Ultrafast nonadiabatic dynamics probed by nitrogen K-edge absorption spectroscopy.

The emergence of X-ray free electron lasers (X-FELs) has made it possible to probe structural dynamics on the femtosecond timescale. This extension of experimental capabilities also calls for a simultaneous development in theory to help interpret the underlying structure and dynamics encoded within the experimental observable. In the ultrafast regime this often requires a time-dependent theoretical treatment that describes nuclear dynamics beyond the Born-Oppenheimer approximation. In this work, we perform quantum dynamics simulations based upon time-evolving Gaussian basis functions (GBFs) and simulate the ultrafast X-ray Absorption Near-Edge Structure (XANES) spectra of photoexcited pyrazine including two strongly coupled electronically excited states and four normal mode degrees of freedom. Two methods to simulate the excited state XANES spectra are applied, the first is based upon the multi-configurational second order perturbation theory restricted active space (RASPT2) method and the second uses a combination of the maximum overlap method (MOM) and time-dependent density functional theory (TDDFT). We demonstrate that despite the simplicity of the MOM/TDDFT method, it captures several qualitative features of the RASPT2 simulations at much reduced computational effort. However, features such as the conical intersection are a particular exception as they require a multi-configurational treatment. For the nuclear dynamics, we demonstrate that even a small number of GBFs can provide reasonable description of the spectroscopic observable. This work provides perspectives for computationally efficient approaches important for addressing larger systems.

Ab initio simulations of complementary K-edges and solvatization effects for detection of proton transfer in aqueous 2-thiopyridone.

The nitrogen and sulfur K-edge X-ray absorption spectra of aqueous 2-thiopyridone, a model system for excited-state proton transfer in several recent time-resolved measurements, have been simulated from ab initio molecular dynamics. Spectral signatures of the local intra- and inter-molecular structure are identified and rationalized, which facilitates experimental interpretation and optimization. In particular, comparison of aqueous and gas phase spectrum simulations assesses the previously unquantified solvatization effects, where hydrogen bonding is found to yield solvatochromatic shifts up to nearly 1 eV of the main peak positions. Thereby, while each K-edge can still decisively determine the local protonation of its core-excited site, only their combined, complementary fingerprints allow separating all of the three relevant molecular forms, giving a complete picture of the proton transfer.

Sudden cardiac death in diabetes mellitus: risk factors in the Rochester diabetic neuropathy study.

OBJECTIVES: To determine risk factors for sudden cardiac death and the role of diabetic autonomic neuropathy (DAN) in the Rochester diabetic neuropathy study (RDNS). METHODS: Associations between diabetic and cardiovascular complications, including DAN, and the risk of sudden cardiac death were studied among 462 diabetic patients (151 type 1) enrolled in the RDNS. Medical records, death certificates, and necropsy reports were assessed for causes of sudden cardiac death. RESULTS: 21 cases of sudden cardiac death were identified over 15 years of follow up. In bivariate analysis of risk covariates, the following were significant: ECG 1 (evolving and previous myocardial infarctions): hazard ratio (HR) = 4.4 (95% confidence interval (CI), 1.6 to 12.1), p = 0.004; ECG 2 (bundle branch block or pacing): HR = 8.6 (2.9 to 25.4), p<0.001; ECG 1 or ECG 2: HR = 4.2 (1.3 to 13.4), p = 0.014; and nephropathy stage: HR = 2.1 (1.3 to 3.4), p = 0.002. Adjusting for ECG 1 or ECG 2, autonomic scores, QTc interval, high density lipoprotein (HDL) cholesterol, 24 hour microalbuminuria, and 24 hour total proteinuria were significant. However, adjusting for nephropathy, none of the autonomic indices, QTc interval, HDL cholesterol, microalbuminuria, or total proteinuria was significant. At necropsy, all patients with sudden cardiac death had coronary artery or myocardial disease. CONCLUSIONS: Sudden cardiac death was correlated with atherosclerotic heart disease and nephropathy, and to a lesser degree with DAN and HDL cholesterol. Although DAN is associated with sudden cardiac death, it is unlikely to be its primary cause.

A controlled study of peripheral neuropathy after bariatric surgery.

BACKGROUND: Although peripheral neuropathy (PN) occurs after bariatric surgery (BS), a causal association has not been established. OBJECTIVES: To ascertain whether PN occurs more frequently following BS vs another abdominal surgery, to characterize the clinical patterns of PN, to identify risk factors for PN, and to assess if nerve biopsy provides pathophysiologic insight. METHODS: Retrospective review identified patients with PN after BS. The frequency of PN was compared with that of an age- and gender-matched, retrospectively evaluated cohort of obese patients undergoing cholecystectomy. RESULTS: Of 435 patients who had BS, 71 (16%) developed PN. Patients developed PN more often after BS than after cholecystectomy (4/126; 3%) (p < 0.001). The clinical patterns of PN were polyneuropathy (n = 27), mononeuropathy (n = 39), and radiculoplexus neuropathy (n = 5). Risk factors included rate and absolute amount of weight loss, prolonged gastrointestinal symptoms, not attending a nutritional clinic after BS, reduced serum albumin and transferrin after BS, postoperative surgical complications requiring hospitalization, and having jejunoileal bypass. Most risk factors were associated with the polyneuropathy group. Sural nerve biopsies showed prominent axonal degeneration and perivascular inflammation. CONCLUSIONS: Peripheral neuropathy (PN) occurs more frequently after bariatric surgery (BS) than after another abdominal surgery. The three clinical patterns of PN after BS are sensory-predominant polyneuropathy, mononeuropathy, and radiculoplexus neuropathy. Malnutrition may be the most important risk factor, and patients should attend nutritional clinics. Inflammation and altered immunity may play a role in the pathogenesis, but further study is needed.

Increased weakness after pancreas and kidney transplantation.

BACKGROUND: Already there is evidence that simultaneous pancreas and kidney (SPK), or pancreas after kidney (PAK) transplantation, in patients with type 1 diabetes mellitus and end-stage kidney disease prevents worsening of diabetic polyneuropathy, but neuropathic improvement is delayed and incomplete. METHODS: In 85 patients with type 1 diabetes mellitus who underwent SPK or PAK transplantations, we performed sequential neuromuscular evaluations before, every 3 months after, and yearly after transplantation, quantitating muscle weakness separately from overall severity of polyneuropathy. RESULTS: We found that, on average, the weakness subscore of the Neuropathy Impairment Score of the lower limbs [NIS(LL)-W] was significantly worse at 3, 6, 9, and 12 months (by about 5 points) than at baseline. By contrast, for these times after transplantation, a composite score of nerve conduction abnormalities, an independent measure of severity of polyneuropathy, was not significantly worse and, in fact, was significantly improved. In multivariate analysis, length of hospital stay correlated with the increased weakness. CONCLUSIONS: We conclude that: (1) increased neuromuscular impairment after transplantation is mainly due to muscle weakness and not to worsening polyneuropathy; (2) in multivariate analysis, duration of hospitalization after transplantation was significantly associated with this increased weakness; (3) increased weakness is probably due to development of myopathy, which may be related to graft rejection, immunosuppression, sepsis, and intercurrent infections; (4) in future transplantation trials, weakness should be evaluated separately from neuropathic status, and the lowest efficacious dosages of immunotherapy should be used; and (5) essentially all diabetic patients reported that SPK or PAK transplantation was worthwhile because it freed them from diabetic lifestyle concerns.

Methylprednisolone may improve lumbosacral radiculoplexus neuropathy.

OBJECTIVE: To report on an open trial of intravenous methylprednisolone (IV MP) in nondiabetic lumbosacral radiculoplexus neuropathy (LSRPN). BACKGROUND: Lumbosacral radiculoplexus neuropathy is a subacute, unilateral or asymmetric syndrome of pain, weakness, and paresthesia of the lower extremity, which is attributed to ischemic injury from microvasculitis in lumbosacral roots, plexus, and nerves. METHODS: Eleven nondiabetic patients with worsening LSRPN were treated - ten with infusions of IV MP (1 gm/wk) for 8 to 16 weeks and one with an equivalent dosage of oral prednisone. The main endpoints evaluated were: 1) the Neuropathy Impairment Score (NIS), and 2) the Neuropathy Symptoms and Change (NSC) scores. RESULTS: The median age of our patients was 67 years, range 49 to 86 years. Seven patients were women. All 11 patients reported improvement during treatment--nine reported marked improvement. The median NIS improved from 42 points (range 9 to 106 points) before treatment, to 20 points (range 5 to 57 points) (p = 0.005) after treatment. Pain was completely resolved in four patients and much improved in seven. The change subscore and the severity subscore of the NSC were statistically significantly improved after treatment. Prior to treatment, all patients had significant weakness with six confined to wheelchairs and four using mechanical devices to aid in ambulation. After treatment, the weakness was markedly improved in nine patients; only one still required a wheelchair and six walked independently (p = 0.03). CONCLUSIONS: 1) In LSRPN, pain and neurological deficits improved (often dramatically) with IV MP treatment. 2) Although our results should be interpreted with caution since this trial is uncontrolled, IV MP may favorably affect the natural history of LSRPN. 3) The results are sufficiently promising to provide a rationale for prospective, sham controlled, double blind trials.

Non-diabetic lumbosacral radiculoplexus neuropathy: natural history, outcome and comparison with the diabetic variety.

Diabetic lumbosacral radiculoplexus neuropathy (DLSRPN) (other names include diabetic amyotrophy) is well recognized, unlike the non-diabetic lumbosacral radiculoplexus neuropathy (LSRPN), which has received less attention. Our objective was to characterize the natural history and outcome of LSRPN and to assess whether it is similar to the diabetic variety in its symptoms, course, electrophysiological features, quantitative sensory and autonomic findings, and the underlying pathophysiology. We studied 57 patients with LSRPN and 33 patients with DLSRPN. We found that the age of onset, course, kind and distribution of symptoms and impairments, laboratory findings and outcomes are essentially alike. Both disorders are a lumbosacral plexus neuropathy associated with weight loss, often beginning focally or asymmetrically in the thigh or leg but usually progressing to involve the initially unaffected segment and the contralateral side. Both have prolonged morbidity due to pain, paralysis, autonomic involvement and sensory loss. In biopsied distal LSRPN nerves, we found changes similar to those found in DLSRPN-alterations typical of ischaemic injury and of microvasculitis. The long-term outcome was determined in 42 LSRPN patients: two had become diabetic, seven had relapsed and only three had recovered completely, although all had improved. We conclude that: (i) LSRPN is a subacute, asymmetrical, painful and debilitating neuropathy of the lower limbs associated with weight loss, and we think it is under-recognized; (ii) recovery from the long-term impairments of LSRPN is usually delayed and incomplete and only a small minority of patients develop diabetes mellitus; (iii) LSRPN mirrors the diabetic variety in its clinical features, course, pathological findings (ischaemic injury from microvasculitis) and long-term outcome; and (iv) LSRPN should be set apart from chronic inflammatory demyelinating polyradiculoneuropathy and from systemic necrotizing vasculitis. We infer an autoimmune basis for LSRPN and emphasize the need for controlled trials of immune-modulating therapy.

Microvasculitis in non-diabetic lumbosacral radiculoplexus neuropathy (LSRPN): similarity to the diabetic variety (DLSRPN).

Diabetic lumbosacral radiculoplexus neuropathy (DLSRPN) has been shown to be due to ischemic injury from microvasculitis. The present study tests whether ischemic injury and microvasculitis are the pathologic cause of non-diabetic lumbosacral radiculoplexus neuropathy (LSRPN), and whether the pathologic alterations are different between LSRPN and DLSRPN. We studied distal cutaneous nerve biopsies of 47 patients with LSRPN and compared findings with those of 14 age-matched healthy controls and 33 DLSRPN patients. In both disease conditions, we found evidence of ischemic injury (multifocal fiber degeneration and loss, perineurial degeneration and scarring, characteristic fiber alterations, neovascularization, and injury neuroma) that we attribute to microvasculitis (mural and perivascular mononuclear inflammation of microvessels, inflammatory separation, fragmentation and destruction of mural smooth muscle, and previous microscopic bleeding [hemosiderin]). Teased nerve fibers in LSRPN showed significantly increased frequencies of axonal degeneration, segmental demyelination, and empty nerve strands. The segmental demyelination appeared to be clustered on fibers with axonal dystrophy. The nerves with abnormal frequencies of demyelination were significantly associated with nerves showing multifocal fiber loss. We reached the following conclusions: 1) LSRPN is a serious condition with much morbidity that mirrors DLSRPN. 2) Ischemic injury from microvasculitis appears to be the cause of LSRPN. 3) Axonal degeneration and segmental demyelination appear to be linked and due to ischemia. 4) The pathologic alterations in LSRPN and DLSRPN are indistinguishable, raising the question whether these 2 conditions have a common underlying mechanism, and whether diabetes mellitus contributes to the pathology or is a risk factor in DLSRPN. 5) Both LSRPN and DLSRPN are potentially treatable conditions.

Microvasculitis and ischemia in diabetic lumbosacral radiculoplexus neuropathy.

OBJECTIVE: To determine whether microscopic vasculitis explains the clinical and pathologic features of diabetic lumbosacral radiculoplexus neuropathy (DLSRPN). BACKGROUND: DLSRPN is usually attributed to metabolic derangement or ischemic injury, but microscopic vasculitis as the sole cause needs consideration. METHODS: We prospectively studied the clinical, laboratory, and EMG features as well as the pathology of distal cutaneous nerve biopsy specimens of patients with DLSRPN. RESULTS: Study of DLSRPN nerve biopsy specimens (n = 33) compared with those from healthy controls (n = 14) and those with diabetic polyneuropathy (n = 21) provided strong evidence for ischemic injury (axonal degeneration, multifocal fiber loss, focal perineurial necrosis and thickening, injury neuroma, neovascularization, and swollen fibers with accumulated organelles), which we attribute to microscopic vasculitis (epineurial vascular and perivascular inflammation, vessel wall necrosis, and evidence of previous bleeding). Segmental demyelination was significantly associated with multifocal fiber loss. CONCLUSIONS: 1) This severe, debilitating neuropathy begins with symptoms unilaterally and focally in the leg, thigh, or buttock and spreads to involve the other regions of the same and then opposite side and is due to multifocal involvement of lumbosacral roots, plexus, and peripheral nerve (i.e., diabetic lumbosacral radiculoplexus neuropathy). 2) Motor, sensory, and autonomic fibers are all involved. 3) Ischemic injury explains the clinical features and pathologic abnormalities of nerve. 4) The proximate cause of the ischemic injury appears to be microscopic vasculitis. 5) The segmental demyelination is probably secondary to ischemic axonal dystrophy, thus providing a unifying hypothesis for both axonal degeneration and segmental demyelination.

Development of FlexSure HP--an immunochromatographic method to detect antibodies against Helicobacter pylori.

We describe a solid-phase immunochromatographic serologic test, FlexSure HP, to detect IgG antibodies against Helicobacter pylori. H. pylori colonize the stomach and proximal duodenum, cause ulcer disease and mucosa-associated lymphoid tissue lymphoma, and have a role in the development of other disorders, including gastric adenocarcinoma. FlexSure HP consists of a test strip, conjugate pad, and absorbent pad, in a novel reverse-flow chromatography format. In these studies, FlexSure HP was demonstrated to be specific for IgG antibodies against H. pylori. The reactive cutoff of the test was consistent with [13C]urea breath test and commercially available ELISAs. FlexSure HP had 94% sensitivity, 88% specificity, and 91% accuracy relative to [13C]urea breath test; and 95% sensitivity, 94% specificity, and 95% overall agreement relative to high-molecular-mass cell-associated protein enzyme immunoassay (HM-CAP EIA). FlexSure HP is a simple-to-perform, visually read test requiring no specialized training, equipment, or instrumentation, and yields rapid, accurate, qualitative results.

The International Balint Federation: past, present, and future.

In the past 40 years the doctor's role in family medicine has been transformed by Michael Balint. Britain, his adopted country, was the birthplace of this change. Psychoanalysts, who led the original seminars at the Tavistock Clinic in London, conveyed psychotherapeutic skills to those doctors already established as general practitioners. The Balint movement later became world-wide. Leaders now include psychologists and Balint-trained family doctors. Everyone has broader ideas about patient-centred medicine, the doctor-patient relationship, and training-cum-research. Many groups are devoted to trainees and to medical students. The original dependence of family doctors on psychoanalysts has been converted by Michael Balint into interdependence, and he helped preserve the art of medicine by making the art more scientific. The International Federation is devoted to the sharing of experiences, reviewing of ideas, and the continued development of the Balint philosophy.

Teaching about the primary care team: an experiment in vocational training.

As part of their regular half-day release course trainee general practitioners met with paramedical colleagues and ancillary practice staff for group discussions on aspects of teamwork. The series of meetings extended over two years. The organizer's aim, that the participants should obtain information about and insight into their colleagues' roles, was achieved. There was also evidence of significant professional maturation and interdisciplinary understanding.