Lithium in patients with amyotrophic lateral sclerosis (LiCALS): a phase 3 multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Lithium has neuroprotective effects in cell and animal models of amyotrophic lateral sclerosis (ALS), and a small pilot study in patients with ALS showed a significant effect of lithium on survival. We aimed to assess whether lithium improves survival in patients with ALS. METHODS: The lithium carbonate in amyotrophic lateral sclerosis (LiCALS) trial is a randomised, double-blind, placebo-controlled trial of oral lithium taken daily for 18 months in patients with ALS. Patients aged at least 18 years who had ALS according to the revised El Escorial criteria, had disease duration between 6 and 36 months, and were taking riluzole were recruited from ten centres in the UK. Patients were randomly assigned (1:1) to receive either lithium or matched placebo tablets. Randomisation was via an online system done at the level of the individual by block randomisation with randomly varying block sizes, stratified by study centre and site of disease onset (limb or bulbar). All patients and assessing study personnel were masked to treatment assignment. The primary endpoint was the rate of survival at 18 months and was analysed by intention to treat. This study is registered with Eudract, number 2008-006891-31. FINDINGS: Between May 26, 2009, and Nov 10, 2011, 243 patients were screened, 214 of whom were randomly assigned to receive lithium (107 patients) or placebo (107 patients). Two patients discontinued treatment and one died before the target therapeutic lithium concentration could be achieved. 63 (59%) of 107 patients in the placebo group and 54 (50%) of 107 patients in the lithium group were alive at 18 months. The survival functions did not differ significantly between groups (Mantel-Cox log-rank χ(2) on 1 df=1·64; p=0·20). After adjusting for study centre and site of onset using logistic regression, the relative odds of survival at 18 months (lithium vs placebo) was 0·71 (95% CI 0·40-1·24). 56 patients in the placebo group and 61 in the lithium group had at least one serious adverse event. INTERPRETATION: We found no evidence of benefit of lithium on survival in patients with ALS, but nor were there safety concerns, which had been identified in previous studies with less conventional designs. This finding emphasises the importance of pursuing adequately powered trials with clear endpoints when testing new treatments. FUNDING: The Motor Neurone Disease Association of Great Britain and Northern Ireland.

Offering choices to people with intellectual disabilities: an interactional study.

BACKGROUND: At the level of policy recommendation, it is agreed that people with intellectual impairments ought to be given opportunities to make choices in their lives; indeed, in the UK, the Mental Capacity Act of 2005 enshrines such a right in law. However, at the level of practice, there is a dearth of evidence as to how choices are actually offered in everyday situations, which must hinder recommendations to change. METHOD: This qualitative interactional study, based on video recordings in British residential homes, combines ethnography with the fine-grained methods of Conversation Analysis. RESULTS: We identify six conversational practices that staff use to offer choices to residents with intellectual disabilities. CONCLUSIONS: We describe the unwanted consequences of some of these practices, and how the institutional imperative to solicit clear and decisive choice may sometimes succeed only in producing the opposite.

Short wavelength-automated perimetry compared with standard achromatic perimetry in autosomal dominant optic atrophy.

BACKGROUND: Autosomal dominant optic atrophy (ADOA, Kjer-type) is a heterogeneous, non-inflammatory degeneration of retinal ganglion cells. The diagnosis of ADOA can be challenging owing to its insidious onset and large variability in phenotypic expression, both within and between individual pedigrees. The earliest literature reports relatively mild centrocaecal scatomas to white targets in ADOA, but extensive and dense peripheral field loss to coloured targets, especially blue, with Bjerrum perimetry. The phrase "inverted peripheral visual fields to coloured targets" has been used to describe this phenomenon. METHODS: Humphrey standard achromatic perimetry (SAP) and short wavelength-automated perimetry (SWAP) were carried out on five patients with ADOA. RESULTS: Regardless of wide variations in patient age, visual acuity, disc appearance and colour vision, the SWAP mean deviation (MD) was between 10 and 20 times more depressed than the SAP MD. The actual differences ranged from 9.38 to 13.78 dB. CONCLUSIONS: These data are consistent with the original reports suggesting that, early in this disease process, the blue-target deficits are typically peripheral and that this difference between SAP and SWAP perimetry may be a robust indicator of ADOA in both early and late stages of this disease.

Relationships between need for cognition, knowledge, and verbal ability.

The authors investigated the relationships between need for cognition, knowledge, and verbal ability. Participants completed scales that measured their need for cognition, verbal ability, and knowledge about people and events that occurred during the Vietnam War era. Correlational analyses showed that the participants' need for cognition scores were modestly but positively correlated with verbal ability and knowledge and that verbal ability and knowledge were also positively correlated. The correlation between need for cognition and knowledge was small but significant when verbal ability was controlled. The conclusion drawn from these results is that need for cognition contributes to the acquisition of knowledge beyond the contribution of verbal ability.

Preformed membrane-associated stores of interleukin (IL)-12 are a previously unrecognized source of bioactive IL-12 that is mobilized within minutes of contact with an intracellular parasite.

The prevailing paradigm is that production of the interleukin (IL)-12 p70 heterodimer, a critical T helper cell type 1 (Th1)-inducing cytokine, depends on the induced transcription of the p40 subunit. Concordant with this paradigm, we found that dendritic cells (DCs) produced IL-12 p70 only after at least 2-4 h of stimulation with lipopolysaccharide plus interferon gamma. However, using several complementary experimental approaches, including electron and confocal microscopy, we now show that resting murine and human myeloid cells, including macrophages/DCs and DC-rich tissues, contain a novel source of bioactive IL-12 that is preformed and membrane associated. These preformed, membrane-associated IL-12 p70 stores are released within minutes after in vitro or in vivo contact with Leishmania donovani, an intracellular pathogen. Our findings highlight a novel source of bioactive IL-12 that is readily available for the rapid initiation of Th1 host responses to pathogens such as Leishmania species.

Initial cervical exploration for parathyroidectomy is not benefited by preoperative localization studies.

Published data is controversial as to the ability of preoperative localization studies (PLS) to enhance the outcome of initial cervical exploration in patients with primary hyperparathyroidism (PHPT). One surgeon's experience was reviewed to compare surgical success, operative time, and morbidity of initial cervical exploration for PHPT in patients who had undergone PLS versus those who had not. From August 1991 to September 1997, 95 patients who had not undergone prior central cervical exploration presented for surgical management of PHPT. Sixty-seven patients underwent initial cervical exploration without any PLS having been performed (Group A). Twenty-eight patients underwent PLS, either alone or in combination, before surgical intervention (Group B). Analysis of intergroup variability was conducted upon the data available using a two-tailed t test for independent samples. In addition, the sensitivities and positive predictive values of the PLS were calculated using study reports and operative and histologic findings. There was no statistically significant difference in surgical success between those patients who had PLS and those that did not undergo PLS. Sixty-four of 67 patients (95.5%) not having PLS were cured with initial surgery, while 27 of 28 patients (96.4%) who had PLS were surgically cured. Mean postoperative calcium and intact parathormone levels were similar between the two groups, and the mean operative time did not differ. Permanent hypocalcemia occurred in one patient, and five patients had transient hoarseness. Thirty-six total PLS were obtained at an average cost of $752.68/patient, and seven patients underwent multiple tests. Overall, sestamibi scan had the highest positive predictive value (81%). For adenomatous disease alone, sestamibi scan was the most sensitive (83%). Our study shows that for matched groups limited to age, sex, and clinical diagnosis, the use of PLS did not shorten operative time, decrease complication frequency, nor alter the success of the operation as measured by postoperative calcium and parathormone levels. Therefore, routine use of preoperative localization studies before initial cervical exploration for PHPT cannot be recommended.

The role of ultrasonography and inferior vena cava filter placement in high-risk trauma patients.

Undetected lower-extremity deep-vein thrombosis (LEDVT) in the trauma patient can lead to significant morbidity and mortality. The purpose of this study was to: 1) evaluate the role of ultrasonography in the early detection of LEDVT in high-risk trauma patients; 2) identify prognostic indicators that predict LEDVT; and 3) evaluate the efficacy of selected inferior vena cava (IVC) filter placement in the prevention of pulmonary emboli. From October 1993 through December 1994, all adult multiple-trauma patients admitted to the Trauma Service who required prolonged bed rest (>3 days) or sustained a lower-extremity, pelvic, or spinal fracture with paralysis were prospectively studied with serial physical examinations and lower-extremity venous ultrasounds within 72 hours of admission and then weekly until discharge. Two hundred twenty-eight patients were entered into the study. Thirty-nine patients (17%) developed ultrasound evidence of LEDVT; of these, only seven (18%) were evident on physical examination. This allowed 32 patients (82%) with unsuspected LEDVT to receive earlier definitive therapy. Multivariate logistic regression analysis of LEDVT with various predictors found age, hospital length of stay, and lower-extremity trauma to be significant predictors of LEDVT (P < 0.05). Twenty-nine patients (74%) had immediate IVC filter placement upon ultrasound identification of proximal LEDVT. None of these patients developed pulmonary emboli. Ten patients (26%) with a LEDVT were treated with systemic anticoagulation alone. One of these patients sustained a fatal pulmonary embolus. In a historic control group of 234 high-risk trauma patients admitted in the 14 months prior to implementing screening ultrasounds, six patients sustained pulmonary emboli (P < 0.05). Screening ultrasounds combined with selective placement of IVC filters play an important role in reducing the morbidity and mortality associated with LEDVT in high-risk trauma patients.

Increased intestinal permeability following blunt and penetrating trauma.

OBJECTIVES: To determine changes in the absorption of lactulose and mannitol in patients undergoing laparotomy following blunt or penetrating trauma and to correlate any changes in permeability with the severity of injury. DESIGN: Nonrandomized study within patient control. PATIENTS: Consecutive patients admitted to the trauma unit following blunt or penetrating trauma with intra-abdominal injuries warranting emergent celiotomy and jejunal access. INTERVENTIONS: Intestinal permeability was measured in 18 patients within 48 hrs post-trauma by the bolus infusion into the jejunum of nonmetabolized probe molecules, lactulose (molecular weight of 342) and mannitol (molecular weight of 182). Because several patients did not tolerate the bolus infusion, a 3-hr continuous infusion of the probe molecules was used in the last eight patients entered into the study. Intestinal permeability was reassessed before discharge or on days 10 to 12. MEASUREMENTS AND MAIN RESULTS: There was a decrease in urinary lactulose excretion and the lactulose/mannitol ratio between the initial posttrauma measurement and the follow-up permeability measurement using both the bolus infusion (lactulose: initial 0.13 +/- 0.032 vs. follow-up 0.047 +/- 0.012 mmol/6 hrs, p < or = .05; lactulose/mannitol: initial 0.067 +/- 0.012 vs. follow-up 0.044 +/- 0.012, p = .11) and the continuous infusion (lactulose: initial 0.044 +/- 0.013 vs. follow-up 0.014 +/- 0.002 mmol/2 hrs, p < or = .05; lactulose/mannitol: initial 0.055 +/- 0.020 vs. follow-up 0.015 +/- 0.007, p < or = .05). Urine excretion of mannitol was not significantly different between posttrauma and follow-up measurements of intestinal permeability, regardless of the technique used to infuse the lactulose and mannitol. Although the decrease in lactulose and the lactulose/mannitol ratio was significant, only one third of the patients had dramatically increased permeability at the initial measure. Abdominal Trauma Index and Injury Severity Score did not correlate with urinary lactulose excretion or the lactulose/mannitol ratio. Patient tolerance of jejunal administration of lactulose and mannitol was better, using a 3-hr continuous infusion of a dilute solution compared with bolus infusion. CONCLUSIONS: Intestinal permeability is increased in the first 48 hrs posttrauma and decreases with recovery. Although one third of the patients had highly increased lactulose/mannitol ratios posttrauma, severity of injury, assessed by common scoring techniques, did not correlate with the degree of permeability. Tolerance to jejunal administration of lactulose and mannitol is improved with a slow infusion of a dilute solution over a 3-hr period compared with bolus administration.

Linkage mapping around the ragged (Ra) and wasted (wst) loci on distal mouse chromosome 2.

Mice that are heterozygous for the ragged (Ra) mutation, which is semidominant, have ragged coats caused by an absence of certain hair types. Ra/Ra homozygous mice usually die soon after birth, are naked, and have edema. Mice that are homozygous for the recessive mutation wasted (wst) appear normal until soon after weaning, but then develop tremors and ataxia, undergo atrophy of the thymus and spleen, and die by around 28 days of age. The Ra and wst loci map to distal mouse chromosome 2, but have never been positioned with respect to molecular markers. We have now mapped each of these genes in interspecific backcrosses that were also typed for available molecular markers. The results show that Ra maps very close to D2Mit74 and Acra-4, with no recombinants in 165 mice, whereas wst maps 3 cM distal to the most telomeric molecular marker on mouse chromosome 2, Acra-4.

Risk of abdominal septic complications after feeding jejunostomy placement in patients undergoing splenectomy for trauma.

Compared with total parenteral nutrition, enteral feeding via jejunostomy reduces septic complications in patients with severe trauma. However, violation of the bowel with insertion of a jejunostomy tube may increase the risk of intra-abdominal abscess (IAA), particularly if no simultaneous gastrointestinal tract injury exists. The records of 123 patients requiring splenectomy for trauma at a level I trauma center during a 6-year period (1986 to 1992) were reviewed to examine the incidence of IAA in patients with and without simultaneous jejunostomy placement in the presence and absence of gastrointestinal tract injuries. Thirty patients had jejunostomies placed (J), and 93 did not (NoJ). There were no significant differences between the groups in age, Abdominal Trauma Index, Injury Severity Score, or transfusion requirements. The incidence of IAA was not significantly different between the J and NoJ groups in the presence or absence of gastrointestinal tract injuries. Thus, jejunostomy placement does not increase the incidence of IAA after splenectomy regardless of the presence of a gastrointestinal tract injury.

Evaluation of a saliva alcohol test stick as a therapeutic adjunct in an alcoholism treatment program.

This study was designed to evaluate the clinical usefulness of a saliva alcohol dipstick by comparing dipstick saliva alcohol concentrations to simultaneous blood and urine alcohol concentrations. The sample consisted of 211 saliva tests and blood alcohol concentrations and 189 urine alcohol concentrations. The dipsticks had a specificity of 0.965, a sensitivity of 0.895, a positive predictive value of 0.850, a negative predictive value of 0.977 and a Pearson's product moment correlation coefficient of 0.609 for blood alcohol concentrations and salivary alcohol concentrations, suggesting that the saliva dipstick is useful as a qualitative test in certain settings but is less useful than previously reported as a semiquantitative test.

Supervision: the residents' perspective.

Psychotherapy supervision is an essential aspect of psychiatric residency training. The authors surveyed the attitudes of the PGY I-IV psychiatry residents in the Baylor College of Medicine residency toward psychotherapy supervision. The results were compared to those of a previous nationwide survey of Canadian psychiatry residents. The Baylor residents identified three factors as the most important elements of satisfactory supervision: the supervisor's teaching ability, rapport between the supervisor and the trainee, and the supervisor's fund of knowledge.