Oral immunoglobulin induces mononuclear cell apoptosis in patients suffering from idiopathic chronic pain syndrome: results from a pilot study.

OBJECTIVE: The objective of this clinical pilot study was to examine the induction of apoptosis in mononuclear cells on treatment of patients with chronic pain syndrome with oral immunoglobulin produced from bovine colostrum (BCC). DESIGN: The 4 patients suffering from chronic idiopathic pain (idiopathic facial pain, CRPS or fibromyalgia) who were enrolled in the study had previously successfully been treated with BCC (varying individual doses). Mononuclear cells from peripheral blood were analyzed for representative cytokines in the serum as well as by TUNEL-assay to detect apoptotic cellular events 14 days after the last treatment with BCC and 14 days after restarting the treatment protocol with BCC. The clinical response (pain and quality of life parameters using a visual analogue scale (VAS)) were determined regularly in each patient. RESULTS: The findings showed a disturbed apoptosis homeostasis in 3 of the 4 patients. These results were accompanied by a relief of the pain symptoms. The 4th patient was found not to need any further analgetic treatment since she demonstrated only nonsignificant changes in her laboratory screening and immunological parameters and by the end of the study she was also completely free of pain (long-term treatment with BCC). CONCLUSIONS: In spite of the low patient number, the results were obtained with a sufficiently high degree of control because of the study design. The agreement of the clinical data with our laboratory measurements suggests that the induction of apoptotic events in mononuclear cells is the result of the dominant immunological effects of BCC treatment.

Bovine colostrum as a biologic in clinical medicine: a review--Part II: clinical studies.

The value of bovine colostrum as a biologic in medicine is documented in clinical trials and supported by relatively large databases containing case reports and anecdotal findings. The main actions include an antibacterial effect and modulation of the immune response. The ability of bovine colostrum concentrates (BCC are polyvalent bovine colostrum concentrates produced from the colostrums of several 100 cows) to neutralize lipopolysaccharides, i.e. endotoxins arising from Gram-negative bacterial pathogens and to inhibit enterogenic endotoxemia in animal models as shown in the last review to have its counterpart in patient therapy. Clinical trials with BCC provide evidence that oral application reduces the influx of LPS from the gut and this appears to be a major mechanism underlying its therapeutic effect in patients at risk for Gram-negative septic shock; data from two well-controlled clinical studies with a total of 100 surgical patients have shown that the inhibition of intestinal LPS absorption measured after the application of BCC not only reduced the LPS levels in the peripheral blood but also inflammatory parameters like IL-6 and CRP were found to be diminished. The usual daily dose of the commercially available BCC preparation, LactobinA (LC1) is 10 â 20 g daily, but higher doses can be used in the majority of patients because of the low incidence of intolerance problems. In chronic diarrhea involving severe forms of secondary immunodeficiencies, patients receiving LC1 were disease-free for about 4 weeks but the response may be lower in patients with AIDS. BCC is effective in infants with hemorrhagic diarrhea caused by infections with enterohemorrhagic E. coli and reduces the likelihood of the disease progressing to a hemolytic uremic syndrome. The safety of newer BCC products obtained from BSE-free regions seems now beyond contention. In the case of LC1, which was used as a commercial dietary foodstuff in Germany until 1992 and tested in three Phase 1 and 5 clinical studies (two trials in patients with secondary immunodeficiencies, one in surgical patients with gastrointestinal disorders, one in patients undergoing open heart surgery and one in pediatric patients with EHEC infections), there were no cases of BSE-associated disease such as the new variant of Creutzfeldt-Jakob disease. Side effects of clinical relevance are limited to possible intolerance to lactose and sensitivity to milk proteins as these are also present in many commonly used foodstuffs. Important synergistic actions with conventional drug therapies have been observed with BCC including a reduction in LPS plasma levels in patients with Gram-negative bacterial infections treated with bactericidal antibiotics. In healthy persons there are only small concentrations of LPS detectable in peripheral blood (normal values: 3 â 10 pg/ ml plasma, i.e. approximately 0.1 EU/ml). In contrast, elevated systemic levels with concentrations > 300 pg/ml are common in patients with severe Gram-negative sepsis and septic shock. Raised LPS levels occur mainly in patients with Gram-negative bacterial infections who have been treated with bacteriocidal antibiotics. The LPS-lowering effects of BCC are probably due to the numerous active components present in BCC which have their origin in the innate humoral and adaptive immune system of their biologic source, the cow.

Altered intestinal permeability in patients with primary fibromyalgia and in patients with complex regional pain syndrome.

OBJECTIVES: The pain intensity of patients with FM has recently been reported to be correlated with the degree of small intestinal bacterial overgrowth (SIBO). SIBO is often associated with an increased intestinal permeability (IP). Increased IP, if shown in FM, may have pathogenetic relevance because it leads to the exposure of immune cells to luminal antigens and consequent immune modulation. It is currently unknown whether IP is altered in FM. We therefore examined the IP in a group of patients with primary FM and in two control groups, healthy volunteers and patients with an unrelated chronic pain syndrome, complex regional pain syndrome (CRPS). We hypothesized that patients with FM, but not volunteers or those patients with CRPS, would have altered IP. METHODS: Both gastroduodenal and small IP were assessed using an established three-sugar test, where urinary disaccharide excretion reflecting intestinal uptake was measured using HPLC. RESULTS: Forty patients with primary FM, 57 age- and sex-matched volunteers and 17 patients with CRPS were enrolled in this study. In the FM group, 13 patients had raised gastroduodenal permeability and 15 patients had raised small intestinal permeability, but only one volunteer had increased gastroduodenal permeability (P < 0.0001, chi-square test for the three groups). The IP values were significantly increased in the patient groups (P < 0.0003 for all comparisons, one-way analysis of variance). CONCLUSIONS: The IPs in primary FM and, unexpectedly, CRPS are increased. This study should stimulate further research to determine the implication of altered IP in the disease pathophysiology of FM and CRPS.

Bovine colostrum as a biologic in clinical medicine: a review. Part I: biotechnological standards, pharmacodynamic and pharmacokinetic characteristics and principles of treatment.

Mammals supply their newborn before birth, at birth or shortly after birth with antibodies, immunocytes and humoral constituents. This "borrowed immunity" is a form of passive immunization to protect the newborn against environmental pathogens until it establishes its own pathogen recognition and disposal systems. In cows, goats, horses and some other animal species, most immunoglobulins are obtained from the colostrum, the first milk after birth, via the gut but in humans the majority of immunoglobulins, and those of the IgG-class in particular, are acquired from the mother by placental transport in the weeks prior to parturition. It has long been known that the consumption of bovine colostrum by humans has therapeutic effects e.g. in gastrointestinal infections, but only since the second half of the last century has it been possible to prepare stable, standardized preparations of colostrum. These biologics are administered to patients in combination with standard therapies as so-called balanced supportive diets. Investigations with standardized colostrum preparations in animal models of human disease and estimates of bovine IgG activity in the human GI-tract, described in this review, have provided preclinical data supporting the use of bovine colostrum in human diseases. On the other hand, the number of bovine colostrum products with a sufficiently large and reliable database is limited and the precise nature of the therapeutic targets is still being evaluated.

[An atraumatic needle for continuous epidural and plexus anesthesia]. / Eine atraumatische Kanüle für die kontinuierliche Peridural- und Plexusansthesie.

The needle type introduced by Edward Tuphy for continuous spinal anaesthesia in 1944 is still used as the standard instrument for epidural anaesthesia up to the present day. Puncture of the dura and severance of the epidural catheter are the typical, though fare, complications of this procedure, giving rise to most of the actions brought for damage suffered during obstetric anaesthesia. The cerebral spinal fluid loss caused by thick needles can have serious consequences, including subdural and intracranial haematoma, cranial nerve pareses, labyrinthine hearing impairments and pneumocephalus. Special Sprotte needle for catheter introduction. In spinal anaesthesia and lumbar puncture the Sprotte needle has proven a very suitable instrument for the CSF loss syndrome and, to a large degree, post-spinal headaches. To adapt the atraumatic properties of this needle point for epidural anaesthesia the needle has been equipped with a plastic ramp to direct catheter insertion, and the opening geometry has been slightly modified for epidural application (see Fig. 1). The lateral catheter channel projects into the base of the needle point, which is thus shortened, and the edges of the needle opening are rounded so that the catheters cannot be severed. This needle bears the type designated "Special Sprotte needle" (EP no. 271715, USP no. 4842585). Needle diameter and application fields. The 1.1-mm (19.5 G) needle with 23-G catheter was introduced for epidural anaesthesia and continuous plexus anaesthesia at the Würzburg University Hospital and has proven itself in routine clinical practice. A 20-G version is being tested with a 25-G catheter for continuous spinal anaesthesia at several centers in USA, because finer spinal catheters are not permitted there by the FDA. For continuous spinal anaesthesia this needle has been available without the modified opening geometry since 1989 in sizes 22 G and 24 G and is wide by used in Europe. CSE technique with special and standard Sprotte needles. Spinal analgesia or anaesthesia) can be performed with the special needle and 123-mm-long 27 G or 29 G standard Sprotte needles before placement of the peridural catheter.

[Experimental studies on peripheral nerve injuries caused by injection needles]. / Experimentelle Untersuchungen zur peripheren Nervenverletzung durch Injektionsnadeln.

Differences in neural damage due to different injection needles were investigated in vitro on sciatic nerve specimens of adult rabbits. METHODS. Three types of 22-gauge needles were tested: one typical, long-bevelled venous puncture needle; a short bevelled, typical nerve block needle; and a tapered, atraumatic spinal needle. Both sciatic nerves of 50 adult rabbits weighing from 2.5 to 3.0 kg were used for electrophysiological investigations on one side and fluorescence microscopy on the other. ELECTROPHYSIOLOGY. The nerve specimens were placed in an experimental chamber on silver-silver chloride electrodes that were aligned at a distance of 10 mm. Two electrodes at the distal ends of the nerve were used for stimulation by rectangular waves (6-10 v) of 0.01 ms duration. The compound action potential (CAP), its amplitude, and its latency were measured by monopolar recording from four additional electrodes (R1 to R4). Ten nerves were apportioned to each of five groups and the needles were perpendicularly pierced three times in the middle of the nerve trunk at the midpoint between recording sites R2 and R3. THE GROUPS. 1. Long-bevelled needle, the face of the bevel inserted rectangular to the nerve fibers; 2. long-bevelled needle, the face of the bevel parallel to the nerve fibers; 3. short-bevelled needle, the face of the bevel inserted rectangular to the nerve fibers; 4. short-bevelled needle, the face of the bevel parallel to the nerve fibers; 5. tapered, pencil-point needle pierced perpendicularly through the nerve trunk. The amplitude of the CAP was recorded before and after nerve injury from R1 to R4. FLUORESCENCE MICROSCOPY. According to the method described by Steinwall and Olsson, the other five groups of injured nerves were immersed in Evans blue albumin (EBA) and, after washing in saline solution, fixed in 5% formalin. The extent of nerve damage was evaluated by fluorescence microscopy of the glycerol-imbedded frozen sections (longitudinal and transverse). RESULTS. Electrophysiology. After injuring the area between R2 and R3 there was almost no change in the amplitude of the CAP at sites R1 and R2. The amplitude at R3 and R4 was reduced in comparison with the controls. This reduction was most marked in group 1 and very slight in group 5. The percentages of amplitude at R3 after injury compared with control values (mean +/- SD) were 42.2% +/- 22.0% in group 1; 60.9% +/- 18.2% in group 2; 51.0% +/- 22.3% in group 3; 71.0% +/- 18.0% in group 4; and 90.1% +/- 10.9% in group 5. Statistically significant differences were obtained between the tapered, atraumatic needle group and the other four groups (Fig. 3). Fluorescence microscopy. With the tapered injection needle there was the least leakage of EBA, which suggests the least damage to the perineurium, and almost no rupture or tearing of the nerve fibers was observed. In the short- and long-bevelled needles, the damage was reduced when the face of the bevel was inserted parallel to the fibers.

[An "atraumatic" universal needle for single-shot regional anesthesia: clinical results and a 6 year trial in over 30,000 regional anesthesias]. / Eine "atraumatische" Universalkanüle für einzeitige Regionalanaesthesien. Klinische Ergebnisse nach sechsjähriger Erprobung bei über 30,000 Regionalanaesthesien.

The so-called "atraumatic" needle was developed by modification of two essential features of the Whitacre Spinal needle. The new atraumatic needle tip is universally suitable for all single-shot techniques of regional anesthesia. This is the result of a 6-year test period with 34,950 applications of 24- and 22-Gauge needles in spinal anesthesia, diagnostic lumbar puncture, peridural anesthesia, plexus anesthesia, peripheral nerve blocks with a Teflon-coated version (unipolar electrostimulation), and lumbar sympathetic and celiac plexus blocks. Postspinal headache was observed following 0.02% of punctures for anesthetic or diagnostic purposes. Transient monosymptomatic nerve damage occurred in 1 case after axillary block (0.009%). No permanent neurological sequelae were observed due to vascular, neural, or dural lesions. In comparison, 10 cases of persistent traumatic nerve damage were reported to be caused by conventional needles during the last decade. An analysis of these cases reveals some reasons for underestimating the risk of neurological sequelae after regional anesthesia. The routine clinical use of this type of atraumatic needle revealed no disadvantages with regard to efficacy of nerve blocks or training of anesthetists. Due to the extremely low incidence of postspinal headache, this needle has been used for spinal therapy and diagnostic lumbar punctures in outpatient pain therapy for 2 years. As of this time, the overall risk of outpatient lumbar puncture cannot be estimated. Our experience should encourage further controlled studies to evaluate criteria for excluding those patients unsuited for outpatient spinal anesthesia and lumbar puncture.

[Combined infusion analgesia--an alternative concept in postoperative pain therapy]. / Die kombinierte Infusionsanalgesie--Ein alternatives Konzept zur postoperativen Schmerztherapie.

This is to introduce a combined infusion analgesia for postoperative pain treatment. The analgetic efficiency would increase by combining analgetic substances specifically focussed. This method has the enormous advantage not to be limited to the intensive care; it might be applied to any peripheral surgery. Its main and side effects have been tested in 25 gastrectomized patients, postoperatively.

[Pneumocephalus permangnus. An unusual complication following lumbar anesthesia]. / Pneumocephalus Permagnus. Eine ungewöhnliche Komplikation nach rückenmarksnaher Leitungsanaesthesie.

A case is presented of a 53 year old patient who developed pneumocephalus three days after lumbar anaesthesia. Symptoms and neurosurgical treatment are described. Liquor leakage and lowered intracranial pressure as are discussed as possible mechanisms.

[Differential anesthetic block]. / Etude du blocage anesthésique différentiel.

The concept of differential action of local anaesthetics on nerve fibers of different size is falsified by experiment. The temporal succession of alteration in perception is to be explained by changes at higher levels of integration.

[Morphological changes after permanent nerve block by freezing and ethanol injection of the sciatic nerve of the rabbit (author's transl)]. / Vergleichende histologische Untersuchungen am Nervus ischiadicus des Kaninchens nach Blockade der Nervenleitung durch Vereisung oder Alkoholinjektion.

Permanent nerve blocks by intraneurally injected alcohol are often complicated by alcohol-neuritis. Encouraging clinical experiences with permanent blocks by freezing raises the question whether morphological differences between the nerve lesions could explain the difference in their side effects. On 30 rabbits both sciatic nerves were blocked after surgical preparation. The one by intraneural injection of 0,5 ml of 96% Ethanol, the other by freezing with a cryoprobe. The resulting degeneration and the beginning of recovery of the nerves was followed by histological evaluations of the sciatic nerves during the first 28 days after the blockade. The nerve lesions of both types of blockade were complete. That produced by the cryoprobe was limited to the small area of local freezing, whereas the alcohol-block produced the same type of nerve degeneration but with a wide-spread extension reaching the sacral plexus. We discuss whether this slight morphological difference might be sufficient to explain the higher complication rate of alcohol blocks.

[Differential peridural analgesia for vaginal delivery. A randomised study of its influence on the progress and mode of delivery (author's transl)]. / Differenzierende peridurale Analgesie für die vaginale Entbindung. Eine randomisierte Studie über den Einfluss der PDA auf den Geburtsverlauf.

This randomised study of 611 deliveries deals with the side effects of a modified extradural analgesic technique. The modification is based on a flexible reduction of local anaesthetic concentration (bupivacaine) which allows a reliable analgesia without a marked loss of labour sensation and bearing down reflex. Randomisation was achieved by offering this analgesia to the parturients in an alternating 24 hours rhythm. Statistical comparisons were carried out for the following groups of deliveries: 1. for deliveries on both of the two alternating days (Group A). 2. for deliveries with and without extradural analgesia of the peridural days (Group B). - 3. for all deliveries with and without extradural analgesia (Group C). - 4. For deliveries without extradural analgesia on "peridural days" and on "alternating days" (Group D). - The main subjects of investigation were the duration of the two stages of delivery, the dynamics of both the cervical dilation and the movement of the fetal head and the frequency, modes and causes of operative and instrumental deliveries. The safety of the analgesic technique was investigated by evaluating its influence on the status of the newborn and on the maternal regulation of body temperature and circulation. The results were obtained as follows: 1. In the group of parturients who had chosen extradural analgesia several antenatal factors accumulated which evidently had a greater influence on the course of delivery than the analgesic technique itself. - 2. The low concentration of local anaesthetic adapted to the labour pain produced a sufficient analgesia in almost every case. - 3. The duration of both stages of delivery was not altered directly by this technique. An average increase of the duration of the second stage by 116 minutes was due to postponed indications of instrumental and operative deliveries by analgesia. - 4. There was no influence on the overall frequency of operative and instrumental deliveries. Extradural analgesia, however, significantly reduced the frequency of caesarean sections to the same extent as it increased instrumental deliveries from the bottom of the pelvis. - 5. The extradural analgesia had no influence on the status of the newborn. - 6. The regulatory mechanisms of circulation and body temperature were not altered by this dosage of extradural analgesia.

[Pre- and postoperative analgesia by lumbar plexus anaesthesia (3 in 1 block) in orthopaedics and traumatology (author's transl)]. / Die inguinale Blockade des Plexus lumbalis als Analgesie- Verfahren in der prä- und postoperativen Traumatologie und Orthopädie.

The 3 in 1 block provides effective analgesia for the greater part of the lower limb. The technique is simple, it requires no special positioning and because of the favorable anatomical situation of the femoral nerve it has a particularly low complication rate. The prompt administration in the acute situation considerably reduces the symptoms and consequences of traumatic shock. One should always bear in mind this effect regional anaesthetic technique in elderly patients with fractured neck of femur. The 3 in 1 block enables almost painfree positioning of the side for the performance of spinal and epidural anaesthesia. Finally the 3 in 1 block can be a most potent method of analgesia in postoperative pain. With its minimal effects on vasomotor tone and bladder function the 3 in 1 block is in many cases preferable to continuous blockade via an epidural catheter.