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The incidence of external ventricular drain (EVD) infections remains high. Chlorhexidine dressings have demonstrated efficacy in reducing infections associated with indwelling catheters at other body sites, although evidence for their use with EVDs is limited. The aim of this systematic review and meta-analysis was to evaluate the efficacy of chlorhexidine dressings in reducing EVD-associated cerebrospinal fluid infection (EVDAI). MEDLINE, EMBASE and the Cochrane library were queried for articles from inception. The primary outcome was the incidence of EVDAI. Secondary outcomes included device safety, microbiological outcomes and shunt-dependency. From 896 unique records, five studies were included of which four presented suitable data for quantitative analysis including three case series and one underpowered randomized controlled trial. There was a high risk of bias in all studies. A total of 880 patients were included with a mean age of 57.7 years (95% confidence interval (CI) 57.4-58.0 years). In primary outcome analysis, the chlorhexidine dressing group had a significantly lower incidence of EVDAI (1.7% vs 7.9%, risk difference (RD) = 0.07, 95% CI 0.00-0.13, P=0.04). In conclusion, chlorhexidine dressings may reduce the incidence of EVDAI but require future study in randomized trials to definitively determine efficacy., (Copyright © 2021 The Healthcare Infection Society. All rights reserved.)

A 71-year old retired missionary presented with a 2- week history of increasing dyspnoea, orthopnoea, and peripheral oedema. The patient had no previous significant past medical history. On clinical examination, his heart sounds were dual and his jugular venous pressure was elevated to 7cm. On chest auscultation there were bilateral crepitations at his lung bases.

Constrictive pericarditis though an uncommon diagnosis is a potentially reversible form of heart failure (with surgical pericardiectomy) and hence is imperative to diagnose. Diagnosis is dependent on a high index of clinical suspicion and further testing with appropriate cardiac investigations including cardiac imaging with invasive cardiac catheterisation as the gold standard.

Background: Delayed cerebral ischemia (DCI) is an independent predictor of an unfavorable outcome after aneurysmal subarachnoid hemorrhage (aSAH). Many centers, but not all, use transcranial Doppler (TCD) to screen for vasospasm to help predict DCI. We used the United Kingdom and Ireland Subarachnoid Haemorrhage (UKISAH) Registry to see if outcomes were better in centers that used TCD to identify vasospasm compared to those that did not., Methods: TCD screening practices were ascertained by national survey in 13 participating centers of the UKISAH. The routine use of TCD was reported by 5 "screening" centers, leaving 7 "non-screening" centers. Using a cross-sectional cohort study design, prospectively collected data from the UKISAH Registry was used to compare DCI diagnosis and favorable outcome (Glasgow Outcome Score 4 or 5) at discharge based on reported screening practice., Results: A cohort of 2028 aSAH patients treated ≤ 3 days of hemorrhage was analyzed. DCI was diagnosed in 239/1065 (22.4%) and 220/963 (22.8%) of patients in non-screening and screening centers respectively while 847/1065 (79.5%) and 648/963 (67.2%) achieved a favorable outcome. Odds ratios adjusted for age, injury severity, comorbidities, need for cerebrospinal fluid diversion, and re-bleed returned neutral odds of diagnosing DCI of 0.90 (95% CI 0.72-1.12; p value = 0.347) in screening units compared to those of non-screening units but significantly decreased odds of achieving a favorable outcome 0.56 (95% CI 0.42-0.82; p value < 0.001)., Conclusions: Centers that screened for vasospasm using TCD had poorer in-hospital outcomes and similar rates of DCI diagnosis compared to centers that did not.

Introduction Surgical site infection (SSI) is a significant cause of postoperative morbidity and mortality. Effective preoperative antisepsis is a recognised prophylactic, with commonly used agents including chlorhexidine (CHG) and povidone-iodine (PVI). However, there is emerging evidence to suggest an additional benefit when they are used in combination. Methods We analysed data from our prospective SSI database on patients undergoing clean cranial neurosurgery between October 2011 and April 2014. We compared the case-mix adjusted odds of developing a SSI in patients undergoing skin preparation with CGH or PVI alone or in combination. Results SSIs were detected in 2.6% of 1146 cases. Antisepsis with PVI alone was performed in 654 (57%) procedures, while 276 (24%) had CHG alone and 216 (19%) CHG and PVI together. SSIs were associated with longer operating time (p<0.001) and younger age (p=0.03). Surgery type (p<0.001) and length of operation (p<0.001) were significantly different between antisepsis groups. In a binary logistic regression model, CHG and PVI was associated with a significant reduction in the likelihood of developing an SSI (adjusted odds ratio [AOR] 0.12, 95% confidence interval [CI] 0.02-0.63) than either agent alone. There was no difference in SSI rates between CHG and PVI alone (AOR 0.60, 95% CI 0.24-1.5). Conclusions Combination skin preparation with CHG and PVI significantly reduced SSI rates compared to CHG or PVI alone. A prospective, randomized study validating these findings is now warranted.

Background: Cerebrospinal fluid (CSF) infection is the primary complication associated with placement of an external ventricular drain (EVD). The use of silver-impregnated EVD catheters has become commonplace in many neurosurgical centres., Aim: To assess the effect of silver-impregnated EVD catheter usage on catheter-related CSF infections., Methods: A meta-analysis was performed by systematically searching Medline, Embase and the Cochrane Library. All randomized controlled trials (RCTs) and non-RCTs comparing silver-impregnated and plain EVD catheters were identified and analysed., Findings: Six non-RCTs were included. The crude infection rate was 10.8% for plain catheters and 8.9% for silver-impregnated catheters [pooled odds ratio (OR) 0.71, 95% confidence interval (CI) 0.46-1.08; P = 0.11]. In a microbiological spectrum analysis, silver-impregnated catheters demonstrated a significantly lower rate of CSF infections caused by Gram-positive organisms (2.0% vs 6.7% in the silver-impregnated and plain catheter groups, respectively; pooled OR 0.27, 95% CI 0.11-0.63; P = 0.002)., Conclusion: The antimicrobial effects of silver-impregnated EVD catheters may be selective, and may need to be evaluated further in a prospective, controlled manner., (Copyright © 2015 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)

Objectives: ASDH in the elderly is a common and increasing problem, and differs in its pathophysiology from ASDH in younger people. Admitting doctors may have difficulty identifying those elderly patients whose lesions may benefit from surgery. The objective of this study was to determine whether simple neuroradiological measurements could identify those patients, who need urgent neurosurgical referral for consideration for surgery., Design: A retrospective cohort study., Participants: All patients aged 65 years or greater referred to Salford Royal Foundation Trust with the diagnosis of ASDH between 01/01/2008 and 31/12/2011., Methods: The initial presenting CT brain scans were reviewed. The linear dimensions, degree of midline shift and haematoma volume (using ABC/2 method) of all scans were measured and recorded. All presenting radiology was also assessed by a consultant neurosurgeon blind to clinical and CT scan measurement data and patients were categorised as having "surgical" lesions or not. Receiver operating characteristic (ROC) curves were generated and cut point value for 100% sensitivity and specificity were tabled to assess which combination of scan parameters best predicted a "surgical" ASDH., Results: 212/483 patients were considered to have a 'surgical' lesion. All 'surgical' lesions had a volume of >35ml (range 35-435), maximum thickness of ≥10mm (range 10-49) and 99% had midline shift ≥1mm (range 0-32). The best predictor of a 'surgical' lesion was a combination of maximum haematoma thickness and midline shift which offered 100% (95% CI 98.3-100) sensitivity with 83% (95% CI 77.6-87) specificity., Conclusion: Surgically relevant cases of ASDH in the elderly can be reliably and objectively identified by two easily performed scan measurements, haematoma thickness and midline shift. If used in routine practice, these measurements could clarify those patients who may need urgent neurosurgical referral and might avoid unnecessary transfer to neurosurgical units in this cohort., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Intracranial hypertension can occur following aneurysmal subarachnoid haemorrhage (SAH). It can be treated with decompressive craniectomy (DC) with the aim of reducing intracranial pressure, increasing cerebral perfusion and reducing further morbidity and mortality. We studied the outcome of patients undergoing DC following SAH at our institution, to ascertain whether the use of this treatment can be rationalized.

Objective: Because of potential risks of poor outcome, lumbar puncture (LP) is recommended to exclude the presence of blood breakdown products in patients with suspected subarachnoid haemorrhage (SAH) and a normal CT scan. The aim of this study was to document how often this test proved useful., Method: A retrospective analysis of prospectively recorded data was conducted. Patients with suspected SAH and a normal CT scan in whom LP was recommended between May 2008 and May 2010 were identified using the neurosurgical referral database. CT scan results, LP results, inpatient stay, investigations and interventions were recorded., Results: One hundred and sixty-three patients were identified in whom LP was recommended after a reported negative CT scan. Thirty-six of these 163 patients had a positive LP of which seven had evidence of SAH on the initial CT scan. In 66 patients, the LP was not diagnostic and 59/66 (90%) patients underwent secondary imaging in whom five with aneurysms were identified and treated., Conclusion: LP-driven decision making in patients with a normal scan and suspected SAH is suboptimal in over a third of cases. Patients with a non-diagnostic LP harboured five aneurysms that merited treatment. These results support the need for secondary investigations following suspected SAH, but suggest that these could take the form of secondary imaging rather than a lumbar puncture.

Background: The outcome in patients who present with an aneurysm related intracerebral haemorrhage (ICH) is poor. There are many treatment strategies now available to treat this group of patients. The management approach is dominated by a direct surgical approach for both aneurysm treatment and clot evacuation. It remains unclear, however, whether overall outcomes justify an aggressive treatment approach in this group of patients. We report our results of a pragmatic strategy based on availability of expertise and patient condition in patients presenting with an aneurysm related intracerebral haemorrhage., Methods: We retrospectively identified and analysed prospectively collected data of SAH patients with concurrent ICH. The grade at presentation, treatment decision, complications, length of hospital stay, discharge destination, and 6 month outcome (Glasgow Outcome Score (GOS) at 6 months) were recorded., Findings: Between August 2008 and January 2010, 40 patients (9.2%) with ICH were identified from the 433 patients with SAH. Twenty five patients (63%) were transferred across to the neurosurgical centre for further investigations and management. Most patients presented with poor WFNS grade (61%) and had right sided middle cerebral artery aneurysms (58%) with frontotemporal (42%) or temporoparietal (42%) haematomas. Management included craniotomy/craniectomy and clipping of the aneurysm in 18 patients (72%), coiling followed by surgical clot evacuation in five (20%), and craniectomy and coiling (4%) or coiling alone (4%). The outcome in treated patients was favourable (GOS 4 or 5) in 46% of patients with a 35% overall mortality., Conclusion: The presence of an aneurysm related ICH does not justify a nihilistic approach, as aggressive treatment is associated with a favourable outcome in 46% of patients. In the post-ISAT era, management should be patient specific and consideration should be given to both endovascular and open surgical therapy.

Background: Age is an important factor in determining prognosis following severe head injury (SHI), although mortality in patients > or =65 years is poorly reported. The aim of this study was to document mortality in patients with SHI > or =65 years., Methods: A retrospective analysis of prospectively collected data from the TARN (Trauma Audit and Research Network) database (1996-2004) was performed. Six hundred and sixty-nine patients aged > or =65 with a GCS <9 after a head injury were identified, and mortality at 3 months was recorded., Findings: Mortality was 71% in 65- to 70-year-old patients (n = 137) (CI, 64-79), 75% for patients aged 70-75 years (n = 147) (CI, 68-82), 85% in patients aged 75-80 years (n = 160) (79-91), and 87% for patients >80 years (n = 225) (CI, 83-91). Mortality for all patients > or =65 years with a GCS 3-5 was >80%. A better outcome was observed in patients with a GCS = 6-8 [65-70 years, 47% (CI, 30-64); 70-75 years, 56% (CI, 43-69); 75-80 years, 73% (CI, 62-85); >80 years, 79% (CI, 70-87)]., Conclusions: SHI-related mortality continues to increase with age. Overall, these data support a conservative approach to the severely head-injured elderly patient; however, patients presenting with a GCS = 6-8 and below the age of 75 may represent a group where more aggressive therapy may be indicated.

Cerebral revascularisation with extracranial - intracranial (EC-IC) bypass is generally indicated in patients with complex anterior circulation aneurysms who have failed parent artery occlusion. We report on the process and outcome of our early experience of performing high flow bypass in patients with complex anterior circulation aneurysms. We have reviewed patients who have undergone an EC-IC bypass for treatment of complex anterior circulation aneurysms, and report our outcome on graft patency, surgical complications, discharge destination, and obliteration rates. Nine patients that underwent 11 bypasses are described. Seven patients had a giant saccular aneurysm of the carotid, and these were all obliterated on post-operative imaging. Two patients presenting with an intracranial carotid dissection required trapping of the diseased segment following the bypass. The overall graft patency rate was 88%. One patient developed a post operative subdural collection (managed conservatively), and one patient required early graft revision. Discharge destination was home in 8/9 patients. There was no mortality. Although EC-IC bypass is a technically challenging procedure, it provides a valuable treatment option for patients with complex anterior circulation aneurysms. Good graft patency rates can be achieved with low surgical morbidity in patients with a disease process that otherwise attracts a highly unfavourable natural history.

High flow extracranial-intracranial (hfEC-IC) vascular bypass remains an important surgical technique in selected patients. For example, in those with giant aneurysms where the natural history of the condition is poor, and direct surgical approaches are recognised as excessively hazardous. hfEC-IC also allows for major carotid vessel occlusion in the treatment of skull base tumours which would otherwise be untreatable. We describe the indications, techniques, complications, and outcomes of this procedure in an era where few neurosurgeons are exposed to high volume vascular neurosurgery, and fewer still are trained to perform hfEC-IC. We emphasise the need for a stereo-typed and meticulous technique, highlighting key points at each stage of the operation, to ensure graft survival and minimal chances of morbidity.

We report a patient that developed an aneurysm on a grafted saphenous vein following an extracranial-intracranial (EC-IC) bypass. Although saphenous vein graft aneurysms (SVGAs) have been described as a rare complication following coronary surgery, we are unaware of any previously reported cases of SVGAs following EC-IC bypass.

Introduction: We report two cases of radiation-induced intracranial tumours after treatment for medulloblastoma presenting in children with nevoid basal cell carcinoma syndrome., Discussion: These cases illustrate the need for judicious use of post-operative radiotherapy as secondary tumors are commonly reported. This is particularly important as the initial tumour in this cohort is of the 'less aggressive' desmoplastic subtype.

The aim of this study was to assess the prevalence of otological symptoms in patients with chlamydial conjunctivitis. We report four cases of chlamydial conjunctivitis, in association with otitis media, that were investigated by an otologist.

The cytokine interleukin-1 (IL-1) is an established and important mediator of diverse forms of neuronal injury in experimental animals. However, its mechanisms of action remain largely unknown. We have reported previously that IL-1 markedly enhances excitotoxic injury induced in the rat by striatal administration of the excitotoxin alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), leading to widespread neuronal loss throughout the ipsilateral cortex. Here we tested the hypothesis that IL-1 causes this injury through induction and/or enhancement of seizure activity in the rat. Consistently with this hypothesis, intrastriatal injection of AMPA or AMPA with IL-1 in the rat brain increased c-Fos expression in regions similar to those in which c-Fos has been reported previously in response to seizures. A significant increase in cortical neuronal activity (number of c-Fos positive cells) was observed in response to AMPA with IL-1 compared with AMPA (8 hr after injection). Increased seizure duration [3,522 +/- 660 sec (SEM) vs. 1,415 +/- 301 sec; P < 0.001] and cell death volume (140 +/- 20 mm3 vs. 52 +/- 6 mm3; P < 0.001) were seen in response to coinfusion of AMPA with IL-1 vs. AMPA alone. In addition, the anticonvulsant diazepam (intraperitoneal) significantly reduced cell death (P < 0.001) and seizure duration (P < 0.001) induced by AMPA with IL-1, and a significant correlation was found between seizure duration and cell death volume. These findings support our hypothesis that IL-1 enhances excitotoxic injury by enhancement of seizures, which may be of relevance to IL-1 actions in other forms of neuronal injury, including cerebral ischemia., (Copyright 2005 Wiley-Liss, Inc.)

Background: Case fatality rates after all types of blunt injury have not improved since 1994 in England and Wales, possibly because not all patients with severe head injury are treated in a neurosurgical centre. Our aims were to investigate the case fatality trends in major trauma patients with and without head injury, and to establish the effect of neurosurgical care on mortality after severe head injury., Methods: We analysed prospectively collected data from the Trauma Audit and Research Network database for patients presenting between 1989 and 2003. Mortality and odds of death adjusted for case mix were compared for patients with and without head injury, and for those treated in a neurosurgical versus a non-neurosurgical centre., Findings: Patients with head injury (n=22,216) had a ten-fold higher mortality and showed less improvement in the adjusted odds of death since 1989 than did patients without head injury (n=154,231). 2305 (33%) of patients with severe head injury (presenting between 1996 and 2003) were treated only in non-neurosurgical centres; such treatment was associated with a 26% increase in mortality and a 2.15-fold increase (95% CI 1.77-2.60) in the odds of death adjusted for case mix compared with patients treated at a neurosurgical centre., Interpretation: Since 1989 trauma system changes in England and Wales have delivered greater benefit to patients without head injury. Our data lend support to current guidelines, suggesting that treatment in a neurosurgical centre represents an important strategy in the management of severe head injury.

Interleukin-1 (IL-1) exerts a number of diverse actions in the brain, and it is currently well accepted that it contributes to experimentally induced neurodegeneration. Much of this is based on studies using the IL-1 receptor antagonist, which inhibits cell death caused by ischemia, brain injury, or excitotoxins. Our aim is to determine how and where in the brain IL-1 acts to produce these effects. Most of the neurodegenerative effects of IL-1 are thought to be through IL-1 beta. However, we have data implicating IL-1 alpha in excitotoxic cell death. Furthermore mice lacking both IL-1 alpha and IL-1 beta show dramatically reduced ischemic cell death, whereas deletion of IL-1 alpha or IL-1 beta alone fails to modify damage. It has also been demonstrated that IL-1 exacerbates ischemic injury in mice in the absence of the type I IL-1 receptor, suggesting the existence of novel IL-1 receptors in the brain. IL-1 also dramatically exacerbates neuronal loss in response to intrastriatal administration of the excitotoxin AMPA in the rat brain, an effect accompanied by marked increases in cytokine expression in the frontoparietal cortex, which precedes subsequent cell death in this region. Intrastriatal AMPA also results in limbic seizures that are exacerbated by IL-1, and we hypothesize, therefore, that IL-1 exacerbates cell death through increased seizure activity. Therefore, IL-1 appears to induce acute neurodegeneration through a number of mechanisms.

A methodology called quantitative component analysis of mixtures (QCAM) was used to analyze an existing set of product formulation data to determine if the irritating ingredients in the mixtures could be identified. Eye irritation scores, based on a rat model, for 18 mixtures having a composite total of 37 components, were analyzed by QCAM. QCAM relates a net toxicity measure of a mixture to the toxicities of the individual components of the mixture through linear, quadratic, and pairwise cross-component concentration-dependent interactions. A correlation model is established using a particular genetic algorithm employing either multidimensional linear regression or partial least-squares regression fitting. Cornea eye irritation and average eye irritation are well-explained in terms of a linear model of, at most, three components over the set of mixtures. Moreover, extensive cornea and average eye irritations are due to only one of these three components of the mixtures. Also, one of the three significant components was predicted to decrease the extent of eye irritation, and subsequently identified as an "anti-irritant" in contact lens solutions. A reasonable linear correlation model could also be developed for conjunctiva irritation, but no significant iris irritation model could be constructed. The addition of quadratic and/or cross-component concentration terms to a linear correlation model did not statistically improve the overall resultant model. The QCAM models permit estimation of the intrinsic (self) toxicity of each of the components of a mixture, and may aid in the reduction, and ultimate elimination, of the need for animal eye irritation studies.

The presence of subarachnoid blood following head injury is a significant risk factor for poor outcome. Treatment aims to prevent and treat secondary hypoxia, hypotension, intracranial haematoma, epilepsy and infection. There is good evidence for the benefit of nimodipine in aneurysmal subarachnoid haemorrhage. Its role in preventing cerebral ischaemia following trauma is currently under investigation.

Antidotes for cyanide (CN) intoxication include the use of sulfane sulfur donors (SSDs), such as thiosulfate, which increase the conversion of CN to thiocyanate by the enzyme rhodanese. To develop pretreatments that might be useful against CN, SSDs with greater lipophilicity than thiosulfate were synthesized and assessed. The ability of SSDs to protect mice against 2LD50 of sodium cyanide (NaCN) administered either 15 or 60 min following administration of an SSD was assessed. To study the mechanism of action of the SSD, the candidate compounds were examined in vitro for their effect on rhodanese and 3-mercaptopyruvate sulfurtransferase (MST) activity under increasing SSD concentrations. Tests were conducted on nine candidate SSDs: ICD1021 (3-hydroxypyridin-2-yl N-[(N-methyl-3-aminopropyl)]-2-aminoethyl disulfide dihydrochloride), ICD1022, (3-hydroxypyridin-2-yl N-[(N-methyl-3-aminopropyl)]-2-aminoethyl disulfide trihydrochloride), ICD1584 (diethyl tetrasulfide), ICD1585 (diallyl tetrasulfide), ICD1587 (diisopropyl tetrasulfide); ICD1738 (N-(3-aminopropyl)-2-aminoethyl 2-oxopropyl disulfide dihydrochloride), ICD1816 (3,3'-tetrathiobis-N-acctyl-L-alanine), ICD2214 (2-aminoethyl 4-methoxyphenyl disulfide hydrochloride) and ICD2467 (bis(4-methoxyphenyl) disulfide). These tests demonstrated that altering the chemical substituent of the longer chain sulfide modified the ability of the candidate SSD to protect against CN toxicity. At least two of the SSDs at selected doses provided 100% protection against 2LD50 of NaCN, normally an LD99. All compounds were evaluated using locomotor activity as a measure of potential adverse behavioral effects. Positive hypoactivity relationships were found with several disulfides but none was found with ICD1584, a tetrasulfide. Separate studies suggest that the chemical reaction of potassium cyanide (KCN) and cystine forms the toxic metabolite 2-iminothiazolidine-4-carboxylic acid. An alternative detoxification pathway, one not primarily involving the sulfur transferases. may be important in pretreatment for CN intoxication. Although studies to elucidate the precise mechanisms are needed. it is clear that these newly synthesized compounds provide a new rationale for anti-CN drugs, with fewer side-effects than the methemoglobin formers.

Purpose: The purpose of this study was to identify the key physicochemical molecular properties of polymeric materials responsible for gaseous diffusion in the polymers., Methods: Quantitative structure-property relationships, QSPRs were constructed using a genetic algorithm on a training set of 16 polymers for which CO2, N2, O2 diffusion constants were measured. Nine physicochemical properties of each of the polymers were used in the trial basis set for QSPR model construction. The linear cross-correlation matrices were constructed and investigated for colinearity among the members of the training sets. Common water diffusion measures for a limited training set of six polymers was used to construct a "semi-QSPR" model., Results: The bulk modulus of the polymer was overwhelmingly found to be the dominant physicochemical polymer property that governs CO2, N2 and O2 diffusion. Some secondary physicochemical properties controlling diffusion, including conformational entropy, were also identified as correlation descriptors. Very significant QSPR diffusion models were constructed for all three gases. Cohesive energy was identified as the main correlation physicochemical property with aqueous diffusion measures., Conclusions: The dominant role of polymer bulk modulus on gaseous diffusion makes it difficult to develop criteria for selective transport of gases through polymers. Moreover, high bulk moduli are predicted to be necessary for effective gas barrier materials. This property requirement may limit the processing and packaging features of the material. Aqueous diffusion in polymers may occur by a different mechanism than gaseous diffusion since bulk modulus does not correlate with aqueous diffusion, but rather cohesive energy of the polymer.

The current studies were aimed at investigating why certain murine anti-CD3 isotypes (e.g. IgG2b) were poor activators of human T cells despite binding to the same epitope as the IgG2a anti-CD3. Most experiments were conducted with a human T cell line (HuT-78) and U937 a human histiocytic cell line with Fc gamma RI and Fc gamma RII. HuT-78 cells lack Fc gamma R. Anti-CD3-TCR of IgG2a isotypes and some antibodies of the IgG1 isotype, but not IgG2b, activated HuT-78 to secrete IL-2 only in the presence of U937. Epitope binding differences could not entirely explain these observations as OKT3E(IgG2a) but not its switch variant (IgG2b) activated HuT-78 in the presence of U937. Of interest, OKT3D(IgG1) in its intact form, but not its F(ab')2, activated HuT-78 to secrete IL-2 in the absence of U937 suggesting therefore that OKT3D activates T cells in the absence of macrophages and provided its Fc domain is intact. All three anti-CD3 with IgG2b isotypes (but none with the IgG2a isotypes) activated HuT-78 to secrete IL-2 only when these antibodies were immobilized onto plastic (in the absence of U937). Of considerable importance, anti-CD3 activation of human T cells with the IgG2b isotype was efficient in the presence of murine macrophages. These observations would suggest that murine anti-CD3 with IgG2b and certain antibodies of IgG1 isotypes, have inherent human T cell activating potential provided the Fc domain is in some manner activated, as for example, by binding to plastic or to Fc gamma R on murine macrophages. Macrophage cytokines are not essential. Therefore, ineffectual anti-CD3-mediated human T cell activation when using murine mAb with the IgG2b isotypes can best be explained on lack of Fc domain activation by human macrophages. This may indeed be the case as IgG2b and certain antibodies of IgG1 isotype, failed to bind to Fc gamma R on macrophages at 37 degrees C. These studies would indicate that murine mAb with the IgG2b isotype may be potentially useful for human use, especially in situations where receptor blockade (without cell activation) is of prime importance.

A set of 54 anticoccidial triazine analogs were analyzed in terms of molecular shape analysis, MSA, with the goal of constructing a three-dimensional quantitative structure-activity relationship (3D-QSAR). This same dataset was previously investigated using alternate QSAR methods including comparative molecular field analysis (CoMFA). A complete 3D-QSAR was realized using MSA which included (a) identification of the active conformation of each individual analog, (b) the relative intramolecular stability of each analog in its active conformation, (c) general intramolecular stability requirements for activity, (d) a statistically significant correlation equation, and (e) mapping of the receptor space explored by the analogs. The MSA-3D-QSAR indicates that the steric shape and dipole moment of each analog governs its activity. The MSA-3D-QSAR correlation equations are more predictive than other QSARs as measured by cross-validation correlation coefficients.

Objective: To study: (a) the chlamydial antibody response (to the D-K serovars) using the micro-immunofluorescence (micro-IF) test in the following groups: (I) chlamydial genital infection only, (II) chlamydial ocular infection only, (III) combined chlamydial ocular and genital infection (oculo-genital infection), (IV) chlamydial ocular infection with chlamydia-negative non-gonococcal urethritis, (V) adenovirus conjunctivitis (control group 1), (VI) male partners of group I-IV with no chlamydial oculogenital infection or non-gonococcal urethritis (control group 2) (b) the cross reactivity of antibodies in patients' sera between the three chlamydial species and within the serovars of C trachomatis in those with culture-positive chlamydial oculo-genital infection., Setting: oculogenital (diagnostic) clinic at Moorfields Eye Hospital, London, UK., Subjects: 209 consecutive patients attending the clinic with Chlamydia trachomatis oculogenital infection and 86 patients with adenovirus conjunctivitis (control group 1) and 55 male partners with no evidence of chlamydial oculogenital infection or non-gonococcal urethritis (control group 2)., Results: Of all the patients with proven chlamydial oculogenital infection, 10.5% (22/209) and 94% (197/209) had IgM and IgG antibodies respectively. The geometric mean IgG antibody titres (GMT) were 1:98, 1:123, 1:245 and 1:101 in groups I to IV respectively. The IgG GMT values seen in control groups 1 and 2 were 1:45 and 1:36 respectively. Only 2/86(2%) patients in group V (control group 1) had IgG chlamydial antibodies of 1:32 and 1:64, whilst only 1/55(1.8%) and 4/55(7.3%) of patients in group VI(control group 2) had chlamydial IgG antibody titres of > or = 1:256 and > or = 1:128 respectively. A four-fold rise or fall in IgG antibody titre occurred in 56%(107/192) of patient groups I-IV over 2-6 weeks. Low titre cross-reactive antibody responses against different chlamydial species and serovars were commonly seen; 71%(148/209) of all patients showed cross-reactivity with Chlamydia pneumoniae or psittaci species or both, whilst 92% (193/209) of patients showed some level of cross reactivity to other pooled serovars of C trachomatis (A-C and L 1-3)., Conclusions: Serological diagnosis of chlamydial infection as evidenced by a positive IgM antibody response, high IgG titre (> or = 1:256) or > or = 4-fold rise or fall in IgG antibody titre was seen in 78%(163/209) of patients with culture-positive chlamydial oculogenital infection. Chlamydial IgG antibody titres of > or = 1:256 had a sensitivity of 42.6%, specificity of 98.2%, positive predictive value of 98.8% and a negative predictive value of 31% for chlamydial infection at any site, when considering groups I-IV and control group 2. In this study of 216 patients with conjunctivitis, a positive IgG antibody response (titre > or = 1:16) had a sensitivity of 98.5%, specificity of 97.7%, positive predictive value of 98.5% and a negative predictive value of 97.7%, for chlamydial conjunctivitis. Patients with dual chlamydial infection of conjunctiva and genital tract had a higher IgG GMT titre than those with ocular or genital infection alone: infection at a second site may produce an anamnestic response. Although the micro-IF test is a useful adjunct for the diagnosis of chlamydial infection, cross-reactivity between different chlamydial species and serovars is common. Chlamydial seroepidemiological studies should be interpreted with caution, as studies may attribute a serological response to a particular species or serovar in a setting where two or more are prevalent.

There are several lines of evidence clearly demonstrating that major histocompatibility complex (MHC) class I antigens are important in protecting haemopoietic tumour cells from natural killer (NK)-mediated cell lysis. In the present studies we examined the role of MHC class II antigens in affording such protection to haemopoietic tumour cell lines. NK and lymphokine-activated killer (LAK) lysis were performed on two human B lymphoma cell lines and their mutants lacking HLA class II expression, i.e. DR, DP and DQ. Raji and T5-1 were compared to their mutants RM3 and 6.1.6, respectively. Significantly more lysis was observed with the mutants compared to the parent cell line. Effectors used included (1) peripheral blood NK effectors, (2) a human NK cell line (NK 3.3), and (3) peripheral blood LAK effectors. The increased lysis with the mutants could not be explained on the basis of (1) increased conjugate formation, (2) increased cell fragility or (3) ineffectual expression of HLA class I and other non-HLA antigens. These findings suggest that HLA class II molecules may have a novel role. They may be relevant not only in antigen presentation but may also protect tumour cells (and possibly normal activated lymphoid cells) against lysis mediated by NK and LAK cells.

Fungal (Penicillium chrysogenum) and yeast (Saccharomyces cerevisiae) ATP sulfurylases were shown to have very similar kinetic and chemical properties except that the fungal enzyme (a) contains a highly reactive Cys residue (SH-1) whose modification results in sigmoidal velocity curves (Renosto, F., Martin, R. L., and Segel, I. H. (1987) J. Biol. Chem. 262, 16279-16288) and (b) is allosterically inhibited by 3'-phosphoadenosine 5'-phosphosulfate (PAPS), while the yeast enzyme displays neither of these properties. The fungal enzyme subunit (64.3 kDa, 572 amino acids) is also larger than the yeast enzyme subunit (59.3 kDa, 521 amino acids). To correlate the unique allosteric properties of the fungal enzyme with specific structural features, we cloned and sequenced the ATP sulfurylase gene (aps) from P. chrysogenum. The yeast and fungal enzymes are homologous over the first 400 amino acids and contain two regions high in basic residues which are conserved in sulfurylases from Arabidopsis and the Riftia pachyptila (hydrothermal vent tube worm) chemolithotrophic symbiont. These regions may participate in forming the binding sites for MgATP2- and SO4(2-). The fungal enzyme has no sites for MgATP2- and SO4(2-). The fungal enzyme has no significant sequence homology to the yeast enzyme in the C-terminal 172 amino acids. This C-terminal region contains SH-1 (Cys-508) and has homology to MET14 (S. cerevisiae), CYSC (E. coli), and NODQ (Rhizobium meliloti), i.e. adenosine 5'-phosphosulfate (APS) kinase. The cumulative results suggest that (a) the allosteric PAPS binding site of P. chrysogenum ATP sulfurylase is located in the C-terminal domain of the protein and (b) that this domain may have evolved from APS kinase. In spite of the homology, this C-terminal region does not account for the APS kinase activity of P. chrysogenum. Fungal ATP sulfurylase has no significant homology to (or regulatory properties in common with) CYSD or CYSN, proteins reported to comprise E. coli ATP sulfurylase (Leyh, T., Vogt, T. F., and Suo, Y. (1992) J. Biol. Chem. 267, 10405-10410).

Records on 254 patients with chlamydial ocular infection observed over a period of 67 months at the Moorfield's Eye Hospital were reviewed retrospectively in relation to sexual partners in the 6 months prior to diagnosis. Contactable partners were given an appointment through index patients to attend our clinic. Those unable to attend were issued contact slips, as used by the sexually transmitted disease (STD) clinics in the United Kingdom, to attend elsewhere: 175/328 (53%) of all partners were seen in our clinic: 161/218 (74%) of current regular partners compared to only 7/57 (12%) of ex-regular and 7/53 (13%) of casual partners. However, of those given appointments 175/201 (87%) attended: 161/179 (90%) of current regular, 7/14 (50%) of ex-regular and 7/8 (88%) of casual partners. Seventy of 328 (21%) of all partners were issued contact slips, of whom 47/70 (67%) were reported to have attended elsewhere. No contact slips were returned by other clinics, indicating a failure in the contact slip system. Thirty-five of 53 (66%) of casual, 22/57 (39%) of ex-regular and none of the current regular partners were untraceable. One hundred and five of 196 (54%) female partners were examined, of whom 59/105 (56%) had chlamydial genital infection, 45/105 (43%) had other genital infections and 35/105 (33%) had multiple genital infections. Seventy of 132 (53%) male partners were examined, of whom 58/70 (83%) had chlamydial or non-specific urethritis, 5/70 (7%) had other genital infections and 4/70 (6%) had multiple genital infections. Partner notification is important to interrupt chlamydia transmission.(ABSTRACT TRUNCATED AT 250 WORDS)

Two forms of ATP sulfurylase were purified from spinach leaf. The major (chloroplast) form accounts for 85 to 90% of the total leaf activity (0.03 +/- 0.01 adenosine-5'-phosphosulfate (APS) synthesis units x gram fresh weight-1). Both enzyme forms appear to be tetramers composed of 49- to 50-kDa subunits with the minor (cytosolic) form being slightly larger than the chloroplast form. The specific activities (units x milligram protein-1) of the chloroplast form at pH 8.0, 30 degrees C, were as follows: APS synthesis, 16; molybdolysis, 229; ATP synthesis, 267; selenolysis, 4.1; fluorophosphate activation, 11. Kinetic constants for the physiological reaction were as follows: KmA = 0.046 mM, K(ia) = 0.85 mM, KmB = 0.25 mM, KmQ = 0.37 microM, K(iq) = 64-85 nM, and KmP = 10 microM, where A = MgATP, B = SO4(2-), P = total PPi at 5 mM Mg2+, and Q = APS. The kinetic constants for molybdolysis were similar to those of the APS synthesis reaction. The kinetic constants of the minor (cytosol) form were similar to those of the major form with two exceptions: (a) The molybdolysis activity was 120 units x milligram protein-1, yielding a Vmax (ATP synthesis)/Vmax (molybdolysis) ratio close to 2 (compared to about unity for the chloroplast form) and (b) KmA was greater (0.24 and 0.15 mM for APS synthesis and molybdolysis, respectively). Initial velocity measurements (made over an extended range of MgATP and SO4(2-) concentrations), product inhibition studies (by initial velocity methods and by reaction progress curve analyses), dead end inhibition studies (with monovalent and divalent oxyanions), and kcat/Km comparisons (for SO4(2-) and MoO4(2-) support a random AB-ordered PQ kinetic mechanism in which MgATP and SO4(2-) bind in a highly synergistic manner. Equilibrium binding studies indicated the presence of one APS site per subunit. HPLC elution profiles of chymotryptic and tryptic peptides were essentially the same for both enzyme forms. The N-terminal sequence of residues 5-20 of the cytosol enzyme was identical to residues 1-16 of the chloroplast enzyme.

This study indicates that 3-mercaptopyruvate sulphurtransferase (MPST; EC 2.8.1.2) activity may serve as a useful in vitro indicator for the analysis of cyanide detoxification to thiocyanate. The time course and capacity of MPST to detoxify cyanide was equal to or exceeded that of rhodanese. Picrylsulphonic acid strongly inhibited purified rhodanese, but in the presence of mercaptopyruvate, it could increase the formation of thiocyanate catalysed by MPST. Formation of thiocyanate by MPST followed a linear time course and had a linear relation to enzyme level. However, substrate dependence did not produce linear Lineweaver-Burk plots when either mercaptopyruvate or cyanide concentration was varied. The differential effect of picrylsulphonic acid on the activities of these two enzymes was confirmed by using a crude kidney extract as the source of both enzymes. Picrylsulphonic acid may provide a useful scientific tool to examine which sulphurtransferase is most responsible for the detoxification of cyanide.

Conformations of model peptides of the adhesive protein of the mussel, Mytilus edulis L were investigated using molecular mechanics. The protein structure was represented as the repeat of a 10-residue unit. This decamer, and di- and tri-decamers of it, were considered in the modeling. Incorporation of the unusual dopamine residue in the decamer repeat may be explained by its hydrogen bond forming ability via its 3-OH group to a proline carbonyl oxygen. This bond contributes to maintaining a double reverse beta-turn structure in the decamer. This conformation was found more stable than 3(1) and alpha helical conformations. Adjacent reverse beta-turn structures are connected by short segments (2 to 3 residues) having little conformational preference. Thus, the overall protein can possess a significant random nature, yet have a highly ordered embedded conformational component. Hydrophilic character is in line with the larger number of OH groups on the phenyl ring for residue 9 (the site of the Dopa residue). The dehydration free energy of the (3-OH)-Phe as compared to the Dopa derivative is less by 1.4 kcal per decamer unit. This amounts to more than 100 kcal energy gain in the dehydration process for the total protein.

The results of X-ray studies on 19 structures containing dehydro residues have been analysed. The observed average C alpha = C beta distance in the dehydro residues is 1.331 (2) A. The average values of the C alpha = C beta - C gamma bond angle in dehydro-Phe and dehydro-Leu are 131.2 (2) and 127.3 (1) degrees, respectively. The dehydro residue is essentially planar. A beta-turn of type II is formed if the dehydro residue is placed either at the (i + 1) or at the (i + 2) corner position of the beta-turn. If the dehydro residues occur consecutively in an amino-acid sequence, the backbone folds into an alternating right- and left-handed alpha-helix. The peptide bond is planar in all these structures. The beta-turn is stabilized by an intramolecular hydrogen bond between CO of the ith and NH of the (i + 3)th residue.

The peptide N-Boc-L-Phe-dehydro-Leu-L-Val-OCH3 was synthesized by the usual workup procedure and finally by coupling the N-Boc-L-Phe-dehydro-Leu-OH to valine methyl ester. It was crystallized from its solution in methanol-water mixture at 4 degrees C. The crystals belong to the triclinic space group P1 with a = 5.972(5) A, b = 9.455(6) A, c = 13.101(6) A, alpha = 103.00(4) degrees, beta = 97.14(5) degrees, gamma = 102.86(5) degrees, V = 690.8(8) A, Z = 1, dm = 1.179(5) Mg m-3 and dc = 1.177(5) Mg m-3. The structure was determined by direct methods using SHELXS86. It was refined by block-diagonal least-squares procedure to an R value of 0.060 for 1674 observed reflections. The C alpha 2-C beta 2 distance of 1.323(9) A in dehydro-Leu is an appropriate double bond length. The bond angle C alpha-C beta-C gamma in the dehydro-Leu residue is 129.4(8) degrees. The peptide backbone torsion angles are theta 1 = -168.6(6) degrees, omega 0 = 170.0(6) degrees, phi 1 = -44.5(9) degrees, psi 1 = 134.5(6) degrees, omega 1 = 177.3(6) degrees, phi 2 = 54.5(9) degrees, psi 2 = 31.1(10) degrees, omega 2 = 171.7(6) degrees, phi 3 = 51.9(8) degrees, psi T3 = 139.0(6) degrees, theta T = -175.7(6) degrees. These values show that the backbone adopts a beta-turn II conformation. As a result of beta-turn, an intramolecular hydrogen bond is formed between the oxygen of the ith residue and NH of the (i + 3)th residue at a distance of 3.134(6) A.(ABSTRACT TRUNCATED AT 250 WORDS)

The peptide N-Boc-L-Pro-dehydro-Phe-L-Gly-OH was synthesized by the usual workup procedure and finally coupling the N-Boc-L-Pro-dehydro-Phe to glycine. The peptide crystallizes in monoclinic space group P2(1) with a = 8.951(4) A, b = 5.677(6) A, c = 21.192(11) A, beta = 96.97(4) degrees, V = 1069(1) A3, Z = 2, dm = 1.295(5) Mgm-3, and dc = 1.297(4) Mgm-3. The structure was determined by direct methods using SHELXS86. The structure was refined by the block-diagonal least-squares procedure to an R value of 0.074 for 1002 observed reflections. The C alpha 2-C beta 2 distance of 1.33(2) A is an appropriate double bond length. The angle C alpha 2-C beta 2-C gamma 2 is 133(1) degrees. The peptide backbone torsion angles are theta 1 = -167(1) degrees, omega 0 = 179(1) degrees, phi 1 = -48(1) degrees, psi 1 = 137(1) degrees, omega 1 = 175(1) degrees, phi 2 = 65(2) degrees, psi 2 = 15(2) degrees, omega 2 = -179(1) degrees, and phi 3 = -166(1) degrees. These values show that the Boc group has a trans-trans conformation while the peptide backbone adopts a beta-turn II conformation, which is stabilized by an intramolecular hydrogen bond of length of 3.05(1) A. The structures of dehydro-Phe containing peptides suggest that the dehydro-Phe promotes the beta-turn II conformation. The five-membered pyrrolidine ring of the Pro residue adopts an ideal C gamma-exo conformation with torsion angles chi 1(1) = -24(1) degrees, chi 2(1) = 34(1) degrees, chi 3(1) = -30(1) degrees, chi 4(1) = 15(1) degrees, and theta 0(1) = 6(1) degrees. The side-chain torsion angles in dehydro-Phe are chi 1(2) = -1(2) degrees, chi 2,1(2) = -176(1) degrees, and chi 2,2(2) = 8(2) degrees. The plane of C alpha 2-C beta 2-C gamma 2 is rotated with respect to the plane of the phenyl ring at 7(1) degrees, which indicates that the atoms of the side chain of dehydro-Phe are essentially coplanar. The molecules form a 2(1) screw axis related hydrogen-bonded rows along the b axis.

Addition of biotin to culture medium NL-406 significantly increased alkaloid yield during submerged cultivation of Claviceps sp. strain SD-58. Alkaloid yield was further enhanced by incorporating leucine in biotin-supplemented culture medium. Increased alkaloid production was associated with an increase in the lipid content of cells and in the number of chlamydospores. Biotin deficiency caused a reduction in alkaloid yield and a parallel decrease in lipid content and chlamydospore numbers.

An 86-year-old woman with visual impairment who developed a vivid, visual hallucinatory state in clear sensorium is described. This picture conforms to the description of Charles Bonnet Syndrome. She also experienced musical hallucinations. The role of sensory deprivation in the pathogenesis of this syndrome is discussed.