Perspectives on skeletal muscle stem cells.

Skeletal muscle has remarkable regeneration capabilities, mainly due to its resident muscle stem cells (MuSCs). In this review, we introduce recently developed technologies and the mechanistic insights they provide to the understanding of MuSC biology, including the re-definition of quiescence and Galert states. Additionally, we present recent studies that link MuSC function with cellular heterogeneity, highlighting the complex regulation of self-renewal in regeneration, muscle disorders and aging. Finally, we discuss MuSC metabolism and its role, as well as the multifaceted regulation of MuSCs by their niche. The presented conceptual advances in the MuSC field impact on our general understanding of stem cells and their therapeutic use in regenerative medicine.

Trends in the incidence of cancer in the black population of Harare, Zimbabwe 1991-2010.

Incidence rates of different cancers have been calculated for the black population of Harare, Zimbabwe for a 20-year period (1991-2010) coinciding with continuing social and lifestyle changes, and the peak, and subsequent wane, of the HIV-AIDS epidemic. The overall risk of cancer increased during the period in both sexes, with rates of cervix and prostate cancers showing particularly dramatic increases (3.3% and 6.4% annually, respectively). By 2004, prostate cancer had become the most common cancer of men. The incidence of cancer of the esophagus, formerly the most common cancer of men, has remained relatively constant, whereas rates of breast and cervix cancers, the most common malignancies of women, have shown significant increases (4.9% and 3.3% annually, respectively). The incidence of Kaposi sarcoma increased to a maximum around 1998-2000 and then declined in all age groups, and in both sexes The incidence of squamous cell cancers of the conjunctiva is relatively high, with temporal trends similar to those of Kaposi sarcoma. Non-Hodgkin lymphoma, the fifth most common cancer of men and fourth of women, showed a steady increase in incidence throughout the period (6.7-6.9% annually), although rates in young adults (15-39) have decreased since 2001. Cancer control in Zimbabwe, as elsewhere in sub-Saharan Africa, involves meeting the challenge of emerging cancers associated with westernization of lifestyles (large bowel, breast and prostate), while the incidence of cancers associated with poverty and infection (liver, cervix and esophagus) shows little decline, and the residual burden of the AIDS-associated cancers remains significant.

Complete regression of early diffuse B-cell lymphoma in an HIV-positive patient on antiretroviral therapy alone.

There is no evidence that antiretroviral therapy (ART) alone may result in complete remission of aggressive non-Hodgkin's lymphomas even though it improves the overall prognosis. We report a case in which early diffuse large B-cell lymphoma regressed completely after ART alone, raising the possibility that this may be sufficient therapy in selected cases.

Cancer survival in Harare, Zimbabwe, 1993-1997.

The Zimbabwe national cancer registry was established in 1985 as a population-based cancer registry covering Harare city. Cancer is not a notifiable disease, and registration of cases is done by active methods. The registry contributed data on randomly drawn sub-samples of Harare resident cases among 17 common cancer sites or types registered during 1993-1997 from black and white populations. Follow-up was carried out predominantly by active methods with median follow-up ranging from 1-54 months for different cancers. The proportion with histologically verified diagnosis for various cancers ranged from 20-100%; death certificate only (DCO) cases comprised 0-34%; 58-97% of total registered cases were included for survival analysis. Complete follow-up at five years ranged from 94-100%. Five-year age-standardized relative survival rates of selected cancers among both races combined were cervix (42%), breast (68%), Kaposi sarcoma (4%), liver (3%), oesophagus (12%), stomach (20%) and lung (14%). Survival was markedly higher among white than black populations for most cancers with adequate cases. Five-year relative survival by age group was fluctuating, with no definite pattern or trend.

A historical perspective of registered cases of malignant ocular tumors in Zimbabwe (1990 to 1999). Is HIV infection a factor?

INTRODUCTION: Anecdotal and published reports suggest that ocular tumours are on the increase in Zimbabwe. OBJECTIVES: To determine the trends in incidence rates of common malignant ocular tumours registered with the Zimbabwe Cancer Registry during the last decade (1990 to 1999). DESIGN: Retrospective study. SETTING: Data were collected from the Zimbabwe National Cancer Registry, the Zimbabwe National Census 1992 and 2002 Reports, and patient records from hospitals. SUBJECTS: All cases of malignant ocular tumours registered with the Zimbabwe National Cancer Registry between 1 January 1990 and 31 December 1999. MAIN OUTCOME MEASURES: Age standardized annual incidence rates for registered cases of common ocular tumours. RESULTS: The age-adjusted annual incidence rates of squamous cell carcinoma of the conjunctiva had a more than 10-fold increase from 0.17 to 1.8 per 100,000 people during periods 1990 and 1999 respectively. Retinoblastoma dropped by more than half from 0.8 to 0.34 per 100,000 during the same period. The annual age standardised incidence rates for all ocular tumours showed a significant upward linear trend (chi2: 362.78, df=9 and p < 0.001). There was no significant gender difference in the distribution of these tumours amongst the study population. CONCLUSION: The increasing trend in the age-adjusted annual incidence rates of ocular surface squamous neoplasms could be attributed to the worsening HIV and AIDS pandemic in Zimbabwe or improved access/utilization of health services by the public.

Clinicopathological features of cutaneous histoplasmosis in human immunodeficiency virus-infected patients in Zimbabwe.

Reports of disseminated Histoplasma infection in African AIDS patients are scanty. In Zimbabwe, 12 patients presented in 1994-2000 with facial nodular/papular cutaneous lesions, which became umbilicated and finally ulcerated. Histology revealed non-granulomatous inflammation and macrophages stuffed with Histoplasma. Recognition of these clinical features may lead to more rapid diagnosis of disseminated histoplasmosis in Africa.

Relationship of human herpesvirus 8 peripheral blood virus load and Kaposi's sarcoma clinical stage.

OBJECTIVE: To determine the relationship between human herpesvirus 8 (HHV-8 or Kaposi's sarcoma-associated herpesvirus) peripheral blood virus load and Kaposi's sarcoma (KS) clinical stage. DESIGN: Blinded, cross-sectional analysis of peripheral blood HHV-8 DNA levels in persons with AIDS-related KS in Harare, Zimbabwe. METHODS: Subjects were stratified by KS clinical stage. The amount of HHV-8 DNA in plasma and peripheral blood mononuclear cells (PBMC) was determined by quantitative real-time PCR amplification of the HHV-8 open reading frame 26. RESULTS: Thirty-one HIV-1/HHV-8-coinfected persons were studied: 26 subjects had histologically confirmed KS (one stage II, 11 stage III and 14 stage IV) and five subjects had antibodies to HHV-8 but did not have KS. The age, CD4 lymphocyte count and plasma HIV-1 RNA levels were similar in all groups. HHV-8 DNA was detected in the plasma of all HHV-8-infected subjects (range < 2.4 to 5.2 log10 copies/ml), but plasma HHV-8 DNA levels were not associated with KS disease stage. In contrast, the amount of HHV-8 DNA in PBMC (range < 0.7 to 4.5 log10 copies/microg) was strongly associated with KS clinical stage (P = 0.005). Among stage IV KS cases, there was a linear relationship between plasma and PBMC HHV-8 DNA levels (r2 = 0.42; P = 0.01). CONCLUSION: The strong association observed between the extent of KS disease and the levels of HHV-8 DNA in PBMC provides further evidence for a relationship between HHV-8 virus load and KS pathogenesis.

Detection of Kaposi's sarcoma-associated herpesvirus in oral and genital secretions of Zimbabwean women.

Kaposi's sarcoma-associated herpesvirus (KSHV) in oral and genital secretions of women may be involved in horizontal and vertical transmission in endemic regions. Nested polymerase chain reaction assays were used to detect KSHV DNA sequences in one-third of oral, vaginal, and cervical specimens and in 42% of peripheral blood mononuclear cell (PBMC) specimens collected from 41 women infected with human immunodeficiency virus type 1 who had Kaposi's sarcoma (KS). KSHV DNA was not detected in specimens from 100 women without KS, 9 of whom were seropositive for KSHV. A positive association was observed between KSHV DNA detection in oral and genital mucosa, neither of which was associated with KSHV DNA detection in PBMC. These data suggest that KSHV replicates in preferred anatomic sites at levels independent of PBMC viremia. Detection of genital-tract KSHV only among relatively immunosuppressed women may provide an explanation for infrequent perinatal transmission of KSHV.

Aids and cancer in Africa: the evolving epidemic in Zimbabwe.

BACKGROUND: Zimbabwe is severely affected by the AIDS epidemic, and many cancers in African populations are related to infectious agents. OBJECTIVE: To study the current pattern, and short-term changes in incidence, of cancers related to infectious agents (and especially to HIV), with respect to the evolving epidemic of AIDS. METHODS: Analysis of data on the African population of Harare, Zimbabwe, from the Zimbabwe Cancer Registry, for the period 1990-1995. Comparison with data on prevalence of HIV seropositivity, and notifications of AIDS. RESULTS: Comparing results from 1993-1995 with those for 1990-1992 shows a continuing increase in the incidence of Kaposi's sarcoma with a doubling of the rates in both men and women. A dramatic increase in the incidence of squamous cell tumours of the conjunctiva was also observed, as well as a significant increase in the incidence of non-Hodgkin's lymphoma in women. There was no apparent increase in risk for Hodgkin's disease, myeloma, liver cancer, or cancer of the cervix. CONCLUSIONS: The AIDS epidemic has had a dramatic effect on the profile of cancer. The changes in incidence involve several cancers previously linked to AIDS in North America and Europe.

Clinicopathological features of Zimbabwean patients with sustained proteinuria.

OBJECTIVE: To describe clinico-pathological features of patients admitted with significant proteinuria. DESIGN: Hospital based prospective survey conducted from 1982 to 1987. SETTING: Paediatric and medical wards at both tertiary referral hospitals in Harare. SUBJECTS: 119 patients who presented with significant proteinuria were investigated. RESULTS: Of the primary nephritides, diffuse mesangial proliferative glomerulonephritis was the most common finding (25/119); IgM was the dominant or sole immunoglobulin identified in 17/25. Minor glomerular abnormalities were common (19/119); there were 11 patients with minimal change disease and this number accounted for 42% of the children aged three to 12 years who were nephrotic. This incidence is higher than previously reported from Africa. Diffuse membranous nephropathy was frequent (18/119); hepatitis B surface antigen was present in only five of these patients. Focal sclerosing glomerulo-sclerosis was as frequent as diffuse membranous nephropathy (18/119) and appeared to be idiopathic. Diffuse mesangiocapillary glomerulonephritis (membranoproliferative) was present in 15/119 patients; no causal association was made. CONCLUSION: The pattern of primary glomerulonephritis is described from 1982 to 1987. We describe a slightly higher number of patients with minimal change disease and minor glomerular abnormalities than previously reported and a surprisingly small number of patients with diffuse endocapillary glomerulonephritis. In common with other African series, no patient with IgA nephropathy was found.

Alpha-galactosidase A deficiency (Fabry's disease) in a black Zimbabwean.

We describe a patient with Fabry's disease with renal and myocardial involvement. He has been followed up for 10 years. This metabolic defect has not been noted before in southern Africa; the clinical course is similar to that of western European and American cases.

Effects of 13-cis retinoic acid therapy on human antibody responses to defined protein antigens.

We have evaluated the in vivo effects of 13-cis retinoic acid (13-cis RA) on human antibody responses to immunization with tetanus toxoid (TT) and keyhole limpet hemocyanin (KLH). Subjects with severe cystic acne were immunized with suboptimal doses (10 micrograms) of KLH 7 d and 3 months after starting retinoid therapy (13-cis RA, 1 mg/kg/day for 4 mo). A standard booster immunization with TT was given along with the initial KLH sensitization. A control group of acne patients received identical immunization regimens, but no 13-cis RA. Plasma retinoid levels were evaluated by reverse-phase HPLC and confirmed that blood-level concentrations of 13-cis RA and metabolites in these acne patients reached values previously demonstrated to be immunomodulatory in vitro. The retinoid had no effect on responses to TT as reflected by the characteristics of increased anti-TT IgG levels or the isotype distribution of the antibody. In contrast, the anti-KLH response was significantly enhanced in the 13-cis-RA-treated group. Whereas anti-KLH antibody was detected in only 4 of 13 control subjects after the secondary immunization, 10 of 13 retinoid-treated subjects had measurable levels of anti-KLH IgG (p less than 0.05). Among the responders, no differences were noted in the isotype distribution of anti-KLH antibody. These results showing enhanced anti-KLH responses induced by 13-cis RA therapy represent the first demonstration in humans that in vivo administration of a retinoid can modulate antigen-specific immune responses.

Pityriasis rubra pilaris. Further observations of systemic retinoid therapy.

We report a retrospective review of 18 patients with pityriasis rubra pilaris treated with isotretinoin or etretinate, or both. Of patients treated with only isotretinoin, 60% have achieved sustained resolution. Of four patients treated with etretinate, three have cleared completely and the other patient has shown substantial improvement. Our data suggest that etretinate may be superior to isotretinoin in the treatment of adult-onset pityriasis rubra pilaris.

Kaposi's sarcoma in Zimbabwe. II. Peripheral lymphocytes, immunoglobulin G levels and HIV antibody positivity.

Patients with Kaposi's Sarcoma (KS) were grouped according to their clinical symptoms into "indolent", "locally aggressive", "endemic generalised aggressive" and "epidemic generalised aggressive" disease. Only the patients in the epidemic generalised aggressive disease group had serum antibodies to HIV. Complete peripheral blood counts, including lymphocyte subsets, and serum IgG assays were performed on all patients before treatment was initiated. In all the aggressive disease groups there was evidence of immune deficiency in that T helper/inducer (T4) cells were reduced leading to reduced T4,T8 (suppresser/cytotoxic) ratio. All patient groups had increased levels of serum IgG. Although immune deficiency and aggressive KS can be explained in the HIV infected patients no underlying cause has been found in the HIV negative patients with aggressive KS.

Fish oil supplementation results in decreased hypertriglyceridemia in patients with psoriasis undergoing etretinate or acitretin therapy.

Although retinoid derivatives are an effective treatment for severe psoriasis, they result in systemic toxicity, including hyperlipidemia. In an attempt to reverse this retinoid-related hyperlipidemia in patients with psoriasis, a prospective 4-week pilot study of fish oil supplementation was carried out in 25 patients with psoriasis vulgaris receiving etretinate (Ro-10-9359) or acitretin (Ro 10-1670). Daily fish oil supplements containing 3 gm of omega-3 fatty acids (1.8 gm of eicosapentaenoic acid 20:5 omega 3, and 1.2 gm of docosahexaenoic acid 22:6 omega 3) were found to be effective in reducing hypertriglyceridemia, with a significant mean reduction from 215.6 +/- 92.5 to 156.9 +/- 58.5 mg/dl (-27%) when compared with controls (203.6 +/- 46.9 to 204.1 +/- 54.3 mg/dl). High-density lipoprotein cholesterol levels increased from 41.4 +/- 10.5 to 46.1 +/- 10.8 mg/dl (+11%), and the ratio of total cholesterol to high-density lipoprotein cholesterol decreased from 6.6 +/- 1.9 to 5.9 +/- 1.7 (-11%). It is concluded that fish oil supplementation may prove a valuable adjunct to ameliorate the lipid changes secondary to retinoids.

Phototherapy units: comparison of fluorescent ultraviolet B and ultraviolet A units with a high-pressure mercury system.

Comparison in ultraviolet (UV) dosimetry is reported for three different phototherapy machines. Two of the machines used UV-emitting fluorescent tubes in a standard upright cabinet formation. One of these machines was equipped with predominantly UVB-emitting fluorescent tubes and the other with predominantly UVA-emitting tubes. The third machine consisted of a series of vertically mounted high-pressure mercury halide lamps equipped with two different filters for selection of wavelengths between 295 and 400 nm or 320 and 400 nm. The horizontal UV output of the mercury halide and UVB fluorescent units was reduced between the UV-emitting areas, and it is advised that patients rotate when using these units. It was determined that the vertical uniformity and intensity of UV emission was superior in the mercury halide unit compared with the fluorescent tubed units.

Epidermolysis bullosa acquisita in an 8-year-old girl.

Epidermolysis bullosa acquisita is an autoimmune blistering disease with the distinct feature of having an autoantibody directed against an antigen located below the basement membrane of human skin and mucous membrane. We identified this disease in an 8-year-old girl, the youngest patient documented by immunoelectron microscopy.