Acupuncture in diabetic peripheral neuropathy-protocol for the randomized, multicenter ACUDPN trial.

BACKGROUND: Acupuncture is used to treat patients with diabetic peripheral neuropathy; however, the evidence is unclear. We present the design and methodology of the ACUDPN (ACUpuncture in Diabetic Peripheral Neuropathy) trial, which investigates the effectiveness of acupuncture for the treatment of diabetic peripheral neuropathy (DPN) symptoms. The aim of this study is to investigate whether acupuncture is effective for the treatment of DPN symptoms. METHODS: This study is a two-armed, randomized, controlled, parallel group, open-label, confirmatory, multicenter trial (8-week intervention period plus 16 weeks of follow-up). Physicians in outpatient units in Germany who specialize in acupuncture treatment will treat 110 diabetes type II patients with clinical symptoms of peripheral neuropathy in the feet and legs with signs of neuropathy according to nerve conduction testing. The patients will be randomized in a 1:1 ratio to one of the following two groups: (a) semi-standardized acupuncture plus routine care or (b) routine care alone. Acupuncture will consist of 12 treatments per patient over 8 weeks. The primary outcome will be the overall DPN-related complaints in the extremities after 8 weeks as measured by the Visual Analog Scale (VAS). Further outcome measures will include DPN-related pain, the Neuropathic Pain Symptom Inventory (NPSI), Diabetic Peripheral Neuropathic Pain Impact (DPNPI) scores, and nerve conduction parameters of the sural nerve at weeks 8, 16, and 24. DISCUSSION: The results of this trial will be available in 2021 and will help clarify whether acupuncture can be considered effective for the treatment of DPN with regard to the subdimensions of the neuropathic clinical picture. TRIAL REGISTRATION: ClinicalTrials.gov NCT03755960 . Registered on 11 August 2018.

Restoration of wall shear stress in the cephalic vein during extreme hemodynamics.

The surgical creation of an artery-vein connection via a Brachicephalic fistula (BCF) in patients with end stage renal disease (ESRD) provides a unique opportunity to study blood vessel response mechanisms to extreme hemodynamic conditions in relatively short timeframes. After BCF creation, the flow rate in the vein increases by an order of magnitude leading to separated flows and corresponding abnormally low, or negative, wall shear stress (WSS) in the curved arch segment of the cephalic vein. Locations of abnormally low WSS are shown to correlate with development of neointimal hyperplasia (NH) and subsequent stenosis. It is found that the stenosis, prior to a surgical intervention, restores the normal physiological WSS in the vein. As a result, this investigation provides evidence that the adaptation principle, known to apply in the arterial system, is also valid in the venous system. A novel graphical method is developed that combines clinical and computational data to assist in interpreting these physiological mechanisms including adaptation that lead to changes in vein geometry over time.

Hemodynamics in the cephalic arch of a brachiocephalic fistula.

The care and outcome of patients with end stage renal disease (ESRD) on chronic hemodialysis is directly dependent on their hemodialysis access. A brachiocephalic fistula (BCF) is commonly placed in the elderly and in patients with a failed lower-arm, or radiocephalic, fistula. However, there are numerous complications such that the BCF has an average patency of only 3.6 years. A leading cause of BCF dysfunction and failure is stenosis in the arch of the cephalic vein near its junction with the axillary vein, which is called cephalic arch stenosis (CAS). Using a combined clinical and computational investigation, we seek to improve our understanding of the cause of CAS, and to develop a means of predicting CAS risk in patients with a planned BCF access. This paper details the methodology used to determine the hemodynamic consequences of the post-fistula environment and illustrates detailed results for a representative sample of patient-specific anatomies, including a single, bifurcated, and trifurcated arch. It is found that the high flows present due to fistula creation lead to secondary flows in the arch owing to its curvature with corresponding low wall shear stresses. The abnormally low wall shear stress locations correlate with the development of stenosis in the singular case that is tracked in time for a period of one year.

Physician and treatment characteristics in a randomised multicentre trial of acupuncture in patients with osteoarthritis of the knee.

OBJECTIVE: The aim of this paper is to describe the treatment and physician characteristics in a randomised trial of acupuncture for osteoarthritis of the knee. DESIGN: Three-armed, randomised, controlled multicentre trial with 1-year follow-up. SETTING: Twenty-eight outpatient centres in Germany. INTERVENTIONS: A total of 294 patients with osteoarthritis of the knee were randomised to 12 sessions of semi-standardised acupuncture (at least 6 local and 2 distant points needled per affected knee from a selection of predefined points, but individual choice of additional body or ear acupuncture points possible), 12 sessions of minimal acupuncture (superficial needling of at least 8 of 10 predefined, bilateral, distant non-acupuncture points) or a waiting list control (2 months no acupuncture). OUTCOME: Participating trial physicians and interventions. RESULTS: Forty-seven physicians specialised in acupuncture (mean age 43+/-8 years, 26 females) provided study interventions in 28 outpatient centres in Germany. The median duration of acupuncture training completed by participating physicians was 350 h (range 140-2508). The total number of needles used was 17.4+/-4.8 in the acupuncture group compared to 12.9+/-3.3 in the minimal acupuncture group. In total, 39 physicians (83%) stated that they would have treated patients in either a similar or in exactly the same way outside of the trial, whereas 7 (15%) stated that they would have treated patients differently (1 missing). CONCLUSIONS: Our documentation of the trial interventions shows that semi-standardised acupuncture strategy represents an acceptable compromise for efficacy studies. However, a substantial minority of participating trial physicians stated that they would have treated patients differently outside of the trial.

Hypothalamic activation in trigeminal autonomic cephalgia: functional imaging of an atypical case.

We report headache induced BOLD changes in an atypical case of trigeminal autonomic cephalgia (TAC). A 68-year-old patient was imaged using fMRI during three attacks of a periorbital head-pain with a average duration of 3 min. During the attacks, left sided conjunctival injection, rhinorrhea, lacrimation, facial sweating and hypersalivation were apparent. These attacks were usually partly responsive to oxygen administration but otherwise refractory to any drug. The patient described either attacks with a duration of one minute or less or longer attacks persisting for maximum of 20 min with headaches occurring up to 100 times a day. When considering the symptoms, frequency, duration and therapeutic response of the patient's headache, no clear-cut classification to one of the subtypes of trigeminal autonomic cephalgias (cluster headache, paroxysmal hemicrania, SUNCT) or trigeminal neuralgia was possible. The cerebral activation pattern was similar but not identical to those previously observed in cluster headache and SUNCT with a prominent activation in the hypothalamic grey matter. This case study underlines the conceptual value of the term TAC for the group of headaches focusing around the trigeminal-autonomic reflex. Our results emphasize the importance of the hypothalamus as key region in the pathophysiology of this entity.

Changes of cerebrovascular response to visual stimulation in migraineurs after repetitive sessions of somatosensory stimulation (acupuncture): a pilot study.

OBJECTIVES: To evaluate the effect of repetitive somatosensory stimulation (acupuncture) on cerebrovascular response in migraineurs by functional transcranial Doppler. METHODS: Changes of cerebral blood flow velocity in the right posterior and left middle cerebral arteries were measured by functional transcranial Doppler during visual stimulation (flickering light over 57 seconds) in 10 migraineurs before and after 10 acupuncture sessions. The same stimulation paradigm was performed in 10 control subjects. Cerebral blood flow velocity data were analyzed with a previously validated technique based on automated stimulus-related averaging. To evaluate the clinical effect of the treatment, a headache diary monitored the frequency and intensity of the migraine attacks. A positive treatment effect was defined as a reduction of at least 50% in the attack frequency or the mean headache intensity (or both). RESULTS: Before treatment, migraineurs showed overshooting cerebral blood flow velocity changes at the beginning and at the end of the stimulation and a delayed decline to baseline compared with control subjects. After treatment, this response pattern was significantly diminished (P

Acupuncture Randomized Trials (ART) in patients with migraine or tension-type headache--design and protocols.

BACKGROUND AND OBJECTIVE: We report the design and essentials of the protocols of two Acupuncture Randomized Trials (ART) investigating whether acupuncture is more efficacious than no treatment and minimal acupuncture in the interval treatment of migraine and tension-type headache. DESIGN: Randomized controlled multicenter trials with three treatment arms and a total observation period of 28 weeks. SETTING: 30 practitioners and outpatient units in Germany specialized in acupuncture treatment. PATIENTS: Per study 300 patients with migraine and episodic or chronic tension-type headache, respectively (diagnosis according to the criteria of the International Headache Society). INTERVENTIONS: Patients are randomly assigned to receive either (1) semi-standardized acupuncture (150 patients), (2) standardized minimal acupuncture (75 patients), or (3) no interval treatment for 12 weeks followed by semi-standardized acupuncture (75 patients, waiting list control). Acupuncture treatment consists of 12 sessions per patient over a period of 8 weeks. MAIN OUTCOME MEASURE: Main outcome measure in the migraine trial is the difference between the number of days with headache of moderate or severe intensity during the 4 weeks before randomization and weeks 9 to 12 after randomization. In the study on tension-type headache the main outcome measure is similar to that described above, but for the number of headache days regardless of intensity. OUTLOOK: The results of these two studies (available in 2004) will provide health care providers and policy makers with the information needed to make scientifically sound assessments of acupuncture therapy.

[Differential and common characteristics of patients with atypical facial pain and craniomandibular dysfunction]. / Differenzielle und gemeinsame Merkmale bei Patienten mit atypischem Gesichtsschmerz und kraniomandibularer Dysfunktion.

BACKGROUND: Craniomandibular disorders (CMD) and atypical facial pain (AFP) represent a clinical challenge. Whereas CMD patients respond to somatic approaches, somatization should be strictly avoided in AFP. The aim of this study was to establish prognostic criteria to identify an aggravated risk of a chronic course in CMD and AFP. METHOD: A total of 124 consecutive patients with CMD ( n=108) or AFP ( n=16) were examined by two interdisciplinary academic pain centers. Psychometric evaluation was conducted with standardized questionnaires (SCL-90R, STAXI, modified SBAS-IV). All patients were clinically assessed by a maxillofacial surgeon or specialized dentist. RESULTS: The following variables proved to be significant: age (risk for AFP vs CMD increased by 6% p.a.), decreased dysfunction index (13% higher risk for AFP vs CMD), and low scores concerning outwardly directed anger (12% higher risk for AFP vs CMD). There was no correlation between initial pain intensity and somatic parameters of disease as assessed by the standardized clinical examination. Low educational status proved to be the best predictor ( p<0.001) for patients presenting high initial pain with a marked discrepancy between somatic findings and subjective status. CONCLUSIONS: CMD patients differ from AFP patients regarding age, psychosocial isolation, outwardly directed anger, and a decreased dysfunction index. Additionally, initial pain intensity in patients presenting indistinct CMD/AFP can be considered as a valid predictor for a chronic course in pain.

Tuberculosis screening in dialysis patients--is the tuberculin test effective?

AIM: Patients with end-stage renal disease are at increased risk for tuberculosis (TB). The Centers for Disease Control and Prevention (CDC) has recommended annual skin testing for TB, with tuberculin-purified protein derivative (PPD), in patients with chronic renal failure. The aim of this study was to identify the incidence and prevalence oftuberculin positivity and assess the utility of the tuberculin test in an inner city dialysis population. METHODS: All patients on chronic hemodialysis at a center affiliated to the University of Chicago, who were tuberculin-tested between 1997 and 2000 or had previously documented PPD positivity precluding retesting, were included. Demographics, comorbidity, and tuberculin and anergy reactivity were recorded. A positive PPD was an induration of > 10 mm in response to 5 tuberculin units of PPD, and anergy an induration of < 2 mm in response to the anergy antigens (Candida and Mumps), at 48 h. PPD-positive patients were compared with PPD-negative patients; Fisher's exact test and t-test were used, p < 0.05 was considered significant. RESULTS: Of 131 patients at the dialysis center, 118 were studied. The remaining 13 refused consent to PPD testing. 41 (35%) were PPD-positive, 77 (65%) were negative. Of the 77 PPD-negative patients, 62 (81%) were anergic. None of the PPD-positive patients had clinical or radiographic signs of active TB. Only 20 patients received INH prophylaxis, the others refused or had contraindications to therapy. The conversion rate ranged from 3 - 8% per year. Demographics, nutritional parameters, comorbidity and adequacy of dialysis did not help predict PPD positivity. CONCLUSION: There is a high prevalence of PPD positivity and anergy among dialysis patients. As the diagnostic utility of the time-tested PPD test is unclear in an anergic dialysis population, the need for a high index of suspicion for active tuberculosis and timely diagnostic work up should be reinforced and not replaced by total dependence on the tuberculin test.

Evanescent-wave trapping and evaporative cooling of an atomic gas at the crossover to two dimensions.

A dense gas of cesium atoms at the crossover to two dimensions is prepared in a highly anisotropic surface trap that is realized with two evanescent light waves. Temperatures as low as 100 nK are reached with 20,000 atoms at a phase-space density close to 0.1. The lowest quantum state in the tightly confined direction is populated by more than 60%. The system provides atoms at a mean distance from the surface as low as 1 microm, and offers intriguing prospects for future experiments on degenerate quantum gases in two dimensions.

Different modes of manual acupuncture stimulation differentially modulate cerebral blood flow velocity, arterial blood pressure and heart rate in human subjects.

The psychophysiological effect of different modes of manual acupuncture stimulation was investigated in 12 healthy, right handed, male subjects (mean age 29). The cerebral blood flow velocity (CBFV) in both middle cerebral arteries, arterial blood pressure (BP), heart rate (HR) and the perceived intensity of the stimulation were monitored while an acupuncture needle in the right dorsal thenar muscle (point Hegu, Li 4) was repetitively rotated with either high frequency (4-8 Hz) and low amplitude (hf-la) or low frequency (1-2 Hz) and high amplitude (lf-ha). Response patterns induced by hf-la and 1f-ha [corrected] stimulation differed significantly (P < 0.05) as tested by Student's t-test: (1), 1f-ha [corrected] stimulation was perceived as more intense and induced a more marked right hemispheric CBFV increase; (2), while hf-la stimulation lead to a slight decrease of BP and HR, lf-ha stimulation induced an initial pressor response (increase of BP, decrease of HR) and a more marked long term decrease of BP. Data indicate that the mode of manual acupuncture stimulation has a differential effect on the perceived stimulation intensity, the cerebral activation and the cardiovascular reflex response.

[Psychic and somatic findings in jaw or facial pain of unclear origin. Comparison of patients with severe and mild symptoms]. / Psychische und somatische Befunde bei ätiologisch nicht eindeutigen Kiefer- bzw. Gesichtsschmerzen Vergleich zwischen hoch und niedrig symptomatischen Patienten.

BACKGROUND: Both for medical and dental specialists, patients with facial arthromyalgia (FAM) and acute or chronic atypical facial pain (AFP) often represent a clinical challenge. Only few empirical studies address the possible interaction between facial pain and increased psychosocial stress with a thereby heightened risk for a chronic course of disease. OBJECTIVE: To evaluate whether FAM or AFP - patients initially presenting with high vs. low pain intensity differ in somatic, psychosocial and socioeconomic parameters. METHOD: We chose to study a population with a primary diagnosis of myofascial pain of the jaw muscles or atypical facial pain and excluded patients with disc displacement, acute arthritis and severe arthrosis. Within nine months, 124 consecutive patients with FAM ( n=108) or AFP ( n=16) were referred to the departments of maxillary surgery, dentistry or neurology of two interdisciplinary academic pain centers. Using the patients'ratings on a 100 mm visual analogue scale concerning their pain intensity, the group was divided in a subgroup initially presenting with low (VAS5; n=45). Psychometric evaluation was conducted with the SCL-90R (general psychopathology), the State-Trait-Anger-Expression Inventory (STAXI) and a special questionnaire addressing different aspects of chronic pain (modified SBAS-IV). All patients were assessed by a maxillary surgeon/specialized dentist with the help of a detailed, standardized clinical examination (Helkimo-Index). RESULTS: The group of FAM-/AFP - patients according to our inclusion-/exclusion - criteria presenting with a high pain intensity showed more psychosocial withdrawal ( p=0.013), a worse self-rated psychological status ( p=0.033) and a trend towards more somatization ( p=0.093) than patients with lower pain intensity. There was no correlation between initial pain intensity and somatic parameters of disease as assessed by the standardized clinical examination. Low educational status proved to be the best predictor (p<0.001) for belonging to the high (extensive) pain group. CONCLUSIONS: These data suggest that FAM-/ AFP - patients initially presenting with a high pain intensity have an increased risk for psychosocial stress and maladaptive coping behaviour. As both variables are empirically validated risk factors for a chronic course in pain-related disease, these patients should be of special interest for an interdisciplianary therapeutic setting including psychotherapeutic approaches.

[Investigations on the effect of acupuncture on affective and sensory components of pain in patients with different stages of chronic pain]. / Wirkung der Akupunktur auf die affektivve and sensorische Schmerzbewertung. Untersuchung beipatienten in unterschiedlichen Chronifizierungsstadien]

OBJECTIVES: The aim of the study was to investigate the effects of acupuncture on the affective and sensory experience of pain in chronic pain patients. Furthermore, the study tried to estimate the therapeutical benefit of acupuncture in relation to the stage of chronic pain according to the Mainz pain staging system for chronic pain (MPSS). METHODS: Patients with chronic pain syndromes who received acupuncture treatment answered a standardized pain questionnaire before and after treatment. The questionnaire included the visual-analogue-scale for the intensity of pain, the pain perception scale for the assessment of affective and sensory components of pain perception, and addressed the patients to the three stages of chronic pain (MPSS). RESULTS: From April 1997 to October 1999, patients (n = 165) suffering from chronic headache and facial pain syndromes (23%), spine associated pain syndromes (48%) or other pain conditions (29%) were subsequently included. Treatment with acupuncture showed a more pronounced reduction of the affective assessment than of the sensory assessment of pain. These effects were particularly pronounced in patients assigned to stage 3 of chronic pain (MPSS). CONCLUSIONS: Acupuncture in patients with high-stage chronic pain syndromes preferentially influences the affective dimension of pain perception. For the estimation of the overall clinical outcome of acupuncture treatment, a differentiation between affective and sensory components of pain is recommended.

Altered cerebrovascular response pattern in interictal migraine during visual stimulation.

A dysbalance of the cerebrovascular response during functional activation of the brain has been postulated as a factor in the pathophysiology of migraine. To determine the dynamic pattern of the cerebrovascular response in migraineurs compared with a control group, changes of the cerebral perfusion during cerebral activation were studied with high temporal resolution by functional transcranial Doppler sonography (fTCD). The cerebral blood flow velocity (CBFV) in the right posterior cerebral artery (PCA) and the left middle cerebral artery (MCA) was measured simultaneously during visual stimulation in 19 interictal migraineurs and in 19 age- and sex-matched control subjects. Data were analysed with a previously validated technique based on automated stimulus-related averaging of the CBFV. The MCA migraineurs exhibited a steady increase of CBFV during the stimulation, while normal subjects showed a habituation of the CBFV response. The lack of habituation in migraineurs was significantly (P < or = 0.05) more pronounced across patients with a high attack frequency (> or = 4 per month) compared with migraineurs with a low attack frequency (< 4 per month). In the PCA, compared with normal subjects, migraineurs showed significantly (P < or = 0.05) stronger CBFV changes at the beginning and after the end of stimulation, with a slower decline to baseline. Data are in accordance with electrophysiological findings in migraineurs. It is assumed that a lack of habituation of the cerebrovascular response in migraineurs might contribute to a disturbance of the metabolic homeostasis of the brain that might induce migraine attacks.

Renal cell osteopontin production is stimulated by calcium oxalate monohydrate crystals.

Specific anions in tubular fluid, including uropontin (UP), the urinary form of human osteopontin (OPN), block adhesion to renal tubular cells of the most common crystal in kidney stones, calcium oxalate monohydrate (COM). In this study, monkey renal epithelial cells (BSC-1 line) in monolayer culture constitutively secreted UP into the culture medium. COM crystals added to the medium avidly bound previously secreted UP, reducing its concentration by 46% one hour later. However, the net UP content of cultures after a 24-hour exposure to COM crystals was increased by 18%. Northern blotting showed that the constitutively expressed gene encoding human OPN was maximally stimulated in BSC-1 cells after exposure to COM crystals for 12 hours. Two other calcium-containing crystals, hydroxyapatite and brushite, did not alter OPN gene expression or protein production. OPN mRNA expression was enhanced in canine renal epithelial cells (MDCK line) after exposure to COM crystals for six hours, whereas the constitutive expression of murine OPN mRNA by 3T3 fibroblasts was unchanged. In vivo this glycoprotein could defend the cell against adhesion of crystals in tubular fluid, and/or promote renal interstitial fibrosis in subjects with heavy crystalluria.

Role of calcium oxalate monohydrate crystal interactions with renal epithelial cells in the pathogenesis of nephrolithiasis: a review.

Renal tubular fluid in the distal nephron is supersaturated with calcium and oxalate ions that nucleate to form crystals of calcium oxalate monohydrate (COM), the most common crystal in renal stones. How these nascent crystals are retained in the nephron to form calculi in certain individuals is not known. Recent studies from this laboratory have demonstrated that COM crystals can bind within seconds to the apical surface of renal epithelial cells, suggesting one mechanism whereby crystals could be retained in the tubule. Adherence of crystals to cells along the nephron may be opposed by specific urinary anions such as glycosaminoglycans, uropontin, nephrocalcin, and citrate. In culture, adherent crystals are quickly internalized by renal cells, and reorganization of the cytoskeleton, alterations in gene expression, and initiation of proliferation can ensue. Each of these cellular events appears to be regulated by extracellular factors. Identification of molecules in tubular fluid and on the cell surface that determine whether a crystal-cell interaction results in retention of the crystal or its passage out of the nephron appears critical for understanding the pathogenesis of nephrolithiasis.

Laparoscopic Swenson pull-through procedure for congenital megacolon.

Constipation that is unresponsive to conventional remedies is the primary symptom of congenital megacolon (ie, Hirschsprung's disease). The cause of congenital megacolon is lack of ganglion cells in the bowel. The laparoscopic Swenson pull-through procedure involves removing the aganglionic segment of the colon, bringing the normally decompressed bowel through the pelvic floor, and anastomosing the bowel to the anorectal verge. Advantages of the laparoscopic approach include shorter lengths of hospital stay and fewer complications resulting from disruption of skin integrity.

Calcium oxalate monohydrate crystals stimulate gene expression in renal epithelial cells.

Primary or secondary hyperoxaluria is associated with calcium oxalate nephrolithiasis, interstitial fibrosis and progressive renal insufficiency. Monolayer cultures of nontransformed monkey kidney epithelial cells (BSC-1 line) and calcium oxalate monohydrate (COM) crystals were used as a model system to study cell responses to crystal interactions that might occur in the nephrons of patients during periods of hyperoxaluria. To determine if COM crystals signal a change in gene expression, Northern blots were prepared from total renal cellular RNA after the cells were exposed to crystals. The immediate early genes c-myc, EGR-1, and Nur-77 were induced at one hour. At two to six hours stimulated expression of the genes encoding plasminogen activator inhibitor (PAI-1) and platelet-derived growth factor (PDGF)-A chain was detected, but constitutive expression of urokinase-type plasminogen activator (u-PA) was not altered. Expression of connective tissue growth factor (CTGF) was induced at one hour and persisted up to 24 hours. The stimulation of gene expression by COM crystals was relatively crystal- and renal cell-type specific. Thus the interaction of kidney epithelial cells with COM crystals alters expression of genes that encode three classes of proteins: transcriptional activators, a regulator of extracellular matrix (ECM), and growth factors. Activation of PAI-1 gene expression without a change in u-PA favors accumulation of ECM proteins, as does increased expression of PDGF and CTGF which can also stimulate fibroblast proliferation in a paracrine manner. These results suggest that COM crystal-mediated stimulation of specific genes in renal tubular cells may contribute to the development of interstitial fibrosis in hyperoxaluric states.

Hypocalcemia in end-stage renal disease: a consequence of spontaneous parathyroid gland infarction.

Advances over the last several years have led to a better understanding of the etiology of hyperparathyroidism in renal disease and to more effective means of medical prevention and therapy. Thus, in most dialysis populations, many of the serious complications, such as bone fractures, refractory hypercalcemia, and hyperphosphatemia with vascular and other extraskeletal calcifications, have diminished. Furthermore, more aggressive medical management has decreased the requirement for parathyroidectomy. Unfortunately, not all patients respond to medical management and few still develop refractory hyperparathyroidism with associated morbidity. Of the many complications of refractory hyperparathyroidism in dialysis patients, the development of life-threatening hypocalcemia has not been described. We describe a patient with severe secondary hyperparathyroidism who presented with the acute development of hypocalcemia. To our knowledge, this represents the fourth case, the first reported in a patient with end-stage renal disease, of parathyroid autoinfarction presenting as acute hypocalcemia.