SILVER IONS IN THE TREATMENT OF LOCAL INFECTIONS

Robert O Becker
Department of Orthopaedic Surgery
Health Science Center at Syracuse
State University of New York
550 Harrison Street13202SyracuseNew YorkUSA

SILVER IONS IN THE TREATMENT OF LOCAL INFECTIONS

A study of the use of free silver ions as an antibacterial and antifungal agent administered to infected local wounds has been conducted over the past two decades. A variety of iontophoretic techniques has been employed utilizing either pure silver wires or several types of silvered nylon fabrics as anodes in a direct current electrical circuit. A new type of silver nylon has recently been evaluated for the same use without iontophoretic current. In vitro studies of both techniques have demonstrated an effective, broad spectrum antibiotic effect including most silver-resistant strains. Over 100 cases of recalcitrant osteomyelitis have been treated with an overall success rate of approximately 65% and no evidence of argyria.

INTRODUCTION

Silver has long been known to have anti-infective properties. Modern usage began with Crede's technique of dilute silver nitrate as prophylasis of gonorrhea opthalmicum in 1881(1). The first recoded use of silver in surgery was Halsted's classic paper in 1913, (2)in which he reported the use of silver foil as the initial dressing for fresh surgical incisions. He demonstrated its anti-bacterial effects and stated, we are wedded to its use, and know of nothing which could quite take its place,". In the same paper, Halsted first advocated the use of rubber gloves and rubber tube surgical drains both of which were immediately accepted by the surgical community and are in use today. For unknown reasons the use of silver foil never quite became popular. In 1967 Fox (3) reported on the use of a silver-sulfadiazine compound in an ointment for the treatment of infected burns which remains the major agent for this use today.

The introduction of natural and synthetic antibiotics totally changed the treatment of systemic diseases such as pneumonia and septicemia. However,their direct use in localized, infected wounds proved unsatisfactory due to their irritative and allergic effects on tissues. As a result, such infections were treated with systemic administration of antibiotics. While this involved the infusion of these agents throughout the body to treat a strictly local condition, it was initially effective. Now, however, the nature of infectious processes has been greatly changed with the introduction of mutated forms resistant to the action of most antibiotics. As a result the effective treatment of local infections has become much more difficult requiring systemic administration of large doses of multiple antibiotics often with attendant undesirable side effects.

Even after the introduction of antibiotics, infections of bone osteomyelitis remained difficult to treat because the limited blood supply to this tissue precluded obtaining adequate bone levels of systemically administered antibiotics. In the early 1970's this situation became more complex with the appearance of mixed infections including resistant bacteria in such wounds. Today, the only effective treatment remains primarily surgical with adequate wound debridement, leaving the wound open and supplementing the treatment with appropriate systemic antibiotics. A method to introduce a competant, broad spectrum, antibacterial agent directly into the infected bone was obviously desirable and considered some type of iontophoresis.

METHODS

In earlier studies on electrical stimulation of bone growth had noted that in a circuit generating current through a body part with metallic electrodes, the anodal current consisted of free metallic ions from the anode. These ions, driven along the voltage gradient, penetrated one to two cm into the conducting medium before other conducting mechanisms took over. This appeared o be a possible technique for introducing free silver ions from a metallic silver anode into an ost. yelitic lesion. Starting in 1974, in vitro experimentation, indicated that the technique was indee ;able, demonstrating an effective, broad spectrum, antibacterial and antifungal effect with no c:/ious adverse effect on living mammalian cells. (4)(5)(6)(7) Animal experimentation also indicated a useful effect no evident harmful side effects. Clinical use was begun in on experimental osteomyelitis with (8) 1977 and the technique proved to be highly effective and not productive of adverse effects.(9-11) Clinical experimentation has continued to today and devices and techniques of administration have continued to be refined.

Initially, 99.99% silver wire anodes were used in the treatment of small, localized, infected bone lesions with the wire surgically inserted into the lesion and the administration of 0.1 volts between it and a remote surface cathode. While this was quite successful, it was not applicable to the majority of osteomyelitic lesions with open wounds ranging in size from 4 to 20 square inches with infected bone visible in the wound. A flexible, nylon fabric material infiltrated with silver produced by a chemical deposition process was located and proved useful in such extensive lesions. This material was a commercial product manufactured by Swift Textile Metalizing Co. Bloomfield, CT for use as a flexible connector in the elecronics industry. Consequently, the silver deposit contained a variety of other trace metals, which however, did not appear to be a problem in its use. The silver fabric was sinply cut generously to fill the wound cavity, wet with sterile water, packed into the wound with a "tail" that exited the wound and was connected to a battery operated, constant voltage generator limited to 0,9 V. Electrodes were changed daily and treatment was continuous except for daily electrode changes. The silver nylon was non-adherant to the wound, dressing changes were painless and the material left no residue in the wound. If, prior to iontophoresis therapy, the wound required surgical debridement the patients were placed on appropriate systemic antibiotics for the initial 3 post operative days to prevent circulatory bacterial spread. Thereafter, antibiotics were found to be not required. Daily bacterial cultures were taken from the wounds and indicated control of the infection by the 7th to 10th day of treatment. Often the 10 day culture indicated a sterile wound, despite no sterile precautions being used during wound care.

It was noted that for wound areas smaller than 2-4 square inches the voltage level of 0,9V was productive of local electrolysis and while antibiotic effects were adequate, wound healing was impeded. Studies indicated the requirement for the applied voltage to be linearly scaled to the wound size, with 0.1 V for wounds 2 square inches and lower in size to a maximum of 0.9 V for wounds of 10 square inches and larger. This completely avoided the interference with wound healing. The fabric tail connection between the moistened anode and the electrical generator must be kept dry to prevent conduction through the aqueous medium. This is accomplished by cutting the "tail" of silver fabric connecting the dressing to the generator adequate in length to protrude through the dressing to a dry area. It was also noted that this tail must be of at least one inch in width initially and tapered wider as it enters the anode to avoid an abrupt step in in the current density distribution.

Five years ago a new silvered nylon material, maufactured by Omnishield Co., Clark Summit, PA became available which contained no trace elements by X-ray spectroscopy. Additionally, a proprietory process for silvering the fabric is employed that results in the deposition of nano -crystals of silver rather than a metallic coating.(Fg .)This deposit has proven to be capable of spontaneously releasing large numbers of free silver ions into the wound environment without the application of electrical current. This material has been found to be as clinically effective as the iontophoretic technique with equivalent antibiotic effects. The technique of use is similar except no connection to an external elecrical source is required. At present, this silver nylon is simply cut generously to fit into the wound, wet with sterile water, placed securely in the wound and covered with a standard surgical dressing also moistened ), and afixed in place with an external dressing. It is important to mantain a level of moisture at the actual wound level as the silver deposit stops emitting ions if it becomes dry. Initially, the dressings are changed twice daily when treatment is first started. After control of infection is obtained, once per day is generally sufficient. Hospitalization has not been necessary. Patients are usually capable of changing their own dressings or a relative or local care giver can do so with minimal instruction.

RESULTS

Over 100 cases of osteomyelitis, many with non-unions of bone in the wound, were treated with the iontophoretic technique with an approximately 75% success rate in controlling the infection permitting the wounds to heal without drainage. Healing of most non-united fractures present in the wound was also noted. The majority of failures to completely control infection were due to retained fragments of dead bone in the deeper portion of the wound. No undesirable side effects were noted and there was no evidence for local or systemic argyria.

The use of the new type of silver nylon without electrical current has thus far been limited to a smaller number of infected traumatic or diabetic wounds smaller than 4 sq. in. that had failed to respond to systemic antibiotics. This use has been found to be very effective in treating all traumatic wounds contaminated with resistant bacteria without the need for concomitant intravenous antibiotics. 60% of similarly infected diabetic wounds have been successfully treated. However, it must be noted that there are certain types of diabetic ulcers and spontaneous tissue necrosis that are not primarily infected with micro-organisms. These appear to be primarily disturbances in the healing control systems and the silver materials have little effect on these conditions. While some instances of silver resistant bacteria, particularly E. coli and Enterobacter, have been reported these have not been encountered in my series thus far. Figure 1. Scanning electron micrograph of the silver deposit on a single nylon fiber. The silver deposit is composed of small units averaging 100 nm which appear to be made of a number of single crystals. Crystal angles can be seen on the edges of individual deposits. Magnification indicated by the scale bar.

DISCLISSlON

Both the silver iontophoresis technique and the simple application of the silver fabric in wound care utilize no agent other than free silver ions given off into the wound as the primary anti-bacterial agent. The method appears to have several advantages not shared by other agents. At present, silver ions appear to have the broadest spectrum of anti-bacterial activity The level of free silver ions produced in the wound is greater than with any silver compound presently available. The method of use is simple and dressing changes are easy and non-painful. The silver nylon material is inexpensive and while commercial versions will obviously be more complex, costs should be very competative.

There are two potential problems with the use of any silver antibiotic usage. First, it does appear that silver resistance can occur in at least some bacterial strains. believe it is extremely important to avoid this circumstance since it appears that, at least in the near future, silver ions may soon be the only remaining effective agent for clinical use. There appears to be a tendency to develop other silver compounds that produce low levels of silver ions in the wound environment or have characteristics permitting long term application with fewer dressing changes as a cost saving measure. Both of these characteristics would appear to favor the development of additional silver resistant strains. Some of this effort may be directed to avoiding the development of argyria. While much of the pathophysiology of argyria remains obscure, the primary pathology is due to the deposition of metallic silver in the skin, possibly under the influence of light converting a silver compound into metallic silver. It would appear obvious that since silver ions are a highly reactive agent, they cannot circulate in the blood stream unless they are present as a compound that dissociates under the effect of light. The silver nylon application, either iontophoretic or as simple dressings releases only free silver ions, in relatively large amounts directly into the wound tissues where, it is believed, the majority combine with any available chemical agent located therein including bacteria and remain "locked" in situ. In a very few cases, had occasion to re-enter a previously iontophoretically treated wound. Random soft tissue biopsies from the site demonstrated a few metallic deposits encased in fibrous capsules. No patient treated over the past 20 years with either technique has demonstrated clinical, dermal argyria.

CONCLUSION

The silver nylon antibacterial therapy appears to offer some important advantages. The free silver ions demonstrate a very wide spectrum of activity. The high concentration of such ions produced in the wound would seem to mitigate against the development of resistant strains of bacteria while at the same time the high level of activity of the silver ions appears to contain them within the wound area obviating the development oif argyria. The ease of usage and the painless nature of the dressing changes make the technique very acceptable to the patient. As a commercial product in optimal form the therapy should be economical.
 ACKNOWLEDGEMENTThe author thanks Mr. John Scofield of OMNISHIELD for making available the scanning electronmicrograph.
. C S F Crede, Arch, GynackoL. 171881Crede, C.S.F. Arch. GynackoL 17; 50, 1881

. W S Halsted, J. Am. Med Assoc. 60Halsted, W.S.J. Am. Med Assoc. 60, 1119-1126, 1913

. C L FoxJr, Mod. Treatment. 4Fox, C.L. Jr. Mod. Treatment 4; 1259-1261, 1967

. S D Barrenco, Spadaro, J.A. Barrenco, S.D.; Spadaro, J.A,;

. T J Berger, R O Becker, Clin, OrthO. Rel. Res. 100Berger, T.J.; Becker, R.O. Clin. OrthO. Rel. Res. 100; 250- 255,1974

. J S Spadaro, T J Berger, S E Barrenco, S E Chapin, R O Becker, Antimico. Agen. Chemo. 6Spadaro, J.S.; Berger, T.J. Barrenco, S.E.; Chapin,S.E.; Becker, R.O. Antimico. Agen. Chemo. 6; 637-642, 1974.

. T J Berger, J A Spadaro, S E Chapin, R O Becker, Antimicro. Agen. Chemo. 9Berger, T.J.; Spadaro, J.A. Chapin, S E.; Becker, R.O. Antimicro. Agen. Chemo. 9; 357-358, 1976.

. T Berger, J , Berger,T,J,;

. J A Spadaro, R Bierman, S E Chapin, R Oo Becker, Antimicro, Agen. Chemo. 10Spadaro, J.A.; Bierman, R.; Chapin, S.E.; Becker, R.Oo Antimicro. Agen. Chemo.; 10, 856-860, 1976.

. J A Spadaro, R O Becker, Trans, R O Becker, J Spadaro, J Ao, Ortho. Res. Soc. 114Bone Joint Surg.Spadaro, J.A.; Becker, R.O. Trans. 22d Ann Meet. Ortho. Res. Soc. 114, 1976 9. Becker, R.O.; Spadaro, J.Ao J. Bone Joint Surg. 60A; 871-881, 1981.

. D A Webster, J A Spadaro, R O Becker, S Kramer, Clin, Ortho. Rel. Res. 161Webster, D.A.; Spadaro, J.A.; Becker, R.O.; Kramer, S. Clin. Ortho. Rel. Res. 161; 105-114, 1981.

in Book Surgery of the Musculoskeletal System. R O Becker, C Evarts, Churchill Moc, Livingstone, 1New YorkBecker, R.O. in Book Surgery of the Musculoskeletal System, Editor, Evarts, C.MoC., Churchill Livingstone, New York, 197-208, 1983. Received" October 1, 1998

Accepted in final form. Accepted in final form" November 29, 1998


FUNCTIONAL MODULATORS OF RESILIENCE TO AGE-ASSOCIATED DOPAMINERGIC NEURODEGENERATION IN C. ELEGANS

Guy Caldwell
Paul O'Toole from University College Cork, Ireland, and Meng Wang from Baylor College of Medicine
College of Medicine/HHMI
The University of Alabama
Tuscaloosa, HoustonAlabama, TexasUnited States, United States

FUNCTIONAL MODULATORS OF RESILIENCE TO AGE-ASSOCIATED DOPAMINERGIC NEURODEGENERATION IN C. ELEGANS

The societal costs of neurodegenerative diseases demand a sense of urgency and innovative strategies toward therapeutic intervention. We have exploited the experimental attributes of roundworm, C. elegans, as a model to expedite discovery of genetic and chemical modifiers of the age-dependent progressive neurodegeneration of dopaminergic neurons commonly associated with Parkinson's disease (PD). Our model of transgenic nematodes overexpressing the misfolding-prone familial PD gene product, alphasynuclein, has proven prescient in illuminating key aspects of PD pathology, including vesicular trafficking, autophagy, stress response, lipid dynamics, as well as the first evidence of endolysosomal function in effecting dopaminergic neurodegeneration. Subsequent chemical-genetic analyses reveal a mechanism whereby dopamine transport intersects with epigenetic control of gene expression through proteins functioning in endocytic regulation to modulate neuroprotection. We theorize this reflects a "tunable" nexus of gene-by-environmental regulation where dopamine levels, which impact alpha-synuclein misfolding, are coordinately controlled with epigenetic response to mediate resilience to age-dependent neurodegeneration.

SESSION 6520 (SYMPOSIUM)

MICROBIOME: LIVING WELL AND THRIVING WITH YOUR BACTERIA Chair: Meng Wang Co-Chair: William Ludington

This symposium aims to invite speakers who are the leading experts in the field of microbiome and longevity, and select short talks from abstracts submitted by young investigators, postdoctoral fellows and graduate students. We will discuss new progress in this exciting research area and raise new questions for future studies. Confirmed speakers include Evgeny Nudler from NYU, Will Ludington from Carnegie, Paul O'Toole from University College Cork, Ireland, and Meng Wang from Baylor College of Medicine.

MICROBIOME-MITOCHONDRIA COMMUNICATION IN THE REGULATION OF HOST LONGEVITY Meng Wang, Baylor College of Medicine/HHMI, Houston, Texas, United States

Mitochondria are ancient relatives of bacteria in eukaryotic cells and dynamically interconnected through organelle fusion and fission. Given the close relationship between bacteria and eukaryotic mitochondria during evolution, my group is interested in understanding the critical role of their communication in regulating host's longevity. We have conducted genome-scale screens to decipher how bacterial genetic composition impacts host longevity, leading to the discovery of specific bacteria-secreted metabolites that fine-tune the mitochondrial fusion-fission balance and consequently promotes longevity across different host species. We have further developed optogenetic approaches to manipulate bacterial gene expression and metabolite production inside the gut of live organisms, in order to investigate the microbiomemitochondria communication in time and space. Our studies demonstrate a novel mode of signaling communication between bacteria and mitochondria, reveal its vital impacts on host healthy aging, and provide new methods to decipher the spatiotemporal relationship between the microbiome and the host.

INTER-SPECIES INTERACTIONS IN THE FLY GUT MICROBIOME SHAPE AGING

William Ludington, Carnegie Institution, Baltimore, Maryland, United States Gut bacteria affect key aspects of host fitness, including fecundity and lifespan. However, it is unclear to what extent individual species versus complex interactions drive host fitness. We dissected the natural microbiome of Drosophila melanogaster and revealed that interactions between bacteria shape host fitness through life history tradeoffs. Empirically, we made germ-free flies and colonized them with each possible combination of the five core species of bacteria. We measured the microbiome and fly fitness traits including reproduction and lifespan. Notably, flies that reproduced more died sooner. Removing bacteria after reproduction extended lifespan in most cases, suggesting an indirect tradeoff. However, in certain cases, antibiotics did not extend lifespan, indicating a metabolic memory of the microbiome. Overall, complex interactions within the microbiome had significant effects on host fitness. We suggest that model systems with reduced complexity will be instrumental in elucidating mechanisms of microbiome-host interactions.

GENOMICS AND ECOLOGY OF GASTROINTESTINAL BACTERIA IN HUMAN HEALTHSPAN Paul O'Toole

BACTERIAL TOXIC OXIDANTS IN HEALTHY AGING AND DISEASE Evgeny Nudler

SESSION 6525 (SYMPOSIUM)

PHYSIOLOGY AND AGING: NEW UNDERSTANDING OF ORGANS THAT AFFECT THE PHYSIOLOGY OF AGING

Chair: Daniela Drummond-Barbosa As organisms age, many changes occur to their physiology, which in turn impact the function of multiple tissues. It is therefore critical to investigate the fundamental mechanisms of how endocrine organs shape our physiology, and how changes in our physiology affect stem cell lineages, which generate new cells for maintenance and repair of tissues/organs throughout life. This symposium will highlight the research in the laboratories of Dr. Gerard Karsenty (Columbia University) on the multiple endocrine functions of bone, of Dr. Nicholas Buchon (Cornell University) on the role of host-microbe interactions in intestinal homeostasis, of Dr. Jane Hubbard (NYU/Skirball Institute) on the physiological control of the germline, and of Dr. Daniela Drummond-Barbosa (Johns Hopkins University) on how diet and adipocyte factors regulate oogenesis. As research by GSA 2020Annual Scientific Meeting Innovation in Aging, 2020


Factors associated with severe disease from malaria, pneumonia and diarrhea among children in rural Tanzania -A hospital-based cross-sectional study

Catherine Kahabuka
Gunnar Kvåle
Sven Gudmund Hinderaker
Factors associated with severe disease from malaria, pneumonia and diarrhea among children in rural Tanzania -A hospital-based cross-sectional study
R E S E A R C H A R T I C L E Open Access
Background: Mild cases of malaria, pneumonia and diarrhea are readily treatable with complete recovery and with inexpensive and widely available first-line drugs. However, treatment is complicated and expensive, and mortality is higher when children present to the hospital with severe forms of these illnesses. We studied how care seeking behaviours and other factors contributed to severity of malaria, pneumonia and diarrhoea among children less than five years in rural Tanzania. Methods: We interviewed consecutive care-takers of children diagnosed with malaria, pneumonia and/or diarrhea at Korogwe and Muheza district hospitals, in north-eastern Tanzania, between July 2009 and January 2010, and compared characteristics of children presenting with severe and those with non-severe disease.Results: A total of 293 children with severe and 190 with non-severe disease were studied. We found persistent associations between severity of disease and caretaker's lack of formal education (OR 6.6; 95% confidence interval (CI) 2.7-15.8) compared to those with post-primary education, middle compared to high socio-economic status (OR 1.9; 95% CI 1.2-3.2), having 4 or more children compared to having one child (OR 2.5; 95% CI 1.4-4.5), having utilized a nearer primary health care (PHC) facility for the same illness compared to having not (OR 5.2; 95% CI 3.0-9.1), and having purchased the first treatment other than paracetamol from local or drug shops compared to when the treatment was obtained from the public hospitals for the first time (OR 3.2; 95% CI 1.9-5.2). The old officially abandoned first line anti-malaria drug Sulfadoxin-pyrimethamine (SP) was found to still be in use for the treatment of malaria and was significantly associated with childrens' presentation to the hospital with severe malaria (OR 12.5; 95% CI 1.6-108.0).Conclusions:Our results indicate that caretakers with no formal education, with lower SES and with many children can be target groups for interventions in order to further reduce child mortality from treatable illnesses. Furthermore, the quality of the available drug shops and PHC facilities need to be closely monitored.

Background

Mild cases of malaria, pneumonia and diarrhea are treatable with complete recovery from the widely available and inexpensive first line drugs. However, the three diseases still account for the majority of child deaths among children between one month and five years of age in sub-Saharan Africa, including Tanzania [1,2]. Mortality is higher when children present to the hospital with severe compared to mild forms of these illnesses [3,4]. In one of the studies, conducted among children admitted to a Pediatric Emergency Room in India, it was found that the case fatality rates for non-severe, severe and very severe pneumonia were 0%, 8.7% and 47.0% respectively [4].

There have been many efforts to prevent infections in children through vaccination programmes and other community interventions, some with success. One example is the reduction of malaria incidence following the wide distribution of insecticide-treated mosquito nets [5,6]. However, primary prevention of infectious diseases is still difficult to achieve particularly for children in poor families who are continuously exposed to health risks and other hazards typical in poor communities. In addition, many children from poor families are undernourished, making them less resistant to infections. This makes early disease detection and timely management crucial in preventing deaths of these children from treatable illnesses.

There has been an unacceptable widening gap in child mortality between rich and poor countries as well as between wealthy and poor children within many countries (9). Within countries child mortality is often higher in rural areas, and among the poor and less educated families [7,8]. These inequities are compounded by the reduced access to available preventive and curative interventions by children from poor families. Public subsidies for health services frequently benefit rich people more than the poor [8]. Health interventions targeting children from poor families may significantly contribute to further reduction in child mortality from treatable illnesses.

We wanted to know what characterizes children who are more likely to develop severe disease from malaria, pneumonia and diarrhoea. Hence, we conducted a hospital based cross-sectional survey in two predominantly rural districts of Tanzania, and compared children presenting at two district hospitals with severe from those presenting with mild forms of malaria, pneumonia and diarrhoea. Our main objective was to assess determinants of severe disease, particularly health care seeking factors, among under-five children in the study area.

Methods

Study area

The study was conducted at Korogwe and Muheza district hospitals of Tanga Region in north-eastern Tanzania. The two hospitals serve as referral hospitals in the two districts. Korogwe district is located about 100 km inland from Tanga. Based on the 2002 Census and a population growth rate of 1.2% per year [9], the projected population in 2009 was 282,901. The district is served by 47 dispensaries, four health centres, one district hospital and two church owned hospitals. Muheza district is around 25 km from the city of Tanga and is about 70 km from Korogwe. Based on 2002 census and a population growth rate of 1.4%, it had a projected population of 306,862 in 2009 [9], which is served by 54 dispensaries, four health centres, and one district hospital. The two districts are predominantly rural and the people are mainly subsistence farmers of maize, cassava, oranges, coconut, rice and banana. Malaria is the leading cause of admissions and deaths among under-five children in both districts [10,11].

Study design and sample size

This was a cross-sectional hospital based survey among care-takers who brought their sick children at Korogwe and Muheza district hospitals. The target population was care-takers of children between 1 month and 5 years, with a diagnosis of malaria, pneumonia or diarrhoea seen at the outpatient clinics in the two hospitals. In order to detect a difference of 15% in risk of having severe disease, assuming that the risk factor is present in 35% severe and 20% non-severe cases, granted 80% statistical power and a 95% confidence level, we needed at least 296 cases.

Data collection

Data was collected between July 2009 and January 2010. We identified all sick children presenting with symptoms suggestive of our diseases of interest to the outpatient department between 09am and 02pm i.e. fever, cough, difficult or fast breathing, diarrhoea and vomiting. These were reviewed and assigned diagnosis as per WHO guidelines [12] by the principal investigator or a trained clinical officer. Children with a diagnosis of malaria, pneumonia or diarrhoea were included in the study. While the diagnosis of pneumonia and diarrhoea was reached clinically, malaria diagnosis was confirmed with a rapid malaria diagnostic test (Paracheck W ).

Interviews were conducted by trained clinical officers after obtaining a written informed consent. Children who did not need admission were interviewed in a room located near the outpatient department while caretakers of children who were admitted to the hospital were interviewed later within their respective wards, after the child had received initial treatment. The information collected included care-seeking information with all treatments received and places they were obtained from, availability and use of primary care facilities and referral information. Other information collected included questions about indicators of socio-economic status such as household characteristics, composition and assets. All children were also assessed for weight and mid-upper arm circumference (measured at the mid-point between the tip of the shoulder and the tip of the elbow). Caretakers of fifteen severely ill children who died before the interviews could be conducted were not included.

Ethical consideration

Ethical approval was obtained from the National Institute for Medical Research in Tanzania. Prior to conducting the interviews, informed written consent was obtained from all caretakers for their participation and participation of their children, and none refused. All study procedures were conducted with caution not to interfere with the patients' ordinary consultations and only after the child had initiated all the necessary treatment.

Data analysis

Data was double-entered and validated using Epidata version 3.1 and SPSS version 18 was used for analysis. Severe disease included all children with one or more of the following diagnoses: severe malaria, severe and very severe pneumonia, and acute watery diarrhoea (AWD) with some and with severe dehydration. Mild disease included non-severe malaria, mild pneumonia and AWD with no dehydration. We performed bivariate analysis to examine associations between child's disease severity status and potential predictors. Multivariate analyses were used to determine predictors that remained associated with severe disease when adjusted for other factors. The variables selected for the multivariate model were either significant (p-value <0.05) in the bivariate analysis or shown to be significant in previously published studies.

Results

We completed interviews with 560 caretakers of children with a history of symptoms suggestive of malaria, pneumonia or diarrhoea. Out these children, 483 qualified for one or more of above diagnoses and 293 were classified as severe cases. Thirty seven children had more than one diagnosis and if one or more of the diagnoses were severe then the child was categorized as a severe case. Figure 1 summarises the proportion of children with the three diseases together and their severity classification.

The number of study participants enrolled from each district was fairly equal; 258 (53.7%) from Korogwe versus 225 (46.3%) from Muheza. Children were fairly equally distributed by sex and 37% were below one year ( Table 1). The majority of caretakers had primary education (75.8%) and were peasants (61.1%). Most caretakers reported having two to three living children and 121 (25.1%) had experienced at least one child death (aged less than five years) in the past.

We used logistic regression to explore any potential associations between participants' background characteristics and severe disease in our sample of children (Table 1). We found severe disease to be slightly more common among younger compared to older children (64.8% among infants versus 52.3% among children aged two or more years) as well as among children with smaller mid-upper arm circumference (70.6% among children with MUAC between 8.0-13.9 cm compared to 53.7% among those with MUAC of 15 cm and above). Caretakers with no formal education had significantly higher chances of presenting with a severely ill child compared to those with primary and post-primary education (82.1% versus 57.9% and 43.6% respectively). Risk of severe disease was also positively associated with lower socioeconomic status, increasing number of caretakers' own alive children and increasing travel time from home to the district (study) hospital (Table 1).

Almost all care-takers (442/483; 91.5%) had taken some action within the first 24 hours after recognizing the first child's symptom. Fever was most frequently reported to be among the first symptoms (61.7%), followed by cough (44.5%). Diarrhea and vomiting was reported to be among the first symptoms in 23.4% and 21.6% of children respectively. Convulsions was experienced by 45 (9.3%) children but was only mentioned as the first symptom in 15 (3.1%) children.

The first option of care for the majority (50.5%) was giving treatment purchased from local and drug shops, mainly paracetamol. A few (15.3%) had given treatments available at home, commonly from previous consultations. Only 104 (21.5%) caretakers reported to have taken their children to the public hospitals within the first 24 hours of onset of symptoms.

Medications given at home were commonly leftovers of previous consultations but were also reported to be purchased from local shops. These included, apart from paracetamol and oral rehydration fluid, tablets like metronidazole, zinc, salbutamol, cotrimoxazole, and syrups like quinine and amoxicillin. Drug shops had more medications and also the specially-packed first line antimalaria drug (ALu W ) that was only to be obtained from public facilities at the time of data collection.

The majority of caretakers (60.5%) who reported not to utilize their nearer PHC facilities had obtained their first treatment other than paracetamol at the study hospital, most of them (77.6%) within 1-2 days of onset of child's symptoms. Likewise, majority of caretakers (84.5%) who reported having utilized their nearer PHC facilities had also obtained their first treatment, other than paracetamol, from the public hospitals (PHC facility visited first or study hospital). However, only 24.8% had received this treatment within 1-2 days after the child got symptoms; 35.8% had received it on the 3 rd or 4th day while the remaining 39.4% got it on the 5 th day or later. Severe disease was more common among children with longer symptoms duration and among children who had utilized Primary Health Care (PHC) facilities for the same illness (Table 2). Children who had received treatments other than paracetamol for the same illness before coming to the district hospital had a higher probability of presenting with severe disease as compared to those who had received paracetamol only (67.9% versus 51.8%). Severe disease was also more common among children who had obtained the first treatment other than paracetamol from local sources or drug shops. Table 3 below depicts results from multiple logistic regression analysis to compare risk factors for disease severity in individual diseases. The findings indicate that caretaker's number of living children was strongly associated with malaria severity while it was weakly associated with diarrhoea severity and not with pneumonia severity. On the other hand, caretaker's SES and travel time to district hospital was associated with severity of pneumonia and diarrhoea but not with severity of malaria. Use of a nearer PHC facility was the only factor that was found to be significantly associated with disease severity from all the three diseases. SP (sulphadoxine-pyrimethamine or Fansidar W , formerly first line anti-malaria drug) was reported by 19 caretakers as the only drug provided to their children for the treatment of malaria (suspected or confirmed by tests). Five caretakers reported receiving this drug from public facilities, 6 from drug shops, 7 from private hospitals and 1 from unknown source. Eight out of nine children who received SP and who were confirmed having malaria by tests at the district hospital, had presented with severe malaria, two of them died. SP use for confirmed malaria treatment was highly associated with severe malaria; 89% of children treated with SP had presented with severe malaria compared to only 42% among those who had not received SP (P < 0.01).

Discussion

In this study from rural Tanzania, we found that children had a higher probability of presenting at the district hospital with severe disease if they had utilized PHC facilities for the same illness, had obtained the first treatment other than paracetamol from local sources and drug shops, and if they had received SP as the only treatment for malaria. Presenting with severe disease was also associated with caretakers' low level of education and poor nutritional status of children.

An increased risk of severe disease among children of caretakers who reported having utilized their nearer PHC facilities for the same illness might have resulted from selection bias. Caretakers of children who improved after having utilized PHC facilities obviously needed not to come to the district hospital. In addition to that, caretakers of children with severe disease who do not recover after utilizing PHC facilities might be more often referred to and seen at the district hospitals than those with severe disease who do not seek care at PHC facilities. However it is worth noting that, the majority of caretakers who reported having utilized their nearer PHC facilities had obtained the first treatment other than paracetanol much later (on the third day or later) as compared to those who did not utilize them. Delays in treatment initiation among PHC users could be explained by the reported frequent shortages of drugs at these facilities [13], also reported in the study area [14]. Unavailability of drugs at PHC facilities may result in delays of several days, from the time drugs are prescribed until when caretakers are able to purchase them from the drug shops. This finding needs further investigation.

The preference for drugs from local shops as the first option of care shown in this study is not a new finding [15][16][17]. The positive association between obtaining the first treatment other than paracetamol from these shops and severe disease in children is worth noting. Drug shops in Tanzania are very poorly regulated and some of them sell unregistered and sometimes expired drugs [18]. On the other hand, the reported use of drugs kept at home from previous consultations needs further investigation as this practice could be associated with treatment failures resulting from the use of expired drugs. Oral suspensions of some of the commonly prescribed syrups like amoxicillin and cotrimoxazole should be used only for a maximum of 7 days and then discarded. Caretakers might be using these syrups for extended periods of time.

A quarter of our study participants had experienced at least one child death in the past. This depressing finding calls for urgent measures to improve the situation. The high number of deaths among children may be linked to some of the reported unexpected practices at PHC facilities in the study area [19], including the ongoing provision of SP for malaria treatment in children. Malaria is still the number one killer of children below five years in Africa [20], as well as in Tanzania [21]. Resistance of malaria parasites to SP was commonly reported in many parts of Africa as well as Tanzania between 1999-2000 [22]. In a study conducted in 2000 in Muheza district (one of our study districts), it was found that 45% of the patients treated with SP  failed to clear their parasitemias to below patency levels on day 7 [23]. In 2004, the World Health Organization (WHO) recommended that all countries revise their malaria treatment policies and opt for a combination treatment, preferably an artemisinin-based combination therapy (ACT) [24]. Hence, Tanzania changed its first-line treatment for malaria from sulphadoxine-pyrimethamine (SP) to artemether-lumefantrine (ALu W ) in 2005 [25].

With funding from the Global Fund, Tanzania began, in December 2006, providing ACTs through public and mission health facilities free of charge to all children under five years and at a subsidized price for the rest of the population [26]. Surprisingly, five out of nineteen children who received SP as the only treatment for malaria reported having received it from public hospitals.

At the time of this study (2009/2010), subsidized ALu W was not yet available outside public facilities in the study area [27]. Hence we predict that SP use for malaria treatment at the community level could be even higher than we have reported in this hospitalbased study, and even much higher among caretakers who do not utilize public health facilities (not represented in this study). Further research is needed to ascertain the extent to which this drug is still in use for malaria treatment in children, as this drug was highly associated with severe malaria and death in our sample of children.

Availability of ACT products in the private sector has generally been limited to registered pharmacies in urban areas where the price of a course of therapy is around 8-10 U.S. dollars [28]. The new treatment is well beyond the reach of individuals living in rural and peri-urban communities who need them the most. This has left millions of Tanzanians in rural areas, including the study area, to rely on public sector facilities for access to the recommended first-line treatment for malaria. If they seek treatment from other sources they may end up receiving suboptimal therapies, such as SP, which is more affordable and widely available. However, a few caretakers in our study had reported to occasionally having bought the specially packed subsidized ALu W for public facilities in their nearby local drug shops when these drugs were out of stock at their nearby PHC facilities. This finding raises an alarm.

There have been efforts to make subsidized ACTs available through Accredited Drug Dispensing Outlets (ADDOs) after realizing an important role played by this sector in provision of malaria treatment [28]. In 2007, using funding from the President's Malaria Initiative (PMI) and technical support from Rational Pharmaceutical Management Plus (RPM Plus) Program, Tanzania Food and Drugs Authority (TFDA) and National Malaria Control Programme (NMCP) began a pilot program to make subsidized ACTs available through ADDOs in 10 districts of Morogoro and Ruvuma regions [28]. The program resulted in a gradual increase in the number of malaria patients treated with ACTs, from 3% of all antimalarials sold in July 2007 to 26% in June 2008. At the same time, the use of non-ACT antimalarials like SP declined. Currently, the government of Tanzania is trying to expand the provision of the subsidized ALu W through ADDOs countrywide.

In line with our findings, several previous studies had established severe disease to be more common among younger children and children of caretakers with lower level of education and SES [3,29,30]. In one hospitalbased study conducted in southern Kerala, India, they found that severe pneumonia was less frequent in children over 2 years [30]. Likewise in our study severe disease was found to be more common in children less than two years as compared to those aged two years and above. In the Indian study above [30], paternal and maternal education of up to middle school and above was found to be protective against development of severe pneumonia. Similarly, our study showed an inverse association between severe disease and caretakers' level of education. One community-based study in rural southern Tanzania found that it was more likely for caretakers with higher SES to seek care from an appropriate provider as compared to those with lower SES [8]. In the same study, the frequency of antibiotic use for probable pneumonia among children with the lowest SES was less than half of those with the highest SES, and children in the lowest SES group were half as likely to have been given antimalarials as those in the highest SES category.

The observed positive association between severe disease and more number of children may be due to confounding; explained by the fact that caretakers with low education and SES also tend to have more children. However, the association persisted even after controlling for education and SES. This finding needs more investigation as it could provide another target group for the fight towards child mortality from treatable illnesses.

Methodological strengths and limitations

The present study has reported factors associated with severe disease from the three main childhood killers (malaria, pneumonia and diarrhea), thus providing more areas for further intervention towards child mortality from treatable illnesses. This study inquired care-seeking information related to the current child illness. By using this approach, we believe we minimized recall bias as we were able to pick up easily forgettable care-seeking information which community based studies may miss, often relying on past illness episodes of preceding weeks.

Our study was hospital-based and was conducted at district referral hospitals because this was the most convenient way to study factors associated with severe disease. To avoid the selection bias, the study should ideally have been community-based, including all children with the three diseases in the area. However, it would be very difficult to identify and include a high enough number of severely ill children at the community level. Hence, we acknowledge that we missed mild and severe cases that used other options of care and did not come to the district hospitals. However, biased associations would only arise if an interaction is present between severity of disease and potential predictors in relation to the frequency of seeking hospital care. As discussed above, this might be the case when attending PHC facilities is studied as a risk factor, but seems less likely to influence the findings of the other predictors. Furthermore, our findings are similar to findings from previously community-based studies on risk factors for early childhood deaths [8,31,32].

Thirty seven children had more than one diagnoses; one child had all three diagnoses. We do not think this influenced our findings significantly as the number of children with more than one severe disease was very small. The fact that we did not include caretakers of fifteen children who died before the interviews could be conducted could have biased our findings towards milder disease. However since the number is too small we think the bias should be minimal.

Conclusions

Our study has identified some factors that are associated with severity of disease from malaria, pneumonia and diarrhea. We argue that health interventions addressing the factors and risk groups identified in this study would be important for further reduction of child mortality from treatable illnesses. The findings also indicate the strong need for district health systems strengthening, including strict regulations and close quality monitoring of the available PHC facilities and drug shops. Further studies are needed for providing more evidence of the ways and extent by which low quality of services at the existing PHC facilities and drug shops contribute to high mortality among children in developing countries.

Figure 1
1Distribution of children in relation to the three diseases. SEVERE CASES: Malaria = 51, Pneumonia = 150, Diarrhoea = 102.

Adjusted for child's Age and Sex, and Caretakers Education and socio-economic status (SES). } -Numbers too small to enable any comparison across groups. * -significant findings. PCM = paracetamol. Rx = treatment. PHC = primary health care.

Table 1
1Multiple logistic regression of possible background risk factors for severe disease among studied children (n = 483) OR -Unadjusted odds ratio (from bivariate analysis). AOR-Adjusted for child's Age and Sex, and Caretakers Education and socio-economic status (SES). * -significant findings. **-Varying total due to missing cases . MUAC -Mid Upper Arm Circumference.Risk factor for disease severity
Total cases**
Severe disease cases (%)
OR
AOR

Child's Sex

Female
230
146 (63.5)
1.3 (0.9-1.8)
1.3 (0.9-2.0)

Male
253
147 (58.1)
ref
ref

Child's Age

0-11 months
179
116 (64.8)
1.7 (1.1-2.6)*
1.8 (1.1-2.8)*

12-23 months
131
87 (66.4)
1.8 (1.1-2.9)*
1.9 (1.1-3.0)*

24+ months
172
90 (52.3)
ref
ref

Child's Weight

0-9.9 kg
253
169 (66.8)
1.8 (1.2-2.6)*
1.6 (0.9-3.0)

10.0-14.9 kg
204
109 (53.4)
ref
ref

15.0-20+ kg
22
12 (54.5)
1.0 (0.4-2.5)
1.2 (0.5-3.2)

Child's MUAC

8.0-13.9 cm
160
113 (70.6)
2.1 (1.3-3.3)*
1.6 (1.0-2.6)*

14.0-14.9 cm
139
80 (57.6)
1.2 (0.7-1.8)
1.0 (0.6-1.7)

15.0-20.0 cm
177
95 (53.7)
ref
ref

Caretaker's Education

No formal education
78
64 (82.1)
5.9 (2.5-13.9)*
6.6 (2.7-15.8)*

Primary education
366
212 (57.9)
1.8 (0.9-3.5)
2.0 (1.0-4.0)*

Post-primary education
39
17 (43.6)
ref
ref

Caretaker's SES

Low
174
106 (60.9)
1.6 (1.0-2.7)*
1.5 (0.9-2.6)

Middle
217
142 (65.4)
1.9 (1.2-3.2)*
1.9 (1.2-3.2)*

High
91
45 (49.5)
ref
ref

No. of own alive children

1 child
137
69 (50.4)
ref
ref

2-3 children
240
149 (62.1)
1.6 (1.1-2.5)*
1.7 (1.1-2.7)*

4 or more children
103
74 (71.8)
2.5 (1.5-4.3)*
2.5 (1.4-4.5)*

Home-hospital travel time

0-59 min
164
81 (49.4)
ref
ref

60-119 min
136
79 (58.1)
1.4 (0.9-2.2)
1.4 (0.9-2.3)

120+ min
143
99 (69.2)
2.3 (1.4-3.7)*
2.1 (1.3-3.4)*

Table 2
2Multiple logistic regression of potential care-seeking risk factors for severe disease among studied children (n = 483) OR -Unadjusted odds ratio (from bivariate analysis). AOR -Adjusted for child's Age and Sex, and Caretakers Education and socio-economic status (SES). * -significant findings. **-Varying total due to missing cases. PCM = paracetamol. Rx = treatment. PHC = primary health care.Risk factor for disease severity
Total number
of cases **

Cases with severe
disease (%)

OR
AOR

Symptoms duration

1-2 days
246
121 (49.2)
ref
ref

3-4 days
137
102 (74.5)
3.0 (1.9-4.8)*
2.9 (1.8-4.7)*

5 or more days
100
70 (70.0)
2.4 (1.5-4.0)*
2.1 (1.3-3.6)*

First Rx PCM alone for 24 hrs or more

No
299
203 (67.9%)
2.0 (1.3-2.9)*
1.8 (1.2-2.7)*

Yes
170
88 (51.8%)
ref
ref

Source of first Rx other than PCM

Home/local or drug shop
123
95 (77.2)
2.9 (1.8-4.7)*
3.2 (1.9-5.2)*

Private hospital
25
16 (64.0)
1.5 (0.7-3.5)
1.9 (0.8-4.8)

Public hospital
330
178 (53.9)
ref
ref

Local herbs use

No
433
259 (59.8)
ref
ref

Yes
50
34 (68.0)
1.4 (0.8-2.7)
1.4 (0.7-2.8)

Use of nearer PHC facility

No
191
93 (48.7)
ref
ref

Yes
132
110 (83.3)
5.3 (3.1-9.0)*
5.2 (3.0-9.1)*

Table 3
3Comparison of potential background risk factors for disease severity among individual diseases (n = 483)Risk factor for disease severity
AOR
AOR
AOR
AOR

(All cases)
(Malaria cases)
(Pneumonia cases)
(Diarrhoea cases)

Caretaker's Education

http://www.biomedcentral.com/1471-2334/12/219
AcknowledgementsThis study was funded by the Norwegian government through Quota program and was part of PhD training. We are grateful to all respondents for participating in the study. Special thanks to Mr. Salum Mshamu, Dr. Samuel Gesase, Dr. Selemani Mtunguja and Dr. Monica Billa for their support during data collection.Competing interestsThe authors declare that they have no competing interests.Author's contributions CK planned and wrote the protocol, collected and analysed data, and drafted the manuscript. GK had substantial contribution to the protocol development as well as data analysis and writing the manuscript. SGH supervised data analysis and contributed in writing the manuscript. All authors have read and approved the final version.
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Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution. Kahabuka, BMC Infectious Diseases. 12219Factors associated with severe disease from malaria, pneumonia and diarrhea among children in rural Tanzania -A hospital-based cross-sectional study. Submit your manuscript at www.biomedcentral.com/submitCite this article as: Kahabuka et al.: Factors associated with severe disease from malaria, pneumonia and diarrhea among children in rural Tanzania -A hospital-based cross-sectional study. BMC Infectious Diseases 2012 12:219. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit


Efficiency of vibration exercise for glycemic control in type 2 diabetes pa- tients
2007

Klaus Baum
Institut für Physiologie und Anatomie
Deutsche Sporthochschule Köln
and Trainingsinstitut Prof. Dr. Baum GmbH
KölnGermany, Germany

Tim Votteler
Trainingsinstitut Prof. Dr. Baum GmbH
Wilhelm-Schlombs-Allee 150858Köln, KölnGermany, Germany

Jürgen Schiab
Trainingsinstitut Prof. Dr. Baum GmbH
Wilhelm-Schlombs-Allee 150858Köln, KölnGermany, Germany

Efficiency of vibration exercise for glycemic control in type 2 diabetes pa- tients

Int. J. Med. Sci
42007Received: 2007.02.28; Accepted: 2007.05.29;159 International Journal of Medical Sciences Research Paper Correspondence to: Klaus Baum, Prof. Dr., Trainingsinstitut,diabetesvibration exercisestrength trainingHbA1cglycemic control
Although it is well documented that persons suffering from diabetes type 2 profit from muscular activities, just a negligible amount of patients take advantage of physical exercises. During the last decade, vibration exercise (VE) could be established as an effective measure to prevent muscular atrophy and osteoporosis with low expenditure of overall exercise-time. Unfortunately, little is known about the metabolic effects of VE. In the present study we compared VE with the influence of strength training and a control group (flexibility training) on glycemic control in type 2 diabetes patients. Forty adult non-insulin dependent patients participated in the intervention. Fasting glucose concentration, an oral glucose tolerance test (OGTT), haemoglobin A1c (HbA1c), the isometric maximal torque of quadriceps muscles, and endurance capacity were evaluated at baseline and after 12 weeks of training with three training sessions per week. The main findings are: Fasting glucose concentrations remind unchanged after training. The area under curve and maximal glucose concentration of OGTT were reduced in the vibration and strength training group. HbA1c values tended to decrease below baseline date in the vibration training group while it increased in the two other intervention groups. Theses findings suggest that vibration exercise may be an effective and low time consuming tool to enhance glycemic control in type 2 diabetes patients.

Introduction

Since some decades it is known that beside pharmacological treatments and body weight reduction endurance related exercises are able to enhance glycemic control in type II diabetes patients [13,18,22]. More recently, strength training also became an established treatment in that world-wide spreading metabolic disease [2,3,4,9]. However, till today only a negligible amount of patients take advantage of any sport activity. There are some reasons to explain that phenomenon, one of the most important may be that nearly all patients are obese and follow a lifelong sedentary life style. Obviously, these patients can hardly be motivated for longer lasting physical activities.

Vibration exercise is a new and effective measure to prevent muscular atrophy and osteoporosis [14,15,19,21]. It is assumed that vibrations with an amplitude of 2 to 6 mm and a frequency of 20 to 30 Hz evoke muscle contractions probably induced via the monosynaptic stretch reflex [17]. Compared to traditional training regimes, VE needs significant less time and, therefore, can be expected to reach a higher compliance in previously inactive patients. Unfortunately, rare information exists about the metabolic consequences of VE. It is just known that oxygen consumption increases with body weight as well as frequency and amplitude of VE [14]. In the present study we investigated the influence of a three month vibration-exercise period on parameters of glucose metabolism in type II diabetes patients. The results were compared to a control group (FT-group) and a group performing strength training (ST).

Research Design and Methods

Subjects characteristics and general experimental design

Prior to recruitment of subjects the study protocol was approved by the ethic committee of the German Sports University. Volunteers were included if they met three conditions: A diagnosed type II diabetes, not insulin depending, and not regularly involved in sport activities. All patients were under oral medication. Subjects were excluded if they suffered from retinopathy or other medical problems which did not allow for participating in vibration exercises or strength training.

Patients were encouraged to follow their habitual life style including medication throughout the whole investigation period. After verbal introduction of the study 40 subjects (24 male, 16 female) gave their written consent and participated in the study (Table 1). Subjects were randomly divided into three groups: A flexibility training group, a strength training group and a vibration training group. They trained for 12 weeks at three days per week. All sessions were supervised and participation assessed. Training volume and intensity were stepwise increased after 6 and 9 weeks. The detailed training regimen was as follows:

Flexibility training

Each FT session consisted of eight static exercises which involved main muscles of the upper and lower body. During the initial six weeks, one set was performed with the positions kept for 20 s each. From week 7 to 9 volume was increased by one more set. During the last three weeks two sets with exercise durations of 30 s were applied. The total training duration did not exceed 15 minutes per session.

Strength training

Commercially available weight machines (Conex © multiform) were used for strengthening muscle groups of the upper and lower body. Eight stations were included in each session, e.g. leg extension, seated leg flexion, leg press, seated calf raise, lat pulley, horizontal chest press, butterfly, and rowing. Subjects performed dynamic contractions with intermittent relaxations after each concentric-eccentric phase in order avoid critical blood pressure responses [1]. After familiarization with the correct movements, the one repetition maximum (1RM) was established prior to the training period. During the first six weeks of training, 1 set with 12 repetitions at 70 % of 1 RM was performed. From week 7 to 9 volume was increased by an additional set. In weeks 10 to 12, 3 sets with 10 repetitions at 80 % of 1 RM were realized. About 45 minutes was needed for a training session of the last three weeks.

Vibration exercise

Subjects exercised on a horizontal swinging platform with an amplitude of 2 mm (Vibrogym Professional © ). Vibration frequency was set to 30 Hz from weeks 1 to 9 and to 35 Hz during the last three weeks. The duration of a single exercise bout was constant throughout the training period and amounted to 30 s. A training session consisted of 8 different exercises including muscles of the whole body ( Fig. 1). Subjects were encouraged to work isometricaly against the swinging platform.The number of sets was identical with the strength training regimen. It took about 20 minutes to fulfill a training session of the last three weeks.

Test procedure and Outcome Measures

Before and three to four days after the training period, subjects entered the laboratory after 12 h fasting and an oral glucose tolerance test was performed. Time of drug ingestion was individually kept constant prior to both tests. Micro-blood samples were taken from an ear lobe before and for 2,5 h every 30 min after administering a 75 g glucose drink (Dextro © O.G-T., Roche Diagnostics Ltd). Blood samples were analyzed by means of HemoCue © Glucose 201+ (HemoCue Ltd). HbA 1C levels were determined by a HPLC-System (Tosoh G7, Eurogenics) from a blood sample taken from the antecubital vein.

On separate days, maximal torque of quadriceps muscles and endurance capacity were tested. Maximal torque was detected isometrically with participants in an upright sitting posture and the hip and knee joint flexed to 90 o . A force transducer (Digimax © , Mechatronic Ltd) was used and the lever arm calculated as the distance between knee joint space and contact point of force transduction. The best of three trials of each leg were taken for further computation.

Endurance capacity was determined by an incremental cycle ergometry (Ergoline Ergoscript 2012 EL). Load was increased every 3 min for 25 w until lactic acid concentration exceeded 4 mmol/l. Heart rate (ECG leads) and lactic acid concentration (Accutrend © Lactate, Roche Mannheim) were measured at rest and within the last 30 s of each load.

In addition, body weight and blood pressure were measured before each training session. The mean values of the initial and last five sessions were taken for further computations.

Statistical analysis

Statistical analysis was conducted using SPSS version 12.0 for Windows. If not otherwise stated data are expressed as mean and standard deviation. The data were analyzed by analysis of variance for repeated measurements (factors: time and training form). In case that the two-factorial analysis yielded a significant result (p < 0,05), a Newman-Keuls test was performed as a posteriori test.

Results

Subjects characteristics

Body weight did not significantly change during the 3-month intervention. A mean reduction of 1,68 kp ± 4,57, 1,30 kp ± 2,36, and 0,86 kp ± 1,77 could be obtained for FT, ST, and VT, respectively. Systolic blood pressure decreased significantly (p < 0,05) in all intervention groups to 126 mm Hg ± 7,4, 133 mm Hg ± 16,4, and 123 mm Hg ± 12,5 for FT, ST, and VT, respectively. Diastolic blood pressure did not change significantly. Three subjects decreased their oral hypoglycemic medication dosage (two persons in ST and one person in VT group). No major complications or injuries were reported from either stretching, strength, or vibration training.

Endurance performance parameters

No significant differences in endurance capacity could be detected between pre and post-training in any group. Subjects reached 4 mmol [lactate] at loads of 89 w ± 8,2 (pre) and 86 w ± 9,7 (post), 99 w ± 14,8 (pre) and 95 w ± 13,3 (post), 89 w ± 6,2 (pre) and 92 w ± 5,9 (post) for FT, ST, and VT, respectively. In contrast, at these loads heart rate was reduced after the training intervention in all groups (Fig. 2), which became significant for VT.

Strength

The relative maximal isometric torque of the quadriceps muscles increased after training in the ST and VT groups. A significant increase of 14 % could be obtained in subject`s left leg of the ST group (Fig. 3).

Fasting glucose concentration and OGTT

After training intervention, fasting glucose concentrations were slightly reduced in all groups (n.s., Tab. 2). Within the 150 minutes observation period of OGTT, pre-and posttraining results in the FT group were nearly identical. In both ST and VT the integrals were reduced by 5,6 % and 6,3 %, respectively (p < 0,05 for both groups with no significant differences between both groups). Fig. 4 shows the time courses of all three training groups as well as the mean of individual maximal glucose concentrations.

HbA1C

At baseline the HbA1c amounted to 6,7 % ± 0,26 (FT), 6,8 % ± 0,17 (ST), and 7,3 % ± 0,66 (VT) (Differences not significant). After training intervention a small decrease in HbA1c occurred in the VT-group (n.s.). In contrast, HbA1c values in the FT and ST group were elevated.

Discussion

Twelve weeks of strength training increased muscular strength and did not affect the endurance capacity while stretching and vibration exercise improved neither strength nor endurance significantly. These results on physical performance parameters reflect just in part the outcome of glycemic control parameters: As it could be expected flexibility training failed to improve glycemic control and strength training showed beneficial effects. Although the duration of VT training sessions were about half of thoses of the strength group, the effect on OGGT was comparable. Obviously, there is a beneficial effect of vibration-exercise on glycemic control without detectable changes in physical performance parameters. A dominant influence of body weight changes appears unlikely since weight reduction was weakest in the VT group and strongest in the FT group. Vibrations applied on skeletal muscles activate muscle spindle receptors [10] and so enlarge the drive to alpha-motoneurons via the monosynaptic reflex [17]. Therefore, compared to exercises without vibrations it may be true that a higher number of motor units are activated. Beside some general health-related beneficial effects of exercise on skeletal muscles such as improvements of endothelial function [8] and an increased enzyme capacity of energy metabolism [13] there are two specific effects of contracting skeletal muscle cells on the ability to transport glucose into these cells: First, a regularly performed training increases the content of the glucose transporter protein GLUT-4 within the cells [9,12]. Secondly, a single bout of muscle contractions leads to a translocation of GLUT-4 to the sarcolemmal membrane, which acutely enhances glucose transport capacity [6,7,11]. Evidence of acute training effects on glycemic control rather then a chronic adaptation to training originates from the findings of Fenicchia et al. [5] and Ostergard et al. [13]. In the first study a single bout of resistance exercise was sufficient to improve glycemic control. In the endurance-training intervention of Ostergaard et al. [13], no correlation between changes in maximal oxygen uptake and insulin sensitivity could be detected. The authors discussed that improvements of insulin sensitivity are dissociated from muscle mitochondrial function.

In spite of significantly reduced peak glucose concentrations and area under curve during OGTT in the post-training intervention, the 4 % reduction of HbA1c levels obtained after VT intervention failed to reach statistical significance. Moreover, in the control group (flexibility training) and the strength training group HbA1c increased by 5 % and 3 %, respectively. This finding is clearly inconsistent with the outcome of other strength-training related interventions [2,4,5]. It is well known that HbA1c reflects glycemia over the preceding two to three month [16]. The obviously missing long-lasting beneficial effect on glycemic control in the present study may be in part due to the fact that we initially used a training of low-volume load. In contrast to other studies our subjects performed only one set per session during the initial 6 weeks and three sets were applied just for the last three weeks. This slow increase in training load was utilized to enhance subject's compliance to physical activity.

Beside a dose-dependent phenomenon an alternative explanation originates from the results of Tseng et al. [20]. They reported a seasonal influence on HbA1c with higher HbA1c values during winter. This epidemiological study included more that 280.000 patients living in different climate conditions. Interestingly, the strongest summer-winter contrast appeared in the regions with an intermediate winter climate (winter temperatures between 0 o C to 4.4 o C). That is close to the conditions of our region. If the assumption holds that seasonal influences provoked the HbA1c increases in the FT and ST groups the 5 % HbA1c de-crease in the vibration-exercise group may become even more meaningful.

The present paper shows, as a pilot study, that vibration exercise may be an effective measure to improve glycemic control in non insulin dependent diabetes type 2 patients. Further studies should be encouraged to optimize frequency, amplitude, and duration of vibration exercises.

Since the time to treat is far beyond traditional training forms, patients without any affinity to traditional sports activities may prefer vibration training as a part of an intended lifestyle modification.

Figure 1 :
1Images of the eight exercises during vibration training.

Figure 2 :
2Mean heart rates at loads corresponding to a lactic acid concentration of 4 mmol / l. gray bars = pretraining, black bars = posttraining. mean ± SE.

Figure 3 :
3Relative maximal isometric torques of the quadriceps muscles. black bars = pre-training, hollow bars = post-training. mean ± SE.

Figure 4 :
4Glucose plasma-concentrations during OGTT before (black) and after the training period (hollow). Left top: Flexibility training group, left bottom: strength training group, right top: vibration training group. Right bottom: mean of individual maximal glucose concentrations. Mean ± SE.

Figure 5 :
5Net changes in HbA1c. Mean ±SE

Table 1 :
1Baseline subjects characteristics. Mean ± SDIntervention
group
(number of
subjects)

Age
(years)

Weight
(kp)

Height
(cm)

Systolic
blood
pressure
(mm
Hg)

Diastolic
blood
pressure
(mm Hg)

Stretching
(13)

63,3 ±
5,9

88,6 ±
24,1

173 ±
14,2

136 ±
13,8

83 ±
7,0
Strength (13)
62,9 ±
7,3

86,5 ±
14,7

172 ±
6,7

142 ±
16,2

87 ±
10,4
Vibration
(14)

62,2 ±
4,0

83,3 ±
13,4

177 ±
7,2

137 ±
15,1

79 ±
7,3

Table 2 :
2Plasma fasting glucose concentrations before and after training intervention. Mean ± SDIntervention
group

Plasma [glu-
cose]
pretraining
(mg / 100 ml)

Plasma [glu-
cose]
posttraining
(mg / 100 ml)

Significance

Flexibility
120 ± 25
115 ± 22
n.s.
Strength
126 ± 23
120 ± 22
n.s.
Vibration
133 ± 57
122 ± 35
n.s.

AcknowledgmentsThis work was funded by a grant of International Biotechnological Future Knowledge GmbH, Krefeld, Germany. We are grateful to Dr. Hiemer for excellent cooperation, Susanne Schuster for her practical assistance during training sessions, the kind cooperation of the study participants, Vibrogym Ltd and Roche Diagnostics Ltd for the supply of equipments.Conflict of interestThe authors have declared that no conflict of interest exists.
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