Ketogenic diet for epilepsy and obesity: Is it the same?

The term "ketogenic diet" (KD) is used for a wide variety of diets with diverse indications ranging from obesity to neurological diseases, as if it was the same diet. This terminology is confusing for patients and the medical and scientific community. The term "ketogenic" diet implies a dietary regimen characterized by increased levels of circulating ketone bodies that should be measured in blood (beta-hydroxybutyrate), urine (acetoacetate) or breath (acetone) to verify the "ketogenic metabolic condition". Our viewpoint highlights that KDs used for epilepsy and obesity are not the same; the protocols aimed at weight loss characterized by low-fat, low-CHO and moderate/high protein content are not ketogenic by themselves but may become mildly ketogenic when high calorie restriction is applied. In contrast, there are standardized protocols for neurological diseases treatment for which ketosis has been established to be part of the mechanism of action. Therefore, in our opinion, the term ketogenic dietary therapy (KDT) should be reserved to the protocols considered for epilepsy and other neurological diseases, as suggested by the International Study Group in 2018. We propose to adjust the abbreviations in VLCHKD for Very Low CarboHydrate Ketogenic Diet and VLEKD for Very Low Energy Ketogenic Diet, to clarify the differences in dietary composition. We recommend that investigators describe the researchers describing efficacy or side effects of KDs, to clearly specify the dietary protocol used with its unique acronym and level of ketosis, when ketosis is considered as a component of the diet's mechanism of action.

Corticosteroids in critical COVID-19: Are all corticosteroids equal?

BACKGROUND: The hyperinflammation seen as part of a dysregulated immune response to SARS-CoV-2 in its most severe form leads to acute respiratory distress syndrome (ARDS), multiorgan failure and death. Corticosteroid therapy targets this hyperinflammation, otherwise known as a cytokine storm. It is the only therapeutic agent to date with a mortality benefit, with clear guidelines from national and international health authorities guiding its use. Objectives. To compare severity-of-illness indices, survival, length of intensive care unit (ICU) stay and potential ICU complications in patients treated with different corticosteroid regimens (high-dose hydrocortisone, high-dose methylprednisolone and lower-dose dexamethasone). Methods. In this single-centre descriptive retrospective observational study of a cohort of patients with severe COVID-19 admitted to a COVID-dedicated ICU, we compared patients treated with the three different corticosteroid regimens. Results. In 242 cases we could not demonstrate any statistically or clinically significant difference in the outcome of patients with critical COVID-19 treated with high-dose intravenous hydrocortisone (n=88) or methylprednisolone (n=46) compared with a relatively lower dose of dexamethasone (n=108). The survival rates were 38.6%, 39.1% and 33.3%, respectively (p=0.68). Patients treated with methylprednisolone tended to have a shorter length of ICU stay (median (interquartile range) 6 (4 - 10), 4 (2 - 8) and 5 (2 - 8) days; p=0.015) and fewer episodes of nosocomial sepsis (47.7%, 32.6% and 48.1%; p=0.01). Conclusions. Hydrocortisone or methylprednisolone can be given as an alternative to dexamethasone in the management of critical COVID-19, and this is a feasible alternative, especially in resource-constrained settings.

Bacterial infection, antibiotic use and COVID-19: Lessons from the intensive care unit.

BACKGROUND: Empirical broad-spectrum antibiotics are frequently prescribed to patients with severe COVID-19, motivated by concern about bacterial coinfection. There is no evidence of benefit from such a strategy, while the dangers of inappropriate antibiotics are well described. OBJECTIVES: To investigate the frequency, profile and related outcomes of infections by bacterial pathogens in patients admitted to an intensive care unit (ICU) with severe COVID-19 pneumonia. METHODS: This was a prospective, descriptive study in a dedicated COVID-19 ICU in Cape Town, South Africa, involving all adult patients admitted to the ICU with confirmed COVID-19 pneumonia between 26 March and 31 August 2020. We collected data on patient comorbidities, laboratory results, antibiotic treatment, duration of admission and in-hospital outcome. RESULTS: We included 363 patients, who collectively had 1 199 blood cultures, 308 tracheal aspirates and 317 urine cultures performed. We found positive cultures for pathogens in 20 patients (5.5%) within the first 48 hours of ICU admission, while 73 additional patients (20.1%) had positive cultures later during their stay. The most frequently isolated pathogens at all sites were Acinetobacter baumannii (n=54), Klebsiella species (n=13) and coagulase-negative staphylococci (n=9). Length of ICU stay (p<0.001) and intubation (p<0.001) were associated with positive cultures on multivariate analysis. Disease severity (p=0.5), early antibiotic use (p=0.5), diabetes mellitus (p=0.1) and HIV (p=0.9) were not associated with positive cultures. Positive cultures, particularly for tracheal aspirates (p<0.05), were associated with longer ICU length of stay and mortality. Early empirical antibiotic use was not associated with mortality (odds ratio 2.5; 95% confidence interval 0.95 - 6.81). CONCLUSIONS: Bacterial coinfection was uncommon in patients at the time of admission to the ICU with severe COVID-19. Avoiding early empirical antibiotic therapy is therefore reasonable. Strategies to avoid coinfection and outbreaks in hospital, such as infection prevention and control, as well as the strict use of personal protective equipment, are important to improve outcomes.

New insights into spontaneous pneumothorax: A review.

A spontaneous pneumothorax is a pneumothorax that does not arise from trauma or an iatrogenic cause. Although the traditional classification of either primary or secondary spontaneous pneumothorax based on the absence or presence of overt underlying lung disease is still widely used, it is now well recognised that primary spontaneous pneumothorax is associated with underlying pleuropulmonary disease. Current evidence indicates that computed tomography screening for underlying disease should be considered in patients who present with spontaneous pneumothorax. Recent evidence suggests that conservative management has similar recurrence rates, less complications and shorter hospital stay compared with invasive interventions, even in large primary spontaneous pneumothoraces of >50%. A more conservative approach which is based on clinical assessment rather than pneumothorax size can thus be followed during the acute management in selected stable patients. The purpose of this review is to revisit the aetiology of spontaneous pneumothorax, identify which patients should be investigated for secondary causes and to give an overview of the management strategies at initial presentation as well as secondary prevention.

Pulmonary manifestations of IgG4­related disease in a South African patient.

Immunoglobin 4-related disease (IgG4-RD) is an auto-immune, multisystem inflammatory disorder characterised by storiform fibrosis, lymphoplasmacytic infiltration and obliterative phlebitis on histology. Its pathophysiology is not well understood, but is thought to occur due to complex interactions between T helper 2 cells, their cytokines, chemokines, and B lymphocytes that become dysregulated and produce dysfunctional immunoglobulins. Here, we present a case report of a 54-year-old man who was initially suspected of having lung cancer on imaging, but was ultimately diagnosed with IgG4-RD on histological analysis of a pneumonectomy specimen. Treatment with glucocorticoids can establish disease remission, with a small proportion of patients relapsing, if the diagnosis is made before significant fibrosis occurs.

Persistent chronic respiratory symptoms despite TB cure is poorly correlated with lung function.

BACKGROUND: Persistent respiratory symptoms and lung function deficits are common after patients with TB. We aimed to define the burden of post-TB lung disease (PTLD) and assess associations between symptoms and impairment in two high TB incidence communities.METHODS: This was a cross-sectional survey of adults in Cape Town, South Africa who completed TB treatment 1-5 years previously. Questionnaires, spirometry and 6-minute walking distance (6MWD) were used to assess relationships between outcome measures and associated factors.RESULTS: Of the 145 participants recruited (mean age: 42 years, range: 18-75; 55 [38%] women), 55 (38%) had airflow obstruction and 84 (58%) had low forced vital capacity (FVC); the mean 6MWD was 463 m (range: 240-723). Respiratory symptoms were common: chronic cough (n = 27, 19%), wheeze (n = 61, 42%) and dyspnoea (modified MRC dyspnoea score 3 or 4: n = 36, 25%). There was poor correlation between FVC or obstruction and 6MWD. Only low body mass index showed consistent association with outcomes on multivariable analyses. Only 19 (13%) participants had a diagnosis of respiratory disease, and 16 (11%) currently received inhalers.CONCLUSION: There was substantial burden of symptoms and physiological impairment in this "cured" population, but poor correlation between objective outcome measures, highlighting deficits in our understanding of PTLD.

High HIV prevalence in an early cohort of hospital admissions with COVID-19 in Cape Town, South Africa.

BACKGROUND: South Africa (SA) has a high prevalence of HIV and tuberculosis. Cape Town was the SA metropole most affected in the early stages of the COVID-19 pandemic. Early observational data from Africa may provide valuable insight into what can be expected as the pandemic expands across the continent. OBJECTIVES: To describe the prevalence, clinical features, comorbidities and outcome of an early cohort of HIV-positive and HIV-negative patients admitted with COVID-19. METHODS: This was a descriptive observational study of an early cohort of adults with COVID-19 pneumonia admitted from 25 March to 11 May 2020. RESULTS: Of 116 patients (mean age 48 years, 61% female) admitted, 24 were HIV-positive (21%). The most common symptoms reported were cough (n=88; 73%), shortness of breath (n=78; 69%), fever (n=67; 59%), myalgia (n=29; 25%) and chest pain (n=22; 20%). The most common comorbidities were hypertension (n=46; 41%), diabetes mellitus (n=43; 38%), obesity (n=32; 28%) and HIV (n=24; 21%). Mortality was associated with older age (mean (standard deviation) 55 (12) years v. 46 (14) years; p<0.01); the presence of hypertension or hypertension along with diabetes and/or obesity; lower partial pressure of arterial oxygen to fraction of inspired oxygen ratio; and higher urea level, white cell count, neutrophil count, and C-reactive protein, lactate dehydrogenase and ferritin levels, and high neutrophil to lymphocyte ratio. The overall survival rate for all hospital admissions was 86/116 (73%). In this early cohort, survival was similar in patients with HIV (n=18; 75%) compared with those without HIV (n=67; 75%) (p=1). Of the 74 patients admitted to the wards, 63 (85%) survived, whereas 22 of 42 (52%) admitted to the intensive care unit survived. CONCLUSIONS: Patients with HIV infection represented a large proportion of all COVID-19 admissions. The presentation and outcome of patients with HIV did not differ significantly from those of patients without HIV.

Postmortem lung biopsies from four patients with COVID-19 at a tertiary hospital in Cape Town, South Africa.

BACKGROUND: An outbreak of a novel coronavirus in China in late 2019 has resulted in a global pandemic. The virus (SARS-CoV-2) causes a severe acute respiratory syndrome and had been responsible for >14 000 deaths in South Africa (SA) at the time of writing, 30 August 2020. Autopsies in our setting have not been prioritised owing to the infective risks for staff, resulting in a lack of information on the histopathology of the disease in the SA setting. Postmortem biopsies are relatively quick and easy to perform and reduce the infective risk posed by full autopsies. OBJECTIVES: To determine whether postmortem biopsies of lung tissue could be used to determine cause of death in lieu of full autopsies in patients dying from COVID-19. METHODS: We performed postmortem biopsies of lung tissue on 4 patients with SARS-CoV-2 confirmed by reverse transcriptase polymerase chain reaction who died in the Tygerberg Hospital (Cape Town, SA) intensive care unit (ICU) in June - July 2020, in order to determine their cause of death. The biopsies were performed in the ICU with the necessary personal protective equipment within 2 hours after death. Clinical information was obtained from the hospital records and the histopathology was reviewed by two consultant histopathologists. Microbiology and electron microscopy were also performed on this tissue. RESULTS: All 4 patients were aged >50 years and had multiple comorbidities. Pulmonary pathology was present in only 3 cases, and the findings were surprisingly heterogeneous. One case demonstrated several findings including diffuse alveolar damage, extensive fibrin thrombi in pulmonary arteries with pulmonary infarction, organising pneumonia and bronchopneumonia. Other findings included type 2 pneumocyte hyperplasia, intra-alveolar macrophages and squamous metaplasia. An organising pneumonia was present in 2 other cases, although these findings were not deemed to be severe enough to be the cause of death. Fibrin thrombi were present in pulmonary arteries of 3 cases. One case showed no significant acute pulmonary pathology. The cause of death could only be determined in 1 case. CONCLUSIONS: The pulmonary findings we observed are in keeping with those described in the international literature. However, the pathology was surprisingly heterogeneous between cases, and was only deemed severe enough to be the cause of death in 1 of 4 cases. While lung-targeted, standardised postmortem biopsies may be safe, easy to perform and provide useful insights into the disease, they are not suitable to replace full autopsies in determining cause of death.

High HIV prevalence in an early cohort of hospital admissions with COVID-19 in Cape Town, South Africa

Background. South Africa (SA) has a high prevalence of HIV and tuberculosis. Cape Town was the SA metropole most affected in the early stages of the COVID-19 pandemic. Early observational data from Africa may provide valuable insight into what can be expected as the pandemic expands across the continent.Objectives. To describe the prevalence, clinical features, comorbidities and outcome of an early cohort of HIV-positive and HIV-negative patients admitted with COVID-19.Methods. This was a descriptive observational study of an early cohort of adults with COVID-19 pneumonia admitted from 25 March to 11 May 2020.Results. Of 116 patients (mean age 48 years, 61% female) admitted, 24 were HIV-positive (21%). The most common symptoms reported were cough (n=88; 73%), shortness of breath (n=78; 69%), fever (n=67; 59%), myalgia (n=29; 25%) and chest pain (n=22; 20%). The most common comorbidities were hypertension (n=46; 41%), diabetes mellitus (n=43; 38%), obesity (n=32; 28%) and HIV (n=24; 21%). Mortality was associated with older age (mean (standard deviation) 55 (12) years v. 46 (14) years; p<0.01); the presence of hypertension or hypertension along with diabetes and/or obesity; lower partial pressure of arterial oxygen to fraction of inspired oxygen ratio; and higher urea level, white cell count, neutrophil count, and C-reactive protein, lactate dehydrogenase and ferritin levels, and high neutrophil to lymphocyte ratio. The overall survival rate for all hospital admissions was 86/116 (73%). In this early cohort, survival was similar in patients with HIV (n=18; 75%) compared with those without HIV (n=67; 75%) (p=1). Of the 74 patients admitted to the wards, 63 (85%) survived, whereas 22 of 42 (52%) admitted to the intensive care unit survived.Conclusions. Patients with HIV infection represented a large proportion of all COVID-19 admissions. The presentation and outcome of patients with HIV did not differ significantly from those of patients without HIV

Adaptation and validation of a self-report measure of youth-friendly primary healthcare services.

AIM: To adapt the Youth-Friendly Health Services-World Health Organization+ questionnaire to suit the health needs of youth in the South African context, and estimate its psychometric properties. BACKGROUND: Youth-friendly health services promote health-seeking behaviour amongst young people. The perceptions of youth and adolescents are thus important whilst assessing the youth-friendliness of health services. METHODS: We conducted six focus group interviews to evaluate the clarity and relevance of the questionnaire items and adapted the questionnaire which was was administered to 101 youth who visited primary healthcare clinics. We reduced the number of items through quantitative analysis of responses and item analysis. Cronbach's alpha was used to optimize internal consistency reliability. Experts established a baseline of youth-friendliness. We ranked the responses from the youth against the baseline of youth-friendliness and used independent two sample t-test to test for construct validity of the final adapted version, titled Youth-Friendly Health Services- South Africa. RESULTS OR FINDINGS: After the focus group interviews, we rephrased 27 items, removed four items and added eight items. We reduced the questionnaire to 57 items whilst optimizing internal consistency reliability. The statistical analysis supported construct validity. CONCLUSION: The Youth-Friendly Health Services-South Africa is the first English validated version and demonstrates good psychometric properties. IMPLICATION FOR NURSING PRACTICE AND HEALTH POLICY: The Youth-Friendly Health Services-South Africa can be useful to evaluate the youths' satisfaction with the health care and nursing service they receive. This study's findings indicate that the original questionnaire can be adapted for use in different contexts to shape local and global nursing practice and policies.

Risks associated with communication delays in infants from underserved South African communities.

BACKGROUND: For optimal development young children need warm, responsive, enriched and communicative environments for learning social, language, and other skills. Infants and toddlers exposed to psychosocial risk lack enriched environments and may present with communication delays. AIM: To investigate the relationship between psychosocial risks and communication delays in infants from underserved communities in South Africa. SETTING: Primary healthcare facilities in Tshwane district, South Africa. METHODS: A parent interview and Rossetti Infant Toddler Language Scales were used to collect data from caregivers of 201 infants aged 6­12 months, selected through convenience sampling. Associations between communication delays and risks were determined (Chi-square and Fisher's exact tests). A log-linear model analysis was used to model the simultaneous effect of significant risks on the probability of having communication delays. RESULTS: Communication delays were present in 13% of infants. Infants with two or more siblings, born from mothers aged 18­29 years who own their house, had a 39% chance of presenting with communication delays. CONCLUSION: Developmental screening and early intervention is important in primary healthcare contexts in South Africa, as a clear relationship has been established between three risk factors and communication delays in infants.

Developmental screening in South Africa: comparing the national developmental checklist to a standardized tool.

BACKGROUND: Worldwide, more than 200 million children in low- and middle-income countries have developmental delays and/or disabilities. In South Africa the only nationally implemented developmental 'screening' tool is integrated as part of 'The Road to Health Booklet (RTHB). METHOD: The study employed a comparative cross-sectional within-subject design to evaluate the accuracy of the RTHB developmental checklist against a standardized international tool i.e. the PEDS tools, consisting of the PEDS and PEDS:DM. A total of 201 participants were included through convenience sampling at primary health care facilities in Tshwane, South Africa. RESULTS: Sensitivity of the RTHB developmental checklist is low, but specificity is high. The RTHB developmental checklist failed to identify more than half the infants at risk of delays or disorders. The nationally implemented developmental checklist is ineffective to identify at-risk infants. It should be adapted and validated or replaced in order to improve identification of at-risk infants.

Association between fluid balance and survival in critically ill patients.

OBJECTIVE: Although the consequences of chronic fluid retention are well known, those of iatrogenic fluid retention that occurs during critical illness have not been fully determined. Therefore, we investigated the association between fluid balance and survival in a cohort of almost 16,000 individuals who survived an intensive care unit (ICU) stay in a large, urban, tertiary medical centre. DESIGN: Longitudinal analysis of fluid balance at ICU discharge and 90-day post-ICU survival. MEASUREMENTS: Associations between fluid balance during the ICU stay, determined from the electronic bedside record, and survival were tested using Cox proportional hazard models adjusted for severity of critical illness. RESULTS: There were 1827 deaths in the first 90 days after ICU discharge. Compared with the lowest quartile of discharge fluid balance [median (interquartile range) -1.5 (-3.1, -0.7) L], the highest quartile [7.6 (5.7, 10.8) L] was associated with a 35% [95% confidence interval (CI) 1.13-1.61)] higher adjusted risk of death. Fluid balance was not associated with outcome amongst individuals without congestive heart failure or renal dysfunction. Amongst patients with either comorbidity, however, fluid balance was strongly associated with outcome, with the highest quartile having a 55% (95% CI 1.24-1.95) higher adjusted risk of death than the lowest quartile. Isotonic fluid balance, defined as the difference between intravenous isotonic fluid administration and urine output, was similarly associated with 90-day outcomes. CONCLUSION: Positive fluid balance at the time of ICU discharge is associated with increased risk of death, after adjusting for markers of illness severity and chronic medical conditions, particularly in patients with underlying heart or kidney disease. Restoration of euvolaemia prior to discharge may improve survival after acute illness.

Studies of a polymorphic Ehrlichia ruminantium gene for use as a component of a recombinant vaccine against heartwater.

A previously identified polymorphic Ehrlichia ruminantium gene, Erum2510, was investigated to determine its ability to induce protective immunity in ruminants following two different DNA immunisation strategies; DNA-only and a DNA prime/recombinant protein (rprotein) boost immunisation. The DNA-only vaccine was also compared to a cocktail of three polymorphic E. ruminantium (Welgevonden) open reading frames (ORFs) adjacent to Erum2510 in the genome. Weak protection was observed in animals immunised with the pCMViUBs_Erum2510 construct alone, while none of the animals immunised with the DNA cocktail were protected. In contrast, all five animals immunised using a DNA prime/rprotein boost strategy survived challenge, thereby indicating that Erum2510 is a good candidate for inclusion in a recombinant vaccine against heartwater. One drawback of using polymorphic genes is a possible lack of cross-protection between genotypes, therefore the genetic diversity of Erum2510 was investigated to establish the degree of polymorphism among different E. ruminantium stocks. Three distinct genotypes were identified indicating that if this gene is used as a vaccine (prime/boost strategy) the vaccine should include a representative Erum2510 gene from each genotype.

A heterologous prime/boost immunisation strategy protects against virulent E. ruminantium Welgevonden needle challenge but not against tick challenge.

Heterologous prime/boost immunisation strategies using the Ehrlichia ruminantium 1H12 pCMViUBs_ORFs [Pretorius A, Collins NE, Steyn HC, Van Strijp F, Van Kleef M, Allsopp BA. Protection against heartwater by DNA immunisation with four Ehrlichia ruminantium open reading frames. Vaccine 2007;25(12):2316-24] were investigated in this study. All the animals immunised twice with a recombinant (r) DNA cocktail of four 1H12 pCMViUBs_ORFs followed by a r1H12 protein and those immunised 3x with 1H12 plasmid rDNA showed 100% protection against a virulent E. ruminantium Welgevonden needle challenge. In addition, 90% of the sheep immunised twice with rDNA and boosted with r1H12 lumpy skin disease virus (LSDV) survived. Only the lymphocytes isolated from the r1H12 protein boost group showed specific proliferation and increased interferon (IFN)-gamma expression. In contrast, only 20% protection was obtained in animals immunised with the rDNA prime/r1H12 protein boost when subjected to natural tick challenge in the field. Thus this heterologous prime/boost immunisation strategy had not conferred any significant protection against a field challenge.

Pharmacokinetic study of a paediatric formulation of amoxycillin and clavulanic acid in children.

A combination of amoxycillin and clavulanic acid 4:1 was administered to 35 children (aged 2 to 10 years) with infections. The combination was administered orally as a suspension, every 8 h for 5 to 7 days. Sixteen children (aged 2 to 5 years), received 125 mg amoxycillin and 31.25 mg clavulanic acid, and 19 (6 to 10 years) received 250 mg amoxycillin and 62.5 mg clavulanic acid per dose. Following the first dose serum concentrations of amoxycillin and clavulanic acid were determined by microbiological assay. In the younger group receiving the lower dosage (mean: amoxycillin 9.11 mg/kg and clavulanic acid 2.34 mg/kg), the mean peak concentration of amoxycillin was 3.5 mg/l and of clavulanic acid 1.2 mg/l, occurring 1.32 h and 1.39 h, respectively, after administration. In the older group receiving the higher dosage (mean: amoxycillin 12.35 mg/kg and clavulanic acid 3.14 mg/kg) the mean peak serum level of amoxycillin was 4.0 mg/l and of clavulanic acid 1.3 mg/l, occurring 1.43 h and 1.23 h, respectively, after administration. The higher dose per kilogram body weight resulted in a higher peak serum concentration both of amoxycillin and clavulanic acid. The formulation was well tolerated by all the children and no serious side-effects were recorded. Treatment was considered clinically effective in all cases.

Adjuvant chemotherapy for operable breast cancer in postmenopausal women.

Survival figures of women with operable breast cancer reached a plateau 40 years ago. It was only with the advent of adjuvant chemotherapy that these figures showed a dramatic improvement. Data obtained in 105 postmenopausal women with operable breast cancer, treated at our clinic, are presented. Patients with axillary node disease were treated on four different protocols: cyclophosphamide + methotrexate + fluoro-uracil (CMF) with or without immunotherapy was compared with CMF + vincristine + prednisone, while other studies compared observation only with CMF + prednisone and CMF + prednisone + tamoxifen. Patients older than 65 years received tamoxifen or placebo. Patient discriminants and treatment regimens are discussed. Results indicating that certain subsets of postmenopausal women definitely need adjuvant chemotherapy are presented. The literature is briefly reviewed and the motivation for our new studies explained.

Adjuvant chemotherapy for operable breast cancer in premenopausal women.

Surgery alone does not cure breast cancer, and adjuvant chemotherapy has changed the management of this disease. Data obtained in 81 premenopausal women with operable breast cancer, treated at our clinic, are presented. Patients with axillary node disease were treated on three different protocols: cyclophosphamide + methotrexate + fluoro-uracil + vincristine + prednisone (CMFVP), cyclophosphamide + methotrexate + fluoro-uracil (CMF), and CMF + immunotherapy with methanol extract residue of BCG (CMF + MER). Patient discriminants and treatment regimens are discussed. Analysis of the results obtained in 49 patients in one study showed an extension of disease-free survival to 4,25 years, that CMFVP was superior to CMF with or without MER, and that immunotherapy was not beneficial. The literature is briefly reviewed and the motivation for our newer studies stated.