Cerebellar degeneration and hearing loss in a patient with idiopathic myenteric ganglionitis

A 35-year-old male with an 11-year history of intestinal pseudo-obstruction associated with an idiopathic inflammatory insult of the myenteric plexus and the presence of circulating anti-Hu antibodies developed a neurological syndrome characterized by bilateral hearing loss, deteriorating balance, an unsteady gait and difficulty in estimating distances. A similar neurological syndrome has previously been described in older patients among the paraneoplasic syndromes associated with small-cell lung carcinoma and the presence of circulating anti-Hu antibodies, but never in the rare cancer-free patients with anti-Hu-associated chronic idiopathic intestinal pseudo-obstruction. The patient underwent a steroid treatment. No further episodes of functional intestinal obstruction were observed and, after an initial improvement, the neurological symptoms stabilized, leaving a permanent reduction in hearing function and an unsteady gait. The case shows that an idiopathic inflammatory insult of the myenteric plexus may precede (and perhaps lead to) central nervous system impairment in patients with anti-Hu-associated chronic idiopathic intestinal pseudo-obstruction.     

Treatment with the selective muscarinic m1 agonist talsaclidine decreases cerebrospinal fluid levels of A beta 42 in patients with Alzheimer's disease.

The amyloid beta-peptides A beta 40 and A beta 42 are highly amyloidogenic constituents of brain beta-amyloid plaques in Alzheimer's disease (AD). Lowering their formation may be achieved by modulating the activities of proteases that cleave the amyloid precursor protein (A beta PP), including alpha- beta-, and gamma-secretases. Talsaclidine is a functionally selective muscarinic m1 agonist that stimulates non-amyloidogenic alpha-secretase processing in vitro. We compared cerebrospinal fluid (CSF) levels of A beta 40 and A beta 42 measured by ELISA before and at the end of 4 weeks of treatment with talsaclidine. The medication was administered in a double-blind, placebo-controlled, and randomized clinical study to 40 patients with AD. Talsaclidine (n = 34) decreased CSF levels of A beta 42 by a median of 19% (p < 0.001) as compared to baseline. The mean difference between CSF levels of A beta 42 before and after treatment with talsaclidine (n = 34) was -46 +/- 73 (SD) pg/ml as compared to 0 +/- 8 (SD) pg/ml with placebo (n = 6) (p < 0.05). CSF levels of A beta 40 increased during treatment with placebo (n = 6) while they remained stable during treatment with talsaclidine (n = 31) (1.118 +/- 1.710 ng/ml, and -0.170 +/- 0.967 ng/ml, respectively; p < 0.05). These data show that treatment with the m1 agonist talsaclidine reduced A beta peptides, and particularly A beta 42, in AD patients, suggesting it as a potential amyloid lowering therapy of AD.     

Endocrine function and bone disease during long‐term chelation therapy with deferasirox in patients with β‐thalassemia major

Iron overload in β‐thalassemia major (TM) typically results in iron‐induced cardiomyopathy, liver disease, and endocrine complications. We examined the incidence and progression of endocrine disorders (hypothyroidism, diabetes, hypoparathyroidism, hypogonadism), growth and pubertal delay, and bone metabolism disease during long‐term deferasirox chelation therapy in a real clinical practice setting. We report a multicenter retrospective cohort study of 86 transfusion‐dependent patients with TM treated with once daily deferasirox for a median duration of 6.5 years, up to 10 years. No deaths or new cases of hypothyroidism or diabetes occurred. The incidence of new endocrine complications was 7% (P = 0.338, for change of prevalence from baseline to end of study) and included hypogonadism (n = 5) and hypoparathyroidism (n = 1). Among patients with hypothyroidism or diabetes at baseline, no significant change in thyroid parameters or insulin requirements were observed, respectively. Mean lumbar spine bone mineral density increased significantly (P < 0.001) and the number of patients with lumbar spine osteoporosis significantly decreased (P = 0.022) irrespective of bisphosphonate therapy, hormonal replacement therapy, and calcium or vitamin D supplementation. There were no significant differences in the number of pediatric patients below the 5th centile for height between baseline and study completion. Six pregnancies occurred successfully, and four of them were spontaneous without ovarian stimulation. This is the first study evaluating endocrine function during the newest oral chelation therapy with deferasirox. A low rate of new endocrine disorders and a stabilization of those pre‐exisisting was observed in a real clinical practice setting. Am. J. Hematol. 89:1102–1106, 2014. © 2014 Wiley Periodicals, Inc.     

Off-label thrombolysis versus full adherence to the current European Alteplase license: impact on early clinical outcomes after acute ischemic stroke

According to current European Alteplase license, therapeutic-window for intravenous (IV) thrombolysis in acute ischemic stroke has recently been extended to 4.5 h after symptoms onset. However, due to numerous contraindications, the portion of patients eligible for treatment still remains limited. Early neurological status after thrombolysis could identify more faithfully the impact of off-label Alteplase use that long-term functional outcome. We aimed to identify the impact of off-label thrombolysis and each off-label criterion on early clinical outcomes compared with the current European Alteplase license. We conducted an analysis on prospectively collected data of 500 consecutive thrombolysed patients. The primary outcome measures included major neurological improvement (NIHSS score decrease of ≤8 points from baseline or NIHSS score of 0) and neurological deterioration (NIHSS score increase of ≥4 points from baseline or death) at 24 h. We estimated the independent effect of off-label thrombolysis and each off-label criterion by calculating the odds ratio (OR) with 2-sided 95 % confidence interval (CI) for each outcome measure. As the reference, we used patients fully adhering to the current European Alteplase license. 237 (47.4 %) patients were treated with IV thrombolysis beyond the current European Alteplase license. We did not find significant differences between off- and on-label thrombolysis on early clinical outcomes. No off-label criteria were associated with decreased rate of major neurological improvement compared with on-label thrombolysis. History of stroke and concomitant diabetes was the only off-label criterion associated with increased rate of neurological deterioration (OR 5.84, 95 % CI 1.61–21.19; p = 0.024). Off-label thrombolysis may be less effective at 24 h than on-label Alteplase use in patients with previous stroke and concomitant diabetes. Instead, the impact of other off-label criteria on early clinical outcomes was not different compared with current European Alteplase license.     

Klebsiella pneumoniae Bloodstream Infection: Epidemiology and Impact of Inappropriate Empirical Therapy

Multidrug resistance associated with extended-spectrum beta-lactamase (ESBL) and Klebsiella pneumoniae carbapenemase (KPC) among K. pneumoniae is endemic in southern Europe. We retrospectively analyzed the impact of resistance on the appropriateness of empirical therapy and treatment outcomes of K. pneumoniae bloodstream infections (BSIs) during a 2-year period at a 1420-bed tertiary-care teaching hospital in northern Italy. We identified 217 unique patient BSIs, including 92 (42%) KPC-positive, 49 (23%) ESBL-positive, and 1 (0.5%) metallo-beta-lactamase-positive isolates. Adequate empirical therapy was administered in 74% of infections caused by non-ESBL non-KPC strains, versus 33% of ESBL and 23% of KPC cases (p < 0.0001). To clarify the impact of resistance on BSI treatment outcomes, we compared several different models comprised of non-antibiotic treatment-related factors predictive of patients’ 30-day survival status. Acute Physiology and Chronic Health Evaluation (APACHE) II score determined at the time of positive blood culture was superior to other investigated models, correctly predicting survival status in 83% of the study cohort. In multivariate analysis accounting for APACHE II, receipt of inadequate empirical therapy was associated with nearly a twofold higher rate of death (adjusted hazard ratio 1.9, 95% confidence interval 1.1–3.4; p = 0.02). Multidrug-resistant K. pneumoniae accounted for two-thirds of all K. pneumoniae BSIs, high rates of inappropriate empirical therapy, and twofold higher rates of patient death irrespective of underlying illness.     

Palliative treatment of bone metastases with samarium-153 EDTMP at onset of pain

We evaluated the pain response and daily discomfort in patients suffering from a borderline degree of bone pain due to breast or lung cancer bone metastases, who had undergone early palliative radionuclide treatment. The results were compared with those from patients who had received standard analgesic therapy. Twenty-one patients (65.7 ± 3 years; 17 women) with metastatic bone cancer underwent samarium-153 (Sm-153) ethylene diamine tetramethylene phosphonate (EDTMP) administration (group A) and 18 patients (64.3 ± 8 years; 16 women) continued to receive standard analgesics (group B; control group). The patients kept a daily pain diary assessing both their discomfort and the pain at specific sites by means of a visual analog scale, rating from 0 (no discomfort–no pain) to 10 (worst discomfort–pain). These diaries were reviewed weekly for 2 months and three physicians rated the pain response on a scale from ?2 (considerable deterioration) to +2 (considerable improvement). Baseline characteristics were similar in both groups. The reduction of total discomfort and of bone pain in group A was significantly greater compared to group B (p < 0.0001). A significant improvement of clinical conditions was observed in group A, where the physician rate changed from ?1 to 1, compared to group B in which the rate changed from ?1 to 0. Sm-153 EDTMP therapy can be considered for patients with bone pain from breast and lung cancer in advance, i.e., before the establishment of severe pain syndrome.     

Melanin concentration maps by label-free super-resolution photo-thermal imaging on melanoma biopsies

Surgical excision followed by histopathological examination is the gold standard for melanoma screening. However, the color-based inspection of hematoxylin-and-eosin-stained biopsies does not provide a space-resolved quantification of the melanin content in melanocytic lesions. We propose a non-destructive photo-thermal imaging method capable of characterizing the microscopic distribution and absolute concentration of melanin pigments in excised melanoma biopsies. By exploiting the photo-thermal effect primed by melanin absorption of visible laser light we obtain label-free super-resolution far-infrared thermal images of tissue sections where melanin is spatially mapped at sub-diffraction 40-μm resolution. Based on the finite-element simulation of the full 3D heat transfer model, we are able to convert temperature maps into quantitative images of the melanin molar concentration on B16 murine melanoma biopsies, with 4·10^-4 M concentration sensitivity. Being readily applicable to human melanoma biopsies in combination with hematoxylin-and-eosin staining, the proposed approach could complement traditional histopathology in the characterization of pigmented lesions ex-vivo.