Outcome of neurological early rehabilitation patients carrying multi-drug resistant bacteria: results from a German multi-center study.

BACKGROUND: Colonization or infection with multi-drug resistant (MDR) bacteria is considered detrimental to the outcome of neurological and neurosurgical early rehabilitation patients. METHODS: In a German multi-center study, 754 neurological early rehabilitation patients were enrolled and and reviewed in respect to MDR status, length of stay (LOS) and the following outcome variables: Barthel Index (BI), Early Rehabilitation Index (ERI), Glasgow Outcome Score Extended (GOSE), Coma Remission Scale (CRS), Functional Ambulation Categories (FAC). RESULTS: The mean age of the study population was 68.0 ± 14.8 years. Upon admission, the following prevalence for MDRs was observed: MRSA (methicillin resistant staphylococcus aureus) 7.0% (53/754), ESBL- (extended spectrum beta-lactamase) producing bacteria strains 12.6% (95/754), VRE (vancomycin resistant enterococci) 2.8% (21/754). Patients colonized or infected with MDR bacteria (MDR+) were significantly more frequently diagnosed with a critical illness polyneuropathy - CIP - than non-colonized (MDR-) patients: 29.0% vs. 14.8%. In addition, they were more frequently mechanically ventilated (MDR+: 55/138, 39.9%; MDR- 137/616, 22.2%). MDR+ patients were referred to rehabilitation earlier, had a longer LOS in early rehabilitation, lower BI on admission and at discharge, lower ERI on admission and lower CRS at discharge than MDR- patients. There was a highly significant correlation of the BI upon admission with the BI at discharge (rs = 0.492, p < 0.001). GOSE at discharge differed significantly between both groups (χ 2-test, p < 0.01). Perhaps of greatest importance, mortality among MDR+ was higher in comparison to MDR- (18.1% vs. 7.6%). CONCLUSIONS: The outcome of neurological early rehabilitation patients colonized or infected with MDR bacteria including MRSA or ESBL producing strains is significantly poorer than by non-colonized patients. There is some evidence that the poor outcome could be related to the higher morbidity and lower functional status upon admission.

Criterion validity and sensitivity to change of the Early Rehabilitation Index (ERI): results from a German multi-center study.

BACKGROUND: Evaluation of functional status is difficult in neurological and neurosurgical early rehabilitation patients. The Early Rehabilitation Index (ERI) was introduced in Germany over 20 years ago, but since then validation studies are lacking. The ERI (range -325 to 0 points) includes highly relevant items including the necessity of intermittent mechanical ventilation or tracheostomy. METHODS: The present paper analyzed data from a German multi-center study, enrolling 754 neurological early rehabilitation patients. Together with ERI, Barthel Index (BI), Glasgow Coma Scale (GCS), Glasgow Outcome Score Extended, Coma Remission Scale (CRS), Functional Ambulation Categories and length of stay were obtained. RESULTS: ERI showed significant improvements from admission to discharge (p < 0.001). In addition, there were significant correlations of the ERI upon admission and at discharge with BI, CRS and GCS. CONCLUSIONS: Evaluation of our study data suggest that the ERI may be used as a valid assessment instrument for neurological and neurosurgical early rehabilitation patients.

[Course of rehabilitation in early neurological/neurosurgical rehabilitation. Results of a 2014 multi-center evaluation in Germany]. / Rehabilitationsverlauf von Patienten in der neurologisch-neurochirurgischen Frührehabilitation.

BACKGROUND: In Germany, neurological-neurosurgical early rehabilitation is well established in the treatment of severe neurological diseases. To develop quality standards, knowledge of the current rehabilitation course is required. PATIENTS AND METHODS: A retrospective analysis was performed on the course of rehabilitation from patients in an early neurological/neurosurgical rehabilitation program in 16 centers from 10 German states. The odds for a good or poor outcome were investigated using a multivariate logistic regression model. RESULTS: Seven hundred and fifty-four patients were included in the study. The average age of the patients was 68 ± 15 years. Of the patients studied, 26 % were on mechanical ventilation commencing their neurological rehabilitation. The average duration of stay was 56 ± 51 days. Weaning rate from mechanical ventilation was 65 % and the rate of weaning from tracheal cannula was 54 %. Mean improvement in the Barthel Index of 17 points, significant reduction of dysphagia (from 62 to 30 %) and depended walking (from 99 to 82 %), and the achievement of phase C (the next stage of rehabilitation) in 38 % can still be counted as signs of successful rehabilitation. During their course of stay, near 10 % of the patients died. Of these, 67 % received solely palliative care. In the multivariate logistic models, the absence of the factor "necessity for mechanical ventilation on admission" (odds ratio 0.61; 95 % confidence interval (CI): 0.42 … 0.89) increased the chance for good outcome and the presence of this factor the risk of dying with an odds ratio of 8.07 (95 % CI: 4.54-14.34). DISCUSSION: In spite of the severity of neurological deficits, significant functional progress has been made. These results could be interpret as positive proof of the efficacy of neurological/neurosurgical early rehabilitation programs.

Induction cetuximab, paclitaxel, and carboplatin followed by chemoradiation with cetuximab, paclitaxel, and carboplatin for stage III/IV head and neck squamous cancer: a phase II ECOG-ACRIN trial (E2303).

BACKGROUND: E2303 evaluated cetuximab, paclitaxel, and carboplatin used as induction therapy and concomitant with radiation therapy in patients with stage III/IV head and neck squamous cell carcinoma (HNSCC) determining pathologic complete response (CR), event-free survival (EFS), and toxicity. PATIENTS AND METHODS: Patients with resectable stage III/IV HNSCC underwent induction therapy with planned primary site restaging biopsies (at week 8 in clinical complete responders and at week 14 if disease persisted). Chemoradiation (CRT) began week 9. If week 14 biopsy was negative, patients completed CRT (68-72 Gy); otherwise, resection was carried out. p16 protein expression status was correlated with response/survival. RESULTS: Seventy-four patients were enrolled; 63 were eligible. Forty-four (70%) were free of surgery to the primary site, progression, and death 1-year post-treatment. Following induction, 41 (23 CR) underwent week 8 primary site biopsy and 24 (59%) had no tumor (pathologic CR). Week 14 biopsy during chemoradiation (50 Gy) in 34 (15 previously positive biopsy; 19 no prior biopsy) was negative in 33. Thus 90% of eligible patients completed CRT. Overall survival and EFS were 78% and 55% at 3 years, respectively. Disease progression in 23 patients (37%) was local only in 10 (16%), regional in 5 (8%), local and regional in 2 (3%), and distant in 5 patients (8%). There were no treatment-related deaths. Toxicity was primarily hematologic or radiation-related. p16 AQUA score was not associated with response/survival. CONCLUSIONS: Induction cetuximab, paclitaxel, and carboplatin followed by the same drug CRT is safe and induces high primary site response and promising survival. CLINICAL TRIALS NUMBER: NCT 00089297.

Differences in the insulin tolerance test in patients with brain damage depending on posture.

OBJECTIVE: The insulin tolerance test (ITT) is the gold standard for the diagnosis of GH deficiency (GHD) and hypocortisolism. As hypopituitarism is a common disorder after traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH), the test is increasingly used in patients with pre-existing brain damage. DESIGN: A cross-sectional, observational study. METHODS: Fifty-six patients (41 TBI and 15 SAH) were tested with the ITT (0.15 IE/kg body weight, mean glucose 33 mg/dl). In 38 patients, the test was performed in a supine position; the other 18 patients were in a sitting position during the ITT. RESULTS: Hypocortisolism and GHD were more often diagnosed in a supine than in a sitting position (hypocortisolism: 55.3% supine versus 0% sitting, P<0.0001; GHD: 42.1% supine versus 11.1% sitting, P=0.03). Patients in a sitting position suffered more often from symptoms such as tachycardia (61.1% sitting versus 15.8% supine, P=0.001), trembling (22.2 vs 7.9%, NS), and sweating (66.7 vs 28.9%, P=0.007). There were no significant differences between the groups in drowsiness (72.2% sitting versus 65.8% supine, NS), dizziness (44.4 vs 44.7%, NS), and fatigue (33.3 vs 15.8%, NS). Because of somnolence, the hypoglycemic state could only be stopped with i.v. administration of glucose in 25 supine patients (66%). In contrast, none of the 18 patients (0%) tested in a sitting position got somnolent or was in need of i.v. application of glucose (P<0.001). CONCLUSIONS: In patients with brain injury, posture might affect rates of diagnosing GHD and hypocortisolism and sympathetic symptoms in the ITT. These findings are exploratory and need replication in a standardized setting.

Induction chemotherapy and concurrent chemoradiotherapy for locoregionally advanced head and neck cancer: a multi-institutional phase II trial investigating three radiotherapy dose levels.

BACKGROUND: We hypothesized induction chemotherapy (IndCT) would improve distant control (DC) without compromising locoregional control (LRC) for locoregionally advanced head and neck cancer patients. Additionally, we systematically lowered radiotherapy (RT) doses attempting to maintain LRC while decreasing toxicity. PATIENTS AND METHODS: Stages III-IV (M0) locoregionally advanced head and neck cancer patients received carboplatin/paclitaxel (Taxol) IndCT followed by four or five cycles consisting of 5 days of paclitaxel, fluorouracil, hydroxyurea, and BID RT followed by a nine day break. RT dose to gross disease (high risk), intermediate, and low-risk volumes were reduced from cohort A (n = 68): 75, 60, and 45 Gy; to cohort B (n = 64): 75, 54, and 39 Gy; then cohort C (n = 90): 72, 51, and 36 Gy. RESULTS: A total of 222 patients accrued from November 1998 to September 2002. Median follow-up is 56 months. In all, 93/96/76% achieved a complete response to concurrent chemoradiotherapy (CRT) in cohort A/B/C. Three- and 5-year overall survivals (OSs) are 68% and 62%, respectively. Five-year LRC and DC are 91% and 87%, respectively. Response to IndCT predicted for OS, LRC, and time to progression (TTP). Cohort C patients had similar OS (P = 0.95), LRC, and DC, but worse (TTP) (P = 0.027). CONCLUSIONS: IndCT before CRT reduces distant progression while maintaining high LRC. The cohort B schedule provides the best therapeutic ratio. A randomized trial investigating IndCT before CRT has been initiated.

Predictors of anterior pituitary insufficiency after traumatic brain injury.

BACKGROUND: Several studies have reported a high prevalence of hypopituitarism after traumatic brain injury (TBI). Risk stratification is a prerequisite for cost-effective hormonal screening of these patients. However, it is still unclear which risk factors predispose patients to develop anterior hypopituitarism after TBI. OBJECTIVE: To assess clinical and radiological risk factors for post-traumatic hypopituitarism. PATIENTS AND METHODS: Seventy-eight consecutive patients (52 men, 26 women; mean age 36.0 years, range 18-65 years) with mild, moderate or severe TBI were studied. Endocrine and clinical parameters were assessed 3 and 12 months after TBI. RESULTS: We found diffuse axonal injury, basal skull fracture and older age to be major risk factors of post-traumatic hypopituitarism. CONCLUSIONS: We have defined specific risk factors for the development of post-traumatic hypopituitarism that are consistent with pathophysiological considerations. These findings might help to identify at-risk patients.

Prevalence of anterior pituitary insufficiency 3 and 12 months after traumatic brain injury.

OBJECTIVE: Cross-sectional studies report a high prevalence of hypopituitarism after traumatic brain injury (TBI); however, no longitudinal studies on time of manifestation and reversibility exist. This study was conducted to assess hypopituitarism 3 and 12 months after TBI. DESIGN: This was a prospective, longitudinal, diagnostic study. METHODS: Seventy-eight patients (52 men, 26 women, mean age 36.0 years) with TBI grades I-III and 38 healthy subjects (25 men, 13 women, mean age 36.4 years) as a control group for the GHRH + arginine test were studied. The prevalence of hypopituitarism was assessed 3 and 12 months after TBI by GHRH + arginine test, short adrenocorticotropic hormone (ACTH) test, and basal hormone measurements in patients. RESULTS: After 3 months, 56% of all patients had impairments of at least one pituitary axis with axes being affected as follows: gonadotropic 32%, corticotropic 19%, somatotropic 9% and thyrotropic 8%. After 12 months, fewer patients were affected, but in some cases new impairments occurred; 36% still had impairments. The axes were affected as follows after 12 months: gonadotropic 21%, somatotropic 10%, corticotropic 9% and thyrotropic 3%. CONCLUSIONS: Hypopituitarism occurs often in the post-acute phase after TBI and may normalize later, but may also develop after the post-acute phase of TBI.

Visuospatial neglect in near and far space: dissociation between line bisection and letter cancellation.

The differential performance on a line bisection and a cancellation task in near and far space was studied. A group of 10 patients with severe left-sided visuospatial neglect and a group of 10 right-brain damaged patients without neglect were examined. The stimuli were presented at a distance of 60 cm (near space) and 160 cm (far space), respectively, and corrected for visual angle. In the line bisection task, patients were asked to point to the estimated line centre with a pencil (near space) or a stick (far space). In the cancellation task, patients pointed to all target stimuli they could detect using either a pencil (near space) or a stick (far space). Most patients with left hemineglect showed a more prominent neglect in far space as compared to near space for the line bisection task, whereas no difference of performance between near and far space was found in the control patients. In contrast, no group showed a distance effect in the cancellation task. The observation that only line bisection is influenced by the distance of the stimulus suggests that line bisection and cancellation are processed differentially. It is proposed that line bisection requires an allocentric reference system focusing attention on objects, whereas cancellation tasks are based on an egocentric reference system responsible for visuospatial attention. Our results indicate that distance changes perception within the allocentric but not within the egocentric system.

Phenotypic perturbation of B cells in the Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency/platelet disease due to mutations of WASP, a cytoskeletal regulatory protein of blood cells. Patients exhibit a range of immune defects generally attributed to defective T-cell function, including poor response to immunization, skewed immunoglobulin isotypes, eczema, recurrent infections, autoimmune disease and increased frequency of malignancies. Here we show a deficit of total B-cells in WAS patients of various ages and identify phenotypic perturbations involving complement receptors and CD27. Whereas B-cells of normal healthy donors are overwhelmingly CD21/CD35-positive, B-cells expressing these receptors are significantly reduced in number in WAS patients, and their paucity may cause suboptimal antigen capture and presentation. The frequencies of IgD(-) and IgG(+) patient B-cells were not different from healthy donors (although absolute numbers were decreased), indicating that isotype switching is occurring. In contrast, the frequency of cells positive for CD27, the marker of post germinal centre B-cells, was significantly decreased even among isotype-switched cells, and B-cells resembling germinal centre progenitors (CD10(+)CD27(-)CD38(bright)) were more frequent in adult patients, suggesting impaired germinal centre maturation/differentiation. The documentation of these phenotypic perturbations and deficit of total cells suggest that defects intrinsic to B-cells contribute to the impaired humoral immunity that characterizes this disease.

[Pituitary insufficiency following head injury--how common is it, and what is to be done?]. / Unfallfolge Hypophyseninsuffizienz. Hormonmangel nach jedem zweiten Schädel-Hirn-Trauma?

In Germany,traumatic brain injury (TBI) has an annual incidence of approximately 200000. In contrast to earlier assumptions, pituitary insufficiency is a common complication of TBI, with a prevalence of 30-50%. Since the symptoms are often nonspecific and may be masked by the sequelae of head injury, it may go unrecognized and may possibly aggravate the symptomatology of such injury. It is therefore to be recommended that patients who suffer a head injury should be examined to exclude pituitary gland insufficiency, by measuring the basal hormone level--where necessary in combination with stimulation tests.

Patterns of failure, prognostic factors and survival in locoregionally advanced head and neck cancer treated with concomitant chemoradiotherapy: a 9-year, 337-patient, multi-institutional experience.

BACKGROUND: Locoregionally advanced, stage IV head and neck cancer has traditionally carried a poor prognosis. We sought to assess changes in patterns of failure, prognostic factors for recurrence, and overall outcome, using two different strategies of chemoradiotherapy conducted in prospective, multi-institutional phase II trials. PATIENTS AND METHODS: Three hundred and thirty-seven stage IV patients were treated from 1989 to 1998. We compared locoregional and distant recurrence rates, overall survival and progression-free survival from two different treatment strategies: intensive induction chemotherapy followed by split-course chemoradiotherapy (type 1, n=127), or intensified, split-course, hyperfractionated multiagent chemoradiotherapy alone (type 2, n=210). Univariate and multivariate analyses of 12 chosen covariates were assessed separately for the two study types. RESULTS: The pattern of failure varied greatly between study types 1 and 2 (5-year locoregional failure of 31% and 17% for study types 1 and 2, respectively, P=0.01; 5-year distant failure rate of 13% and 22% for study types 1 and 2, P=0.03). Combined 5-year overall survival was 47% [95% confidence interval (CI) 41% to 53%) and progression-free survival was 60% (95% CI 55% to 66%). Both treatment strategies yielded similar survival rates. Poor overall survival and distant recurrence were best predicted by advanced nodal stage. Locoregional recurrence was extremely rare for patients with T0-T3 tumor stage, regardless of lymph-node stage. CONCLUSIONS: This analysis suggests that pattern of failure in primary head and neck cancer may be dependent upon treatment strategy. Randomized clinical trials of induction chemotherapy are warranted as a means to determine if a decrease in distant metastases can lead to an increase in survival rates in the setting of effective chemoradiotherapy for locoregional control. Additionally, this analysis provides impetus for randomized clinical trials of organ preservation chemoradiotherapy in sites outside the larynx and hypopharynx.

Early deficit of lymphocytes in Wiskott-Aldrich syndrome: possible role of WASP in human lymphocyte maturation.

Wiskott-Aldrich syndrome (WAS) is an X-linked platelet/immunodeficiency disease. The affected gene encodes WASP, a multidomain protein that regulates cytoskeletal assembly in blood cells. Patients have recurring infections, and their lymphocytes exhibit deficient proliferative responses in vitro. We report an evaluation of peripheral blood lymphocytes of 27 WAS patients, aged one month to 55 years. Whereas NK cells were normal, a significant deficit of T and B lymphocytes was observed. The number of lymphocytes was already decreased in infant patients, suggesting deficient output. Both CD4 and CD8 T lymphocytes were affected; the decrease was most pronounced for naïve T cells. Naïve CD4 lymphocytes of patients showed normal expression of Bcl-2, and Ki-67, and normal survival in vitro, suggesting that their in vivo survival and proliferation are normal. The collective data suggest that the patients' lymphocyte deficit results from deficient output, likely due to abnormal lymphocyte maturation in the thymus and bone marrow. We propose that WASP plays an important role not only in the function of mature T lymphocytes, but also in the maturation of human T and B lymphocytes and that impaired lymphocyte maturation is central to the aetiology of WAS immunodeficiency.

Ileal adenocarcinoma in a mild phenotype of abetalipoproteinemia.

Abetalipoproteinemia (ABL) is a rare autosomal recessive disorder that is characterized by defective assembly and secretion of plasma apolipoprotein (apo) B-containing lipoproteins. This disorder results from mutations in the MTP gene encoding the microsomal triglyceride transfer protein. We report a 58-year-old male homozygote for a missense mutation, S590I, in MTP. The patient had a lifelong history of fat malabsorption, but was only diagnosed with ABL at age 52, based upon such classic features as absence of apo B-containing lipoproteins, acanthocytosis, atypical retinitis pigmentosa and markedly depressed serum beta-carotene concentration. However, his presentation was notable not only by survival to the sixth decade of life without specific treatment, but also by the absence of neurological involvement and by normal serum vitamin E concentration. He subsequently developed adenocarcinoma of the ileum, which required ileal resection. Therefore, this missense mutation appears to be associated with a late-presenting and relatively mild ABL phenotype that lacks some classical features, particularly neuropathy, but appears to be associated with other atypical features, specifically small intestinal cancer.

A novel protocol to identify mutations in patients with wiskott-Aldrich syndrome.

Mutations of WASP (Wiskott-Aldrich syndrome protein) underlie the severe immunodeficiency/platelet disorder Wiskott-Aldrich syndrome (WAS) and its milder variant X-linked thrombocytopenia (XLT). The affected gene, a 12-exon structure on the X-chromosome, is expressed exclusively in blood cells. The encoded product WASP is a 502-amino-acid scaffolding protein that functions in stimulus-induced nucleation of actin filaments to form dynamic cell surface projections. To date, more than 150 mutations have been identified in 300 WAS/XLT kindred worldwide, generally through methodologies that include sophisticated exon screening steps such as single-strand conformation analysis. We report here a simpler protocol, which was designed for use in clinical settings to identify the mutations of newly diagnosed patients. The approach relies on directly sequencing amplified exons according to a staggered schedule based on statistical evaluation of previous cases. In a 2 1/2-year trial, samples from 28 consecutive patients were analyzed; these included 3 "blindly labeled" previously studied cases. The mutations that were identified include a broad spectrum (8 missense, 3 nonsense, 5 splice site mutations, 11 small insertion/deletions, 1 large deletion) and were broadly distributed (in 10 of the 12 exons). All mutations were verified and no discrepancies were encountered. Per patient, a mean of six DNA sequencing reactions and 6-7 h of staff effort sufficed for mutation identification and verification, indicating that the protocol is cost-effective. This cumulative experience demonstrates the suitability, reliability, and versatility of the new protocol.

WASP and N-WASP in human platelets differ in sensitivity to protease calpain.

Mutations of Wiskott-Aldrich syndrome protein (WASP) underlie the severe thrombocytopenia and immunodeficiency of the Wiskott-Aldrich syndrome. WASP, a specific blood cell protein, and its close homologue, the broadly distributed N-WASP, function in dynamic actin polymerization processes. Here it is demonstrated that N-WASP is expressed along with WASP, albeit at low levels, in human blood cells. The presence of approximately 160 nmol/L rapidly acting N-WASP molecules may explain the normal capacity of WASP-negative patient platelets for early agonist-induced aggregation and filopodia formation. Ex vivo experiments revealed a significant difference between WASP and N-WASP in sensitivity to calpain, the Ca++-dependent protease activated in agonist-stimulated platelets. Through the use of a series of calpain-containing broken cell systems, it is shown that WASP is cleaved in a Ca++-dependent reaction inhibitable by calpeptin and E64d and that N-WASP is not cleaved, suggesting that the cleavage of WASP by calpain functions in normal platelets as part of a Ca++-dependent switch mechanism that terminates the surface projection phase of blood cell activation processes.

N-WASP deficiency reveals distinct pathways for cell surface projections and microbial actin-based motility.

The Wiskott-Aldrich syndrome protein (WASP) family of molecules integrates upstream signalling events with changes in the actin cytoskeleton. N-WASP has been implicated both in the formation of cell-surface projections (filopodia) required for cell movement and in the actin-based motility of intracellular pathogens. To examine N-WASP function we have used homologous recombination to inactivate the gene encoding murine N-WASP. Whereas N-WASP-deficient embryos survive beyond gastrulation and initiate organogenesis, they have marked developmental delay and die before embryonic day 12. N-WASP is not required for the actin-based movement of the intracellular pathogen Listeria but is absolutely required for the motility of Shigella and vaccinia virus. Despite these distinct defects in bacterial and viral motility, N-WASP-deficient fibroblasts spread by using lamellipodia and can protrude filopodia. These results imply a crucial and non-redundant role for N-WASP in murine embryogenesis and in the actin-based motility of certain pathogens but not in the general formation of actin-containing structures.

Rescue of a telomere length defect of Nijmegen breakage syndrome cells requires NBS and telomerase catalytic subunit.

Nijmegen breakage syndrome (NBS) is a rare human disease displaying chromosome instability, radiosensitivity, cancer predisposition, immunodeficiency, and other defects [1, 2]. NBS is complexed with MRE11 and RAD50 in a DNA repair complex [3-5] and is localized to telomere ends in association with TRF proteins [6, 7]. We show that blood cells from NBS patients have shortened telomere DNA ends. Likewise, cultured NBS fibroblasts that exhibit a premature growth cessation were observed with correspondingly shortened telomeres. Introduction of the catalytic subunit of telomerase, TERT, was alone sufficient to increase the proliferative capacity of NBS fibroblasts. However, NBS, but not TERT, restores the capacity of NBS cells to survive gamma irradiation damage. Strikingly, NBS promotes telomere elongation in conjunction with TERT in NBS fibroblasts. These results suggest that NBS is a required accessory protein for telomere extension. Since NBS patients have shortened telomeres, these defects may contribute to the chromosome instability and disease associated with NBS patients.