Chronic lower limb wounds evoke systemic response of the lymphatic (immune) system.

Wound healing should not be considered as a process limited only to the damaged tissues. It is always accompanied by an intensive local immune response and in advanced stages, the systemic lymphatic (immune) structure. In this review we present evidence from our own studies as well as pertinent literature on the role of skin and subcutaneous tissue lymphatics at the wound site and of transport of antigens along with collecting afferent lymphatics to the lymph nodes. We also speculate the role of lymph nodes in raising cohorts of bacterial and own tissue antigen-specific lymphocytes and their participation in healing and not infrequently evoking uncontrolled chronic immune reaction causing a delay of healing. It is also speculated as to why there is a rapid response of lymph node cells to microbial antigens and tolerance to damaged-tissue-derived antigens occurs.

Skin own bacteria may aggravate inflammatory and occlusive changes in atherosclerotic arteries of lower limbs.

AIM: Seroepidemiological studies have given rise to the hypothesis that microorganisms like Chlamydia pneumoniae (CP), Helicobacter pylori (HP), cytomegalovirus (CMV), HCV types 1 and 2, and bacteria involved in dental or other unspecified infection sites may initiate or maintain the atherosclerotic process in lower limb arteries. However, not much attention has been attached to the patient's own limb skin and deep tissues bacterial flora, activated in ischemic tissues. This flora may enhance the inflammatory and thrombotic process in the atherosclerotic arteries. Lower limb tissues are exposed to microorganisms from the environment (foot) and microbes on floating epidermal cells from the perineal and anal regions. The aim of this paper was to identify microbial cells and their DNA in perivascular tissues and arterial walls of lower limbs. METHODS: Bacterial cultures and PCR method for detection of 16sRNA and immunohistopathological staining for identification of immune cells infiltrating vascular bundles. RESULTS: 1) specimens of atherosclerotic calf and femoral arteries contained bacterial isolates and/or their DNA, whereas, in control normal cadaveric organ donors' limb arteries or patients' carotid arteries and aorta bacteria they were detected only sporadically; 2) lower limb lymphatics contained bacterial cells in 76% of specimens, whereas controls only in 10%; 3) isolates from limb arteries and lymphatics belonged in majority to the coagulase-negative staphylococci and S.aureus, however, other highly pathogenic strains were also detected; 4) immunohistopathological evaluation arterial walls showed dense focal infiltrates of granulocytes and macrophages. CONCLUSION: Own bacterial isolates can be responsible for dense neutrophil and macrophage inflitrates of atherosclerotic walls and periarterial tissue in lower limbs and aggravate the ischemic changes.

A video study of pain relief during newborn male circumcision.

OBJECTIVE: The purpose of this investigation was to compare the effectiveness of dorsal penile nerve block and topical lidocaine-prilocaine anesthesia techniques for pain relief during circumcision. METHODS: In total, 18 healthy term newborn males were divided based on anesthesia. The topical lidocaine-prilocaine group had six males undergoing circumcision and three males undergoing a sham procedure. The dorsal penile nerve block group had six males undergoing circumcision and three males undergoing a sham procedure. The procedures were videotaped and viewed by 90 noninvestigator reviewers who scored the infants' pain using the Neonatal Infant Pain Scale and a numeric pain scale. Statistical analysis utilized a P-value of <0.05 as significant. RESULTS: The median Neonatal Infant Pain Scale and numeric pain scores were significantly lower in the dorsal penile nerve block group than in the topical lidocaine-prilocaine group or the sham group (Neonatal Infant Pain Scale: 1.0 (range 0-6) versus 6.0 (range 2-6) versus 4.0 (range 0-6), P < 0.001, respectively; numeric pain scale: 2.0 (range 0-10) versus 8.0 (range 1-10) versus 4.0 (range 0-10), P < 0.001, respectively). In the sham group, procedures with the dorsal penile nerve block had significantly lower pain scores than those with topical lidocaine-prilocaine (Neonatal Infant Pain Scale: 1.0 (range 0-6) versus 5.0 (range 2- 6), P < 0.001; numeric pain scale: 1.0 (0-8) versus 6.0 (range 0-10), P < 0.001). When reviewers were divided by medical background, gender or parental status, no differences in pain scores were observed. CONCLUSION: The dorsal penile nerve block anesthesia technique for newborn male circumcision was significantly more effective for pain relief than topical lidocaine-prilocaine.

Endogeneous sources of infection in transplant recipients.

The mammal organisms carry on their surfaces and in their tissues cohorts of microorganisms of various nature. There is a balance of interests and profits between the host and microbial inhabitants. The bacteria and fungi behave like comensals, colonizers, dormants, however, under certain, mostly unknown, conditions may evoke reaction of the host. This process is damaging both for the host and microbes. Large surgical trauma and allograft itself, as well as, immunosuppression create favorable conditions for imbalance between inhabiting microorganism and the recipient. The host flora and that transplanted with the organ graft become activated. Active combating of the proliferating bacteria with antibiotics becomes necessary. Our knowledge of the bacterial flora of the so called "sterile" tissues remains rudimentary. There is still a great deal of prejudice on the sterility of deep tissues e.g. muscles, fat tissue, etc. This review cumulates pertinent literature data on the microorganisms-host interactions. Our own findings on colonization of arteries and adjacent tissues are discussed in the context of atherosclerosis and grafting.

Maintenance electroconvulsive therapy in affective and schizoaffective disorder.

Twenty-one patients (13 depressives and 8 schizoaffectives) who underwent maintenance electroconvulsive therapy (M-ECT) were compared with controls who received maintenance pharmacotherapy alone. Measures of effectiveness and safety of maintenance treatment were prospectively obtained during a 1-year follow-up. Survival analysis demonstrated a significantly better outcome defined by time to rehospitalization for all patients of the M-ECT group. Regarding the subgroups, depressives of the M-ECT group had markedly decreased rehospitalization rates compared to depressive controls. Furthermore, M-ECT in depressives resulted in a significant reduction in hospitalization rates and duration during follow-up. In schizoaffective patients, a significant difference in survival time was found in favor of the M-ECT group. In both groups, schizoaffectives had a markedly poorer outcome compared to depressive subjects. Our results indicate that in selected patients M-ECT, at least in combination with supporting medication, may be an efficient and safe alternative to pharmacological continuation or maintenance therapy alone.

Preliminary findings of simultaneous 18F-FDG and 99mTc-HMPAO SPECT in patients with depressive disorders at rest: differential correlates with ratings of anxiety.

The assumption of a dynamic coupling between regional cerebral blood flow (rCBF) and cerebral glucose metabolic rates (rCMRGlu) has been challenged by simultaneous measurements of both. Through the use of a dual-headed gamma camera with a 511-keV collimator applying the double isotope 18F-FDG and 99mTc-HMPAO SPECT technique, the uptake rates of these isotopes can be semi-quantitatively evaluated. Sixteen depressed patients, diagnosed by ICD-10 criteria and assessed with the 17-item Hamilton Rating Scale for Depression (HRSD), were studied. Based on the severity of HRSD-rated anxiety (item 10: low=1-21; high=3-4), two eight-patient subgroups were formed and compared with 12 age- and handedness-matched healthy control subjects. As regions of interest, we selected areas implicated in the neuroanatomy of anxiety and depression: hippocampus (hippo), basal ganglia (BG) and gyri temporales superiores (G.t.s.). In the control subjects, a significant statistical coupling between rCBF and rCMRGlu was revealed by the Spearman correlation coefficient only in left hippo and left BG. Patients in the low-anxiety subgroup demonstrated a marked dynamic coupling bilaterally for the G.t.s., while patients in the high-anxiety subgroup showed a significant statistical correlation of rCBF and rCMRGlu only in the left G.t.s. These findings indicate that a dynamic coupling between blood flow and glucose metabolism exists only in distinct brain regions, and that the depressive illness has an uncoupling effect on this correlation in the left BG. Furthermore, our results suggest that the HRSD anxiety score might interact with the underlying depressive illness to influence the relationship of rCBF and rCMRGlu.

Bacteriological studies of blood, tissue fluid, lymph and lymph nodes in patients with acute dermatolymphangioadenitis (DLA) in course of 'filarial' lymphedema.

Filarial lymphedema is complicated by frequent episodes of dermatolymphangioadenitis (DLA). Severe systemic symptoms during attacks of DLA resemble those of septicemia. The question we asked was whether bacterial isolates can be found in the peripheral blood of patients during the episodes of DLA. Out of 100 patients referred to us with 'filarial' lymphedema 14 displayed acute and five subacute symptoms of DLA. All were on admission blood microfilariae negative but had a positive test in the past. Blood bacterial isolates were found in nine cases, four acute (21%) and five subacute (26%). In 10 acute cases blood cultures were found negative. Six blood isolates belonged to Bacilli, four to Cocci and one was Sarcina. To identify the sites of origin of bacterial dissemination, swabs taken from the calf skin biopsy wounds and tissue fluid, lymph and lymph node specimens were cultured. Swabs from the calf skin biopsy wound contained isolates in nine (47%) cases. They were Bacilli in nine, Cocci in three, Acinetobacter and Erwinia in two cases. Tissue fluid was collected from 10 patients and contained Bacilli in four (40%) and Staphylococci in three (30%). Lymph was drained in four patients and contained isolates in all samples (100%). They were Staphylococcus epidermis, xylosus and aureus, Acinetobacter, Bacillus subtilis and Sarcina. Three lymph nodes were biopsied and contained Staphylococcus chromogenes, xylosus, Enterococcus and Bacillus cereus. In six cases the same phenotypically defined species of bacteria were found in blood and limb tissues or fluids. In the 'control' group of patients with lymphedema without acute or subacute changes all blood cultures were negative. Interestingly, swabs from biopsy wound of these patients contained isolates in 80%, tissue fluid in 68%, lymph in 70% and lymph nodes in 58% of cases. In healthy controls, tissue fluid did not contain bacteria, and lymph isolates were found only in 12% of cases. This study demonstrates that patients with acute episodes of DLA reveal bacteremia in a high percentage of cases. Diversity of blood and tissue bacterial isolates in these patients points to a breakdown of the skin immune barrier in lymphedema and subsequently indiscriminate bacterial colonization of deep tissues and spread to an blood circulation.

Bacteriologic studies of skin, tissue fluid, lymph, and lymph nodes in patients with filarial lymphedema.

Filarial lymphedema is complicated by frequent episodes of dermatolymphangioadenitis (DLA). It is not certain whether DLA is of filarial or bacterial etiology. The frequency of episodic DLA does not depend on the presence or absence of microfilariae. Antibiotic therapy is effective in prevention and treatment of DLA. These observations point to the bacterial rather than filarial etiology of DLA. Skin and lymph node biopsies, tissue fluid, lymph, and blood from patients with chronic filarial lymphedema, and during acute episodes of DLA, were cultured for detection of bacteria. A high prevalence of bacterial isolates from the tissue fluid (64%), lymph (75%), and inguinal lymph nodes (66%) of limbs with filarial lymphedema was found. Bacillus cereus, Staphylococcus epidermidis, S. hominis, S. capitis, S. xylosus, and Micrococcus spp. were the most common isolates. Bacteria were also isolated from the blood of patients with recent episodes of DLA, with strains of the same phenotype and antibiotic sensitivity in all specimens from patients with DLA. Bacterial strains of the same phenotype and antibiotic sensitivity were documented on the toe web surface and in tissue fluid (25%), lymph (26%), or lymph nodes (41%). Increasing prevalence of bacterial isolates in tissue fluid, lymph, and lymph nodes was observed in advanced stages of lymphedema. Bacilli and cocci were sensitive to gentamicin, tetracyline, rifampicin, vancomycin, kanamycin and cotrimoxazole, and least sensitive to penicillin. Blood cultures of patients in the periods between DLA attacks were negative. In healthy controls without edema and episodes of DLA, tissue fluid did not contain bacteria. In lymph, only single colonies of Micrococcus and Acinetobacter were cultured in 12% of the cases. Impaired lymph drainage and lack of elimination of penetrating bacteria may be responsible for progression of lymphedema and recurrent attacks of DLA.

[Transcranial magnetic stimulation in depressed patients: a new antidepressive therapeutic principle? Presentation of a pilot trial]. / Die transkranielle Magnetstimulation bei depressiven Patienten: ein neues antidepressives Therapieprinzip?--Präsentation eines Pilotversuchs.

So far Transcranial Magnetic Stimulation (TMS) has been established as a technique for studying function of the pyramidal tract in diverse neurological diseases, being both safe and practically free from undesirable side-effects. 5 depressive patients, diagnosed as ICD 9, 296.1 and 296.3 were treated with amitryptiline and TMS, either immediately at onset or as therapy-refractory patients up to 5 weeks after the beginning of their respective episodes. The results of this pilot study document a significant and swift decrease of depressive symptoms scored on the Hamilton rating scale. A single catatonic patient, ICD 9 295.7, presented a clinically impressive but transient improvement of her psychotic condition. Possible analogies between TMS and ECT are discussed as tentative hypotheses for the postulated efficacy of TMS. Further investigations seem warranted, as this method appears to be swift and effective in the treatment of depressive illness.

Transcranial magnetic stimulation: a novel antidepressive strategy?

Transcranial magnetic stimulation (TMS) is a well-established diagnostic probe in neurological practice. The increasing knowledge of biological mechanisms in electroconvulsive therapy presents a clear case for studying the applicability of TMS as a therapeutic tool in psychiatry. Based on the results of our pilot study showing a possible antidepressive effect of TMS, we conducted a controlled clinical trial on patients affected by major depression (DSM-III-R). Group 1 (n = 12) underwent TMS as add-on therapy to standard antidepressive medication, while group 2 (n = 12) was treated only with antidepressive medication. Already after the third add-on TMS session, a statistically significantly greater remission of depressive symptoms occurred in the patients of group 1 (p = 0.003). This statistically significant difference between the groups became even more marked on the last day of the study (p = 0.001, Wilcoxon). The results and further implications of TMS in psychiatric disorders are discussed.

Pharmacological modulation of endothelial cell-associated adhesion molecule expression: implications for future treatment of dermatological diseases.

Skin diseases with an inflammatory component, regardless of their etiology, are characterized at some point by the extravasation and subsequent infiltration of leukocytes into the dermal and/or epidermal compartments. This trafficking pattern is determined by a complex series of events whereby the leukocytes interact with cell adhesion molecules (CAM), particularly those induced on endothelial cells following activation with various inflammatory mediators. Vascular CAMs belonging to the selectin family (i.e., P-selectin and E-selectin) are thought to mediate early and reversible events involving leukocyte rolling and margination along the lumenal surface of microvascular cells (post-capillary venules). Certain members of the immunoglobulin supergene family (i.e., VCAM-1 and ICAM-1) regulate later and irreversible steps which lead to firm attachment and subsequent diapedesis of leukocytes. Accumulating evidence suggests that if one blocks the ligand-binding sites between leukocytes and endothelial cells, or inhibits vascular CAM expression, hematopoietic cell extravasation and progressive inflammatory events can be greatly diminished. To identify such inhibitors we developed a cell-based Elisa using the human microvascular cell line HMEC-1. As reported in the present paper, this approach yielded a naturally-occurring, low molecular weight compound which potently inhibits cytokine-induced adhesion molecule expression on cultured endothelial cells, without modulating "house-keeping" proteins.

Expression of cathepsin D in head and neck cancer.

To determine overexpression of cathepsin D in head and neck tumours we examined cytosols from 53 primary tumours, nine cytosols of lymph node metastases and 12 cytosols from adjacent normal tissue. We found a significantly lower concentration in normal tissue compared with tumour cytosol as well as with metastases, even when we compared tumours and corresponding metastases pairwise. In addition, we found a significantly higher concentration of cathepsin D in five lymph node metastases than in the corresponding tumours. We conclude that the reported role of cathepsin D is not restricted to breast cancer but could also be important in head and neck cancer.

Genetic variation of lysosomal acid lipase.

Lysosomal acid lipase (LAL) activity was measured using a new fluorometric assay in cultured skin fibroblasts from eight control subjects, two obligate heterozygotes for Wolman's disease (WD), one patient with WD, and one patient with cholesteryl ester storage disease (CESD). The LAL activities (mean+/-SD) were 25.8+/-8.2, 13.2+/-0.1,1.1, and 1.4 nmol 4-methylumbelliferyl oleate (4-MUO) hydrolyzed/min/mg protein, respectively. These results compare favorably with those obtained using standard radioassays. The LAL activities of two cultures of amniotic fluid cells were 12.1 and 10.5. The LAL activity (mean+/-SD) of peripheral leukocytes obtained from 34 laboratory volunteers (19 females, 15 males) was 4.0+/-1.8. Partially purified lymphocytes contained about 25 times as much LAL activity as did granulocytes. Cellogel electrophoresis, followed by staining with 4-MUO, showed at least two bands of LAL (A and B) from normal fibroblasts, amniotic fluid cells, and lymphocytes. Band A was absent from WD and CESD fibroblasts and was reduced in fibroblasts of the WD heterozygotes.