Toward the Copolymerization of Propylene with Polar Comonomers.

Polyolefins are produced in vast amounts and are found in so many consumer products that the two most commonly produced forms, polyethylene (PE) and polypropylene (PP), fall into the rather sparse category of molecules that are likely to be known by people worldwide, regardless of their occupation. Although widespread, the further upgrading of their properties (mechanical, physical, aesthetic, etc.) through the formation of composites with other materials, such as polar polymers, fibers, or talc, is of huge interest to manufacturers. To improve the affinity of polyolefins toward these materials, the inclusion of polar functionalities into the polymer chain is essential. The incorporation of a functional group to trigger controlled polymer degradation is also an emerging area of interest. Currently practiced methods for the incorporation of polar functionalities, such as post-polymerization functionalization, are limited by the number of compatible polar monomers: for example, grafting maleic anhydride is currently the sole method for practical functionalization of PP. In contrast, the incorporation of fundamental polar comonomers into PE and PP chains via coordination insertion polymerization offers good control, making it a highly sought-after process. Early transition metal catalysts (which are commonly used for the production of PE and PP) display poor tolerance toward the functional groups within polar comonomers, limiting their use to less-practical derivatives. As late transition metal catalysts are less-oxophilic and thus more tolerant to polar functionalities, they are ideal candidates for these reactions. This Account focuses on the copolymerization of propylene with polar comonomers, which remains underdeveloped as compared to the corresponding reaction using ethylene. We begin with the challenges associated with the regio- and stereoselective insertion of propylene, which is a particular problem for late transition metal systems because of their propensity to undergo chain walking processes. To overcome this issue, we have investigated a range of metal/ligand combinations. We first discuss attempts with group 4 and 8 metal catalysts and their limitations as background, and then focus on the copolymerization of propylene with methyl acrylate (MA) using Pd/imidazolidine-quinolinolate (IzQO) and Pd/phosphine-sulfonate (PS) precatalysts. Each generated regioregular polymer, but while the system featuring an IzQO ligand did not display any stereocontrol, that using the chiral PS ligand did. A further difference was found in the insertion mode of MA: the Pd/IzQO system inserted in a 1,2 fashion, while in the Pd/PS system a 2,1 insertion was observed. We then move onto recent results from our lab using Pd/PS and Pd/bisphosphine monoxide (BPMO) precatalysts for the copolymerization of propylene with allyl comonomers. These P-stereogeneic precatalysts generated the highest isotacticity values reported to date using late transition metal catalysts. This section closes with our work using Earth-abundant nickel catalysts for the reaction, which would be especially desired for industrial applications: a Ni/phosphine phenolate (PO) precatalyst yielded regioregular polypropylene with the incorporation of some allyl monomers into the main polymer chain. The installation of a chiral menthyl substituent on the phosphine allowed for moderate stereoselectivity to be achieved, though the applicable polar monomers currently remain limited. The Account concludes with a discussion of the factors that affect the insertion mode of propylene and polar comonomers in copolymerization reactions, beginning with our recent computational study, and finishing with work from ourselves and others covering both comonomer and precatalyst steric and electronic profiles with reference to the observed regioselectivity.

Unravelling the Photochemical Transformations of Chromium(I) 1,3 Bis(diphenylphosphino), [Cr(CO)4(dppp)]+, by EPR Spectroscopy.

UV-induced photochemical transformations of the paramagnetic [Cr(CO)4(Ph2PCH2CH2CH2PPh2)]+ complex (abbreviated [Cr(CO)4(dppp)]+) in dichloromethane was investigated by CW EPR spectroscopy. Room-temperature UV irradiation results in the rapid transformation of [Cr(CO)4(dppp)]+ into trans-[Cr(CO)2(dppp)2]+. However, low-temperature (77-120 K) UV irradiation reveals the presence of an intermediate mer-[Cr(CO)3(κ1-dppp)(κ2-dppp)]+ complex which photochemically transforms into trans-[Cr(CO)2(dppp)2]+. The derived spin Hamiltonian parameters for these complexes were confirmed by DFT calculations. The photoinduced reaction is shown to be concentration-dependent, leading to a distribution of the three complexes ([Cr(CO)4(dppp)]+, mer-[Cr(CO)3(κ1-dppp)(κ 2-dppp)]+, and trans-[Cr(CO)2(dppp)2]+). A bimolecular photoinduced mechanism is proposed to account for the formation of mer-[Cr(CO)3(κ1-dppp)(κ2-dppp)]+ and trans-[Cr(CO)2(dppp)2]+.

Time to return to full training is delayed and recurrence rate is higher in intratendinous ('c') acute hamstring injury in elite track and field athletes: clinical application of the British Athletics Muscle Injury Classification.

BACKGROUND: The British Athletics Muscle Injury Classification describes acute muscle injuries and their anatomical site within muscle based on MRI parameters of injury extent. It grades injuries from 0 to 4 and classifies location based on a myofascial (a), musculotendinous (b) or intratendinous (c) description. This is a retrospective cohort study that assessed time to return to full training (TRFT) and injury recurrence in the different British Athletics classifications for hamstring injuries sustained by elite track and field (T&F) athletes over a 4-year period. METHODS: The electronic medical records (EMRs) of 230 elite British T&F athletes were reviewed. Athletes who sustained an acute hamstring injury, with MRI investigation within 7 days of injury, were included. MRI were graded by two musculoskeletal radiologists using the British Athletics Muscle Injury Classification. The EMRs were reviewed by 2 sports physicians, blinded to the new classification; TRFT and injury recurrence were recorded. RESULTS: There were 65 hamstring injuries in 44 athletes (24±4.4 years; 28 male, 16 female). TRFT differed among grades (p<0.001). Grade 3 injuries and 'c' injuries took significantly longer and grade 0 injuries took less TRFT. There were 12 re-injuries; the injury recurrence rate was significantly higher in intratendinous (c) injuries (p<0.001). There was no difference in re-injury rate between number grades 1-3, hamstring muscle affected, location (proximal vs central vs distal), age or sex. CONCLUSIONS: This study describes the clinical application of the British Athletics Muscle Injury Classification. Different categories of hamstring injuries had different TRFT and recurrence rate. Hamstring injuries that extend into the tendon ('c') are more prone to re-injury and delay TRFT.

Adjunctive pregabalin for uncontrolled partial-onset seizures: findings from a prospective audit.

AIMS: Pregabalin (PGB) was licensed in Europe as an add-on antiepileptic drug (AED) for the treatment of partial-onset seizures in 2004. This audit assessed the response to adjunctive PGB in patients with uncontrolled seizures. METHODS: PGB was titrated in 135 patients [73 men; 62 women, aged 18-76 (median 44 years) until one of the following occurred: ≥ 6 months' seizure freedom, ≥ 50% or < 50% seizure reduction over 6 months; PGB withdrawal because of adverse effects, lack of efficacy or both. RESULTS: Of the 135 patients, 14 (10.4%) became seizure-free for ≥ 6 months (median PGB dose 300 mg/day; range 75-600 mg). A ≥ 50% seizure reduction occurred in 33 (24.4%) patients; 20 (14.8%) had < 50% reduction. PGB was withdrawn in 68 (50.4%) (40 adverse effects, seven lack of efficacy and 21 both). Commonest problems resulting in withdrawal were sedation (n = 18), weight gain (n = 14) and ataxia (n = 9). There was a positive correlation between increasing dose and weight gain (r = 0.42, P = 0.045). CONCLUSIONS: Add-on PGB benefited 50% of patients, but only 10% achieved 6 months' seizure freedom. Adverse effects, most commonly sedation, dose-related weight gain and ataxia, led to drug discontinuation by 45%. Prospective audits of novel AEDs are a useful adjunct to randomized, controlled trials in managing epilepsy.

Which electroencephalography (EEG) for epilepsy? The relative usefulness of different EEG protocols in patients with possible epilepsy.

BACKGROUND AND AIMS: Electroencephalography (EEG) is an essential investigative tool for use in young people with epilepsy. This study assesses the effects of different EEG protocols on the yield of EEG abnormalities in young people with possible new epilepsy. METHODS: 85 patients presenting to the unit underwent three EEGs with differing protocols: routine EEG (r-EEG), sleep-deprived EEG (SD-EEG), EEG carried out during drug-induced sleep (DI-EEG). The yield of EEG abnormalities was compared using each EEG protocol. RESULTS: 98 patients were recruited to the study. Of the 85 patients who completed the study, 33 (39%) showed no discernible abnormality on any of their EEG recordings. 36 patients (43%) showed generalised spike and wave during at least one EEG recording, whereas 15 (18%) had a focal discharge evident at some stage. SD-EEG had a sensitivity of 92% among these patients, whereas the sensitivity of DI-EEG and r-EEG was 58% and 44%, respectively. The difference between the yield from SD-EEG was significantly higher than that from other protocols (p < 0.001). Among the 15 patients showing focal discharges, SD-EEG provoked abnormalities in 11 (73%). r-EEG and DI-EEG each produced abnormalities in 40% and 27%, respectively. 7 patients (47%) had changes seen only after sleep deprivation. In 2 (13%), the only abnormalities were seen on r-EEG. In only 1 patient with focal discharges (7%) was the focal change noted solely after drug-induced sleep. These differences did not reach significance. CONCLUSION: EEG has an important role in the classification of epilepsies. SD-EEG is an easy and inexpensive way of increasing the yield of EEG abnormalities. Using this as the preferred protocol may help reduce the numbers of EEGs carried out in young patients presenting with epilepsy.

Structure and dynamics of a dihydrogen/hydride ansa molybdenocene complex.

In contrast to [Cp(2)MoH(3)](+), which is a thermally stable trihydride complex, the ansa-bridged analogue [(eta-C(5)H(4))(2)CMe(2)MoH(H(2))](+) (1) is a thermally labile dihydrogen/hydride complex. Partial deuteration of the hydride ligands allows observation of J(H)(-)(D) = 11.9 Hz in 1-d(1) and 9.9 Hz in 1-d(2) (245 K), indicative of a dihydrogen/hydride structure. There is a slight preference for deuterium to concentrate in the dihydrogen ligand. A rapid dynamic process interchanges the hydride and dihydrogen moieties in complex 1. Low temperature (1)H NMR spectra of 1 give a single hydride resonance, which broadens at very low temperature due to rapid dipole-dipole relaxation (T(1) = 23 ms (750 MHz, 175 K) for the hydride resonance in 1). Low temperature (1)H NMR spectra of 1-d(2) allow the observation of decoalescence at 180 K into two resonances. The bound dihydrogen ligand exhibits hindered rotation with DeltaG(150) = 7.4 kcal/mol, but H atom exchange is still rapid at all accessible temperatures (down to 130 K). Density functional calculations confirm the dihydrogen/hydride structure as the ground state for the molecule and give estimates for the energy of two hydrogen exchange processes in good agreement with experiment. The presence of the C ansa bridge is shown to decrease the ability of the metallocene fragment to donate to the hydrogens, thus stabilizing the (eta(2)-H(2)) unit and modulating the barrier to H(2) rotation.

Peripheral retinal dysfunction in patients taking vigabatrin.

OBJECTIVE: To assess the wide-field multifocal electroretinogram (WF-mfERG) for assessment of retinal function in vigabatrin-treated patients. METHODS: Thirty-two adults who had taken vigabatrin for at least 3 years for localization-related epilepsy underwent WF-mfERG, ERG, logMar visual acuity and color vision evaluation, Humphrey visual field analysis (static perimetry), and funduscopy. The group was matched with a cohort of patients who had never received vigabatrin. Results were compared with a normative data set (120 drug-free controls) with respect to potential bilateral abnormalities in response timing. RESULTS: There were no significant differences between groups in visual acuity or color vision testing. Of the vigabatrin patients, 19 (59%) had bilateral visual field defects compared to none of the controls. Using WF-mfERG, all patients on vigabatrin with visual field defects showed abnormalities (100% sensitivity) and only 2 of the 13 patients without a field defect showed retinal abnormalities (86% specificity). CONCLUSIONS: WF-mfERG may be useful for detecting retinal pathology in patients taking vigabatrin. The majority of previous reports based on subjective testing may have underestimated the prevalence of peripheral retinal toxicity related to the drug.

Hormone profiles in young adults with epilepsy treated with sodium valproate or lamotrigine monotherapy.

PURPOSE: Treatment with sodium valproate (VPA) may be associated with polycystic ovarian syndrome (PCOS) in some women with epilepsy. By comparing hormone profiles in young adults taking VPA or lamotrigine (LTG) as monotherapy, this study aimed to explore whether a pharmacologic effect of VPA could be responsible for this observation. METHODS: Hormone profiles in men and women taking VPA (n = 40) or LTG (n = 36) monotherapy for epilepsy were compared. None of the women were receiving hormonal contraception or replacement. Patients gave details of seizure type and frequency, menstrual cycle, and medical and drug history. Body mass index was calculated, and fasting insulin, glucose, cholesterol, triglycerides (TG), high- and low-density lipoproteins, testosterone, dihydroepiandosterone (DHEA), androstenedione, sex hormone-binding globulin (SHBG), free androgen index (FAI), luteinising hormone (LH), follicle-stimulating hormone (FSH), and antiepileptic drug (AED) concentrations were measured. RESULTS: There were no differences between treatment groups for both sexes in age and seizure control. Only four obese VPA-treated women were hyperinsulinaemic (p = 0.05); three with abnormal menstrual cycles; one with raised testosterone. Testosterone (p = 0.02), FAI (p = 0.03), and TG (p = 0.02) levels were higher, however, in women taking the drug. Obese patients of both sexes (p = 0.01) and VPA-treated men (p = 0.03) had higher insulin concentrations. CONCLUSIONS: VPA therapy may be associated with subclinical elevation in fasting insulin levels. Testosterone and TG levels were higher in VPA-treated women compared with the levels in those taking LTG. However, only a minority of obese females exhibited biochemical characteristics suggestive of PCOS. Biochemical screening may allow women at risk of developing PCOS to avoid VPA.

Does the cause of localisation-related epilepsy influence the response to antiepileptic drug treatment?

PURPOSE: We investigated the response to antiepileptic drug (AED) therapy in patients with localisation-related epilepsy associated with different underlying causes. METHODS: Five hundred and fifty adolescent and adult patients who had partial epilepsy treated with AEDs and who had undergone magnetic resonance imaging of brain were followed up prospectively from 1984 at a single centre. More than 70% were newly diagnosed. None had had epilepsy surgery. RESULTS: Three hundred and twelve (57%) patients had been seizure free at their last clinic visit for at least a year. Patients with mesial temporal sclerosis (MTS; n = 73, 42% seizure free) were less likely to be controlled (p < 0.01) than were those with arteriovenous malformation (AVM; n = 14, 78%), cerebral infarction (n = 46, 67%), primary tumour (n = 35, 63%), cortical gliosis (n = 81, 57%), cerebral atrophy (n = 49, 55%), and cortical dysplasia (CD; n = 63, 54%). Among the seizure-free patients, those with MTS were more likely to require more than one AED compared with those with other aetiologies (48 vs. 35%; p < 0.05). There was no difference in outcome between patients with symptomatic and cryptogenic epilepsy (n = 361, 58% vs. n = 189, 56% seizure free, respectively). Patients with MTS, CD, and cryptogenic epilepsy were more likely (p = 0.02) to have a family history of epilepsy than were the other groups. MTS patients also had a higher incidence of febrile convulsions (p < 0.001). CONCLUSIONS: The majority of patients with focal-onset epilepsy became seizure free on AED treatment. MTS-related seizures had the worst prognosis. Although many patients with this pathology may benefit from epilepsy surgery, a considerable number will be controlled with AED therapy.

Topiramate in refractory epilepsy: a prospective observational study.

PURPOSE: This prospective observational study explored the efficacy and tolerability of topiramate (TPM) in patients with refractory epilepsy attending a single outpatient clinic. METHODS: One hundred seventy patients (82 men, 88 women, aged 18-75 years) with refractory localization-related (n = 134) or idiopathic generalized epilepsy (n = 36) were started on adjunctive TPM using a standard titration schedule. TPM was introduced after a 3-month prospective baseline, and doses were adjusted according to clinical response. End points were seizure freedom for 6 months, > or =50% seizure reduction for 6 months compared with baseline at the highest tolerated TPM dose (responder), or discontinuation of TPM because of side effects, lack of efficacy, or both. RESULTS: Thirty-nine (23%) patients were seizure-free, and 80 (47%) more patients had a useful therapeutic response. Thirteen seizure-free patients and 16 responders took 100 mg of TPM daily or less. TPM was discontinued in 51 (30%) patients. The most common side effects resulting in withdrawal were fatigue, weight loss, irritability, paresthesia, depression, and headache. Concomitant antiepileptic drugs (AEDs) were stopped in 30 patients. Twelve were established on TPM monotherapy, eight of whom remained seizure-free. Final TPM doses and concentrations varied widely among the three outcome groups. CONCLUSIONS: TPM was efficacious as add-on and monotherapy in patients with refractory partial and generalized seizures in everyday clinical use. A good response was obtained in many patients with TPM doses substantially lower than those studied in regulatory clinical trials. The wide variation in dose-response and dose-toxicity relationships may reflect different neurobiologies causing refractory epilepsy and differential efficacy of AED combinations.

Epilepsy in elderly people.

The prevalence and incidence of epilepsy are highest in later life with around 25% of new cases occurring in elderly people, many of whom will have concomitant neurodegenerative, cerebrovascular, or neoplastic disease. Difficulties accepting the diagnosis are frequently compounded by its unpredictable nature. Those affected commonly lose confidence and independence. Seizures in older people can result in physical injury, adding to low morale. Complete control is achievable in around 70% of patients with antiepileptic drug treatment. Optimum management requires rapid investigation, accurate diagnosis, effective treatment, sympathetic education, and assured support. The emergence of seizure disorders in old age places an increasing burden on health-care facilities and costs. A coordinated programme among health-care workers is advised to maintain the independence and improve the quality of life of this vulnerable patient population.

Bone density and antiepileptic drugs: a case-controlled study.

This case-controlled study explored the relationship between bone mineral density (BMD) and long-term treatment with antiepileptic drugs (AEDs) in older adults with epilepsy. Seventy-eight patients (47 post-menopausal females, 31 males, aged 47-76 years) with epilepsy participated in the study. Each had only ever received treatment with either enzyme-inducing (n = 52) or non-inducing (n = 26) AEDs. Individuals were matched for age, sex, height and weight with a drug-naive control. All patients underwent bone densitometry at the lumbar spine and femoral neck and had blood sampling and urine collected for a range of bone markers. Male patients had lower BMD than controls at the lumbar spine (P < 0.01) and neck of the femur (P < 0.005). Female patients had significantly reduced bone density at the femoral neck (P < 0.05) only. AED usage was independently associated with an overall reduction in bone density at femoral sites and contributed to just over 5% of the variance at the femoral neck. Duration of treatment and type of AED were not independent factors for reduction in BMD. This case-controlled study supports the hypothesis that long-term AED therapy is an independent risk factor for reduced BMD in epileptic patients. Adults receiving treatment for epilepsy are at higher risk of osteoporosis and should be offered bone densitometry.

Factors influencing infant feeding practices of mothers in Vancouver.

This study describes factors influencing infant feeding choices of 434 mothers with 9-month-old infants in Vancouver. Consistent with Social Cognitive Theory, both internal personal and socio-environmental factors influence infant feeding choices. Mothers attributed the choice to breastfeed primarily to personal choice, whereas the choice to formula feed was attributed to socio-environmental factors. Among mothers who breastfed < 3 months, the choice to wean was primarily attributed to concern for baby's nutrition; compared to returning to work, concern about milk supply and concern for baby's nutrition among those who breastfed > or = 3 to < 6 months; and returning to work and personal choice among those who breastfed > or = 6 months. Among Caucasian mothers, the choice to wean was primarily attributed to returning to work, compared to concern for baby's nutrition among non-Caucasian mothers. Initiatives to facilitate further advances in breastfeeding promotion could address three areas: 1) prenatal intentions, 2) early postpartum concerns, and 3) later issues surrounding returning to work and infant nutrition.

Cognitive effects of anticonvulsant monotherapy in elderly patients: a placebo-controlled study.

Old age is recognized to be the commonest time in life to develop epilepsy. There is a perception that older patients are more sensitive to the deleterious cognitive effects of antiepileptic drugs (AEDs). Elderly patients (median age 70 years, range 60-88 years) taking anticonvulsant monotherapy (10 carbamazepine [CBZ], 8 sodium valproate [VPA], 5 phenytoin [PHT]) took an extra dose of their usual medication (200mg CBZ, 500mg VPA, 100mg PHT) and matched placebo each for a month in random order. The concentrations of AEDs were higher after 7 and 28 days of active treatment compared with placebo (7 days: CBZ 9.5 vs. 7.8 mg L(-1), p < 0.05; VPA 97 vs. 64 mg L(-1), p < 0.05; PHT 13 vs. 11 mg L(-1), p < 0.05; 28 days: CBZ 9.4 vs. 7.7 mg L(-1); p < 0.01, VPA 85 vs. 60 mg L(-1), p < 0.05; PHT 16 vs. 13 mg L(-1), p < 0.05). Despite these increases in concentration, there were no significant changes in attention, reaction time, finger tapping, memory, side-effect scale or sedation scoring during the active phases compared with placebo phases for the three drugs analysed together and separately. Elderly patients taking standard AEDs as monotherapy did not develop cognitive impairment when the dose was modestly increased within the target range for each drug.

An islander with seizures.

This case describes a man with progressive refractory epilepsy whose death was witnessed during a seizure. Initial brain imaging was normal, but following prolonged episodes of non-convulsive status epilepticus, progressive right-sided temporal atrophy developed over a period of two years. The clinical picture and postmortem examination were consistent with the diagnosis of Rasmussen's encephalitis, a rare condition with a bleak prognosis.

Are 'homeopathic' doses of oral corticosteroids effective in rheumatoid arthritis?

When patients with rheumatoid arthritis whose clinical disease activity was stable had their oral prednisolone of less than 5 mg per day (mean 3.5 mg) replaced by placebo, there was an almost immediate flare in their arthritis. This confirms that such low dose prednisolone therapy is effective in controlling joint inflammation.