levels (only with gly-HDL). Both melatonin and high-density lipoproteins should be regarded as novel promising mechanism-based potential therapeutic targets to prevent atherothrombosis in diabetics.

Endovascular treatment for acute ischemic stroke patients: implications and interpretation of IMS III, MR RESCUE, and SYNTHESIS EXPANSION trials: A report from the Working Group of International Congress of Interventional Neurology.

OBJECTIVE: The results of Interventional Management of Stroke (IMS) III, Magnetic Resonance and REcanalization of Stroke Clots Using Embolectomy (MR RESCUE), and SYNTHESIS EXPANSION trials are expected to affect the practice of endovascular treatment for acute ischemic stroke. The purpose of this report is to review the components of the designs and methods of these trials and to describe the influence of those components on the interpretation of trial results. METHODS: A critical review of trial design and conduct of IMS III, MR RESCUE, and SYNTHESIS EXPANSION is performed with emphasis on patient selection, shortcomings in procedural aspects, and methodology of data ascertainment and analysis. The influence of each component is estimated based on published literature including multicenter clinical trials reporting on endovascular treatment for acute ischemic stroke and myocardial infarction. RESULTS: We critically examined the time interval between symptom onset and treatment and rates of angiographic recanalization to differentiate between "endovascular treatment" and "parameter optimized endovascular treatment" as it relates to the IMS III, MR RESCUE, and SYNTHESIS EXPANSION trials. All the three trials failed to effectively test "parameter optimized endovascular treatment" due to the delay between symptom onset and treatment and less than optimal rates of recanalization. In all the three trials, the magnitude of benefit with endovascular treatment required to reject the null hypothesis was larger than could be expected based on previous studies. The IMS III and SYNTHESIS EXPANSION trials demonstrated that rates of symptomatic intracerebral hemorrhages subsequent to treatment are similar between IV thrombolytics and endovascular treatment in matched acute ischemic stroke patients. The trials also indirectly validated the superiority/equivalence of IV thrombolytics (compared with endovascular treatment) in patients with minor neurological deficits and those without large vessel occlusion on computed tomographic/magnetic resonance angiography. CONCLUSIONS: The results do not support a large magnitude benefit of endovascular treatment in subjects randomized in all the three trials. The possibility that benefits of a smaller magnitude exist in certain patient populations cannot be excluded. Large magnitude benefits can be expected with implementation of "parameter optimized endovascular treatment" in patients with ischemic stroke who are candidates for IV thrombolytics.

Effects of physiologic testosterone therapy on quality of life, self-esteem, and mood in women with primary ovarian insufficiency.

OBJECTIVE: Women with primary ovarian insufficiency (POI) display low androgen levels, which could contribute to mood and behavioral symptoms observed in this condition. We examined the effects of physiologic testosterone therapy added to standard estrogen/progestin therapy on quality of life, self-esteem, and mood in women with POI. METHODS: One hundred twenty-eight women with 46,XX spontaneous POI participated in a 12-month randomized, placebo-controlled, parallel-design investigation of the efficacy of testosterone augmentation of estrogen/progestin therapy. Quality of life, self-esteem, and mood symptoms were evaluated with standardized rating scales and a structured clinical interview. Differences in outcome measures between the testosterone and placebo treatments were analyzed by Wilcoxon rank sum tests. RESULTS: No differences in baseline characteristics, including serum hormone levels (P > 0.05), were found. Baseline mean (SD) Center for Epidemiologic Studies Depression Scale scores were 10.7 (8.6) and 9.2 (7.8) for testosterone and placebo, respectively (P = 0.35). After 12 months of treatment, measures of quality of life, self-esteem, and mood symptoms did not differ between treatment groups. Serum testosterone levels achieved physiologic levels in the testosterone group and were significantly higher compared with placebo (P < 0.001). Baseline testosterone levels were not associated with either adverse or beneficial clinical effects. CONCLUSIONS: A 150-µg testosterone patch achieves physiologic hormone levels in women with POI. Our findings suggest that augmentation of standard estrogen/progestin therapy with physiologic testosterone therapy in young women with POI neither aggravates nor improves baseline reports of quality of life or self-esteem and had minimal effects on mood. Other mechanisms might play a role in the altered mood accompanying this disorder.

Eligibility determination for intravenous thrombolysis based on radiology interpretation report of the head CT scan in patients with acute ischemic stroke.

OBJECTIVE: To evaluate the variability of determining eligibility for intravenous thrombolysis (IV t-PA) by a stroke team interpretation of computed tomographic (CT) scan of the head versus review of the radiology interpretation (presented in final report) in patients with acute ischemic stroke. METHODS: We compiled a database of all IV t-PA-treated ischemic stroke patients at our academic institution based on the stroke team's CT scan interpretation. The CT scan reports of 171 patients were reviewed by an independent board-certified vascular neurologist who was blinded to clinical information except that all patients were being considered for IV t-PA to determine their eligibility for thrombolysis. The reviewer's responses were then compared with the treating team's decision to identify discrepancies, and the impact of the discrepant decisions on clinical outcome including 24-hour National Institute of Health stroke Scale (NIHSS) score and discharge modified Rankin scale (mRS), symptomatic hemorrhage (sICH), and asymptomatic hemorrhage (aICH). We compared the outcomes of patients who received IV t-PA despite cautionary neuroradiologist interpretation and placebo-treated patients from NINDS t-PA study. RESULTS: The independent reviewer decided to treat with IV t-PA 123 patients (72%) after reviewing the radiology reports. The rate of NIHSS score improvement (52.0% vs. 62.5%, P = .22) was not different between patients in whom IV t-PA should or should not have been used based on radiology reports. Favorable clinical outcome defined by mRS of 0-2 at discharge (50.4% vs. 47.9%, P = .77) and in-hospital mortality (15.6% vs. 12.5%, P = .61) were similar between the 2 groups. Favorable outcome (discharge or day 7-10 mRS 0-2) was significantly higher in patients who received t-PA compared with placebo-treated patients (48% vs. 28%, P = .006). CONCLUSION: Our study demonstrates that administering IV t-PA to patients based on the stroke team's interpretation of the CT scan versus review of the radiology interpretation does not lead to significant differences in clinical outcome, aICH, or sICH.

A role for mucosal IL-22 production and Th22 cells in HIV-associated mucosal immunopathogenesis.

Interleukin-22 (IL-22) is a cytokine with epithelial reparative and regenerative properties that is produced by Th22 cells and by other immune cell subsets. Therefore, we explored the hypothesis that disruption of the gut barrier during HIV infection involves dysregulation of these cells in the gastrointestinal mucosa. Sigmoid IL-22-producing T cell and Th22 cells were dramatically depleted during chronic HIV infection, epithelial integrity was compromised, and microbial translocation was increased. These alterations were reversed after long-term antiretroviral therapy. While all mucosal IL-22-producing T-cell subsets were also depleted very early during HIV infection, at these early stages IL-22 production by non-T-cell populations (including NKp44+ cells) was increased and gut epithelial integrity was maintained. Circulating Th22 cells expressed a higher level of the HIV co-receptor/binding molecules CCR5 and α4ß7 than CD4+ T-cell subsets in HIV-uninfected participants, but this was not the case after HIV infection. Finally, recombinant IL-22 was protective against HIV and tumor necrosis factor-α-induced gut epithelial damage in a validated in vitro gut epithelial system. We conclude that reduced IL-22 production and Th22 depletion in the gut mucosa are important factors in HIV mucosal immunopathogenesis.

Intracranial angioplasty and stent placement after stenting and aggressive medical management for preventing recurrent stroke in intracranial stenosis (SAMMPRIS) trial: present state and future considerations.

OBJECTIVE: The results of prematurely terminated stenting and aggressive medical management for preventing recurrent stroke in intracranial stenosis (SAMMPRIS) due to excessively high rate of stroke and death in patients randomized to intracranial stent placement is expected to affect the practice of endovascular therapy for intracranial atherosclerotic disease. The purpose of this report is to review the components of the designs and methods SAMMPRIS trial and to describe the influence of those components on the interpretation of trial results. METHODS: A critical review of the patient population included in SAMMPRIS is conducted with emphasis on "generalizability of results" and "bias due to cherry picking phenomenon." The technical aspects of endovascular treatment protocol consisting of intracranial angioplasty and stent placement using the Gateway balloon and Wingspan self-expanding nitinol stent and credentialing criteria of trial interventionalists are reviewed. The influence of each component is estimated based on previous literature including multicenter clinical trials reporting on intracranial angioplasty and stent placement. RESULTS: The inclusion criteria used in the trial ensured that patients with adverse clinical or angiographic characteristics were excluded. Self-expanding stent as the sole stent, technique of prestent angioplasty, periprocedural antiplatelet treatment, and intraprocedural anticoagulation are unlikely to adversely influence the results of intracranial stent placement. A more permissive policy toward primary angioplasty as an acceptable treatment option may have reduced the overall periprocedural complication rates by providing a safer option in technically challenging lesions. The expected impact of a more rigorous credentialing process on periprocedural stroke and/or death rate following intracranial stent placement in SAMMPRIS such as the one used in carotid revascularization endarterectomy versus stenting trial remains unknown. CONCLUSION: The need for developing new and effective treatments for patients with symptomatic intracranial stenosis cannot be undermined. The data support modification but not discontinuation of our approach to intracranial angioplasty and/or stent placement for intracranial stenosis. There are potential patients in whom angioplasty and/or stent placement might be the best approach, and a new trial with appropriate modifications in patient selection and design may be warranted.

A comparison of parenting stress between mothers of children with spina bifida and able-bodied controls.

OBJECTIVES: To compare parenting stress between mothers of children with spina bifida (SB) and able bodied controls. METHODS: Sixty-six mothers of children with SB and controls (matched for age, sex and ethnicity) completed the Parenting Stress Index Short Form (PSI/SF) and General Health Questionnaire-12 (GHQ-12). Each child's adaptive skills was assessed using the Vineland Adaptive Behaviour Scales (VABS). RESULTS: Mothers of children with SB had significantly higher scores for GHQ-12 and the Parental Distress (PD), Parent-Child Dysfunctional Interaction (P-CDI) and Difficult Child (DC) sub-scales of the PSI/SF, even after adjusting for socioeconomic and caregiver status. Single parent status, having a child with SB and higher Life Stress scores were associated with higher PD and DC scores. Lower VABS scores were associated with higher P-CDI scores. CONCLUSION: Factors such as recent life change events, single parent status and the child's adaptive skills modify the impact of spina bifida on parenting stress.

Depression in women with spontaneous 46, XX primary ovarian insufficiency.

CONTEXT: A high prevalence of depressive symptoms is observed in women with primary ovarian insufficiency (POI) compared with women in whom the menopause is normally timed. Indeed, studies suggest that depression and/or its pharmacological treatment contribute to the onset of POI. OBJECTIVES: We characterize the prevalence of psychiatric disorders and the timing of onset of clinically significant depression relative to both the diagnosis of POI and the onset of menstrual irregularity in women with POI. DESIGN AND SETTING: We conducted a cross-sectional clinic-based study at the National Institutes of Health Clinical Research Center. PATIENTS: A total of 174 women with spontaneous 46, XX POI and 100 women with Turner syndrome participated in the study. MAIN OUTCOME MEASURES: The structured clinical interview for DSM-IV was performed. RESULTS: Lifetime histories of depression in POI exceeded rates of depression reported in women with Turner syndrome and community-based samples of women (P < 0.001). The onset of depression frequently preceded the diagnosis of POI but occurred after the onset of menstrual irregularity. Analyses standardizing the periods of risk for depression showed that similar numbers of depressions occurred before and after these events. CONCLUSIONS: POI is associated with an increased lifetime risk for major depression. Attention to the presence of depression in POI should become an important part of the care for these women. The onset of depression frequently occurs after signs of altered ovarian function but before the diagnosis of POI. Thus, in some women the association between POI and depression suggests an overlapping pathophysiology rather than a causal relationship.

Phenotypic differences in a large family with Kennedy's disease from the Middle Black Sea region of Turkey.

We report the clinical and electrophysiological features of a large Turkish family with genetically confirmed X-linked spinal and bulbar muscular atrophy (SBMA). Family members were identified by field work. A detailed history was obtained from each subject, and each subject received a detailed neurological examination. To confirm the CAG repeat expansion in the AR gene, genomic DNA was extracted from the peripheral blood of patients. The family consisted of 128 individuals over five generations, with two consanguineous parents, one slightly affected female, and 12 affected males with SBMA. We studied the five surviving male patients and one surviving female carrier. The age at disease onset, phenotypic features, and disease severity varied among the family members. DNA analysis was performed on five individuals, belonging to five generations of the family. Four affected males and a slightly affected female carrier were shown to carry an expanded CAG repeat in the androgen receptor gene. This family report is consistent with previous studies suggesting that SBMA may be present with a wide clinical spectrum in affected family members. Further descriptions of SBMA affected families with different ethnic backgrounds may assist in identifying possible phenotypic and genetic features of the disease.

Clinical trial of a novel surface cooling system for fever control in neurocritical care patients.

OBJECTIVE: To compare the efficacy of a novel water-circulating surface cooling system with conventional measures for treating fever in neuro-intensive care unit patients. DESIGN: Prospective, unblinded, randomized controlled trial. SETTING: Neurologic intensive care unit in an urban teaching hospital. PATIENTS: Forty-seven patients, the majority of whom were mechanically ventilated and sedated, with fever > or =38.3 degrees C for >2 consecutive hours after receiving 650 mg of acetaminophen. INTERVENTIONS: Subjects were randomly assigned to 24 hrs of treatment with a conventional water-circulating cooling blanket placed over the patient (Cincinnati SubZero, Cincinnati OH) or the Arctic Sun Temperature Management System (Medivance, Louisville CO), which employs hydrogel-coated water-circulating energy transfer pads applied directly to the trunk and thighs. MEASUREMENTS AND MAIN RESULTS: Diagnoses included subarachnoid hemorrhage (60%), cerebral infarction (23%), intracerebral hemorrhage (11%), and traumatic brain injury (4%). The groups were matched in terms of baseline variables, although mean temperature was slightly higher at baseline in the Arctic Sun group (38.8 vs. 38.3 degrees C, p = .046). Compared with patients treated with the SubZero blanket (n = 24), Arctic Sun-treated patients (n = 23) experienced a 75% reduction in fever burden (median 4.1 vs. 16.1 C degrees -hrs, p = .001). Arctic Sun-treated patients also spent less percent time febrile (T > or =38.3 degrees C, 8% vs. 42%, p < .001), spent more percent time normothermic (T < or =37.2 degrees C, 59% vs. 3%, p < .001), and attained normothermia faster than the SubZero group median (2.4 vs. 8.9 hrs, p = .008). Shivering occurred more frequently in the Arctic Sun group (39% vs. 8%, p = .013). CONCLUSION: The Arctic Sun Temperature Management System is superior to conventional cooling-blanket therapy for controlling fever in critically ill neurologic patients.

The effects of pharmacologically induced hypogonadism on mood in healthy men.

BACKGROUND: The effects of declining androgen secretion on mood regulation and the potential psychotropic efficacy of androgen replacement in men are largely undetermined. OBJECTIVE: To examine the effects on mood of the acute suppression of testosterone secretion. DESIGN: A double-blind, placebo-controlled, crossover (self-as-own-control) study. SETTING: An ambulatory care clinic in a research hospital. PARTICIPANTS: Thirty-one healthy adult men with no history of psychiatric illness or substance or anabolic steroid abuse. INTERVENTIONS: Men received depot leuprolide acetate (Lupron, 7.5 mg intramuscularly) every 4 weeks for 3 months. After the first month of Lupron alone, all men received (in addition to Lupron) testosterone enanthate (200 mg intramuscular) or placebo (sesame oil as color-matched vehicle) every 2 weeks for 1 month each in a crossover design. The order of administration of testosterone and placebo was randomly assigned and counterbalanced. MAIN OUTCOME MEASURES: Mood and behavior rating scores (self-report and rater administered). RESULTS: With the exceptions of hot flushes, libido, and the feeling of being emotionally charged, none of the symptoms measured showed a significant difference across eugonadal, Lupron plus placebo, and Lupron plus testosterone conditions. Despite the absence of a uniform effect of Lupron plus placebo on mood, 3 men experienced clinically relevant mood symptoms during this induced hypogonadal condition. High baseline levels of sexual functioning predicted the greatest decline in sexual function during Lupron plus placebo. CONCLUSIONS: These data, the first to describe the effects on mood of induced hypogonadism in healthy young men, suggest that short-term hypogonadism is sufficient to precipitate depressive symptoms in only a small minority of younger men. The predictors of this susceptibility remain to be determined.

Current and lifetime psychiatric illness in women with Turner syndrome.

Abnormalities in quality of life and cognitive measures have been observed in women with Turner syndrome (TS), and a relationship between these phenomena and chromosomal constitution has been suggested. In contrast, few studies have systematically evaluated the presence of mood and behavioral syndromes in these women. In this study, 100 TS women were administered the Structured Clinical Interview for DSM IV after a two-week period during which their hormone replacement had been discontinued. The majority of women who met criteria for a psychiatric condition had a mood or anxiety disorder. Overall, 52 (52%) of the TS women met criteria for a current or a past depressive or anxiety disorder. Eighteen of the women with TS met criteria for a current Axis I psychiatric disorder [Depression--major (n = 5), minor (n = 5), dysthymia (n = 1); Anxiety (n = 9)]. Forty-six of the women with TS met criteria for a past Axis I psychiatric illness [Depression: unipolar (n = 41), bipolar (n = 3); Anxiety (n= 7); eating disorder (n =6); substance dependence (n = 3)]. Five women with TS met criteria for an Axis II personality disorder. Women with TS reported a higher rate of lifetime depression compared with rates observed in community-based studies but similar to those obtained from gynecologic clinic samples.