Direct evidence on the immune-mediated spontaneous regression of human cancer: an incentive for pharmaceutical companies to develop a novel anti-cancer vaccine.

To develop an effective pharmaceutical treatment for a disease, we need to fully understand the biological behavior of that disease, especially when dealing with cancer. The current available treatment for cancer may help in lessening the burden of the disease or, on certain occasions, in increasing the survival of the patient. However, a total eradication of cancer remains the researchers' hope. Some of the discoveries in the field of medicine relied on observations of natural events. Among these events is the spontaneous regression of cancer. It has been argued that such regression could be immunologically-mediated, but no direct evidence has been shown to support such an argument. We, hereby, provide compelling evidence that spontaneous cancer regression in humans is immunologically-mediated, hoping that the results from this study would stimulate the pharmaceutical industry to focus more on cancer vaccine immunotherapy. Our results showed that patients with >3 primary melanomas (very rare group among cancer patients) develop significant histopathological spontaneous regression of further melanomas that they could acquire during their life (P=0.0080) as compared to patients with single primary melanoma where the phenomenon of spontaneous regression is absent or minimal. It seems that such regression resulted from the repeated exposure to the tumor which mimics a self-immunization process. Analysis of the regressing tumors revealed heavy infiltration by T lymphocytes as compared to non-regressing tumors (P<0.0001), the predominant of which were T cytotoxic rather than T helper. Mature dendritic cells were also found in significant number (P<0.0001) in the regressing tumors as compared to the non regressing ones, which demonstrate an active involvement of the different arms of the immune system in the multiple primary melanoma patients in the process of tumor regression. Also, MHC expression was significantly higher in the regressing versus the non-regressing tumors (P <0.0001), which reflects a proper tumor antigen expression. Associated with tumor regression was also loss of the melanoma common tumor antigen Melan A/ MART-1 in the multiple primary melanoma patients as compared to the single primary ones (P=0.0041). Furthermore, loss of Melan A/ MART-1 in the regressing tumors significantly correlated with the presence of Melan A/ MART-1-specific CTLs in the peripheral blood of these patients (P=0.03), which adds to the evidence that the phenomenon of regression seen in these patients was immunologically-mediated and tumor-specific. Such correlation was also seen in another rare group of melanoma patients, namely those with occult primary melanoma. The lesson that we could learn from nature in this study is that inducing cancer regression using the different arms of the immune system is possible. Also, developing a novel cancer vaccine is not out of reach.

Serum changes in trace elements during thyroid cancers.

The objective was to examine changes in trace elements due to thyroid cancer in humans. Serum levels and tissue contents of trace elements (Zn, Cu, Mn, Mg, Fe and Se) were measured in 43 patients with thyroid cancer before and 4 days after surgery were compared to normal values. The serum levels of zinc in cancer patients were lower than those of normal subjects. Surgical removal of the cancer resulted in the restoration of these levels. Although serum Cu levels in patients were not different from normal, but post-operatively these levels rose significantly (p < 0.001). Levels of Fe, Mg and Mn were significantly lower (p < 0.001) post-operatively. There was no significant change in Serum Se levels. The thyroid tissue contents of these trace elements did not show a difference between the normal (Juxta-tumor) thyroid tissue and the cancerous lesion. Out of the six trace elements examined, the decrease of serum levels of zinc in cancer patients may be linked to the disease condition. It is suggested that this change: (a) may be used to demonstrate successful cancer surgery and (b) may have implications for a long-term follow-up of thyroid cancer patients.

Expression of E-cadherin in human colorectal cancer.

AIM: To investigate the expression of E-cadherin, a calcium-dependent cell-cell adhesion molecule in colorectal carcinoma. Antibodies to E-Cadherin were used to establish the association of their expression with the clinicopathological characteristics of this disease using immunohistochemical methods. METHODS: Immunohistochemical analysis for E-cadherin was carried out in formalin-fixed, paraffin-embedded sections of neoplastic colorectal tissues and non-neoplastic ones adjacent to the lesion from 49 patients who underwent surgery, by the standard peroxidase-antiperoxidase method. Expression of this antigen in normal and malignant epithelium and stromal cells was compared. RESULTS: Both neoplastic and normal tissues showed expression of E-cadherin. There was, however, higher expression of E-cadherin in epithelial cells in both tumour and normal tissues than stromal cells. The percentage of expression in epithelial cells of well-differentiated tumours was significantly higher than moderately differentiated tumours. Loss of normal membranous expression and the presence of cytoplasmic and mixed staining were found frequently in tumour tissues (p = 0.004). This loss of membranous expression, however, did not correlate with Duke's staging, tumour grade, sex, size or site of the tumour. CONCLUSION: This study suggests that the lower expression of E-cadherin in less differentiated tumours may explain their aggressive nature, although loss of membranous expression was not significantly correlated to Duke's staging, tumour grade, sex, size and site of tumour.

Breast cancer in women aged 35 and under: prognosis and survival.

BACKGROUND: Breast cancer comprises 22% of all cancers occurring in females but only 2% of cases occur in women aged 35 years and less. The presentation, behaviour and prognosis of breast cancer in such women, when compared with older women, are unclear and conflicting results have been reported. This study has audited clinical and pathological features in patients aged 35 years and under with breast cancer. METHODS: One hundred and thirteen patients were identified. The details of clinical staging, local and distant disease recurrence and overall survival were obtained for all patients. Histological sections of tumours were examined for type, grade, size, presence of surrounding intraductal carcinoma, presence of vascular space invasion, lymph node involvement and oestrogen receptor (ER) status. RESULTS: Histological examination of the tumours revealed that 94% were invasive ductal carcinoma. In 73% of the cases the tumours were grade 3, 49% of patients who underwent axillary surgery had lymph node involvement and 20% of tumours expressed ERs. The overall 5-year survival was 64%. Predictors of a poorer survival (univariate analysis) were: increasing tumour size, absence of ERs, presence of lymphovascular space invasion, axillary lymph node involvement and detectable metastases at the initial presentation. Multivariate analysis revealed that only lymphovascular space invasion was an independent predictor of a poor survival. CONCLUSION: Breast cancer in young (< or = 35 years) women is biologically aggressive, compared with older women. Factors predicting survival and overall survival rates, however, were comparable with those previously reported for older women with breast cancer.

Expression of CD44s in human colorectal cancer.

CD44s is a cell adhesion molecule, which belongs to the family of hyaluronan binding proteins. Anti-body to CD44s is used to establish the association of its expression with the clinicopathological characteristics of colorectal cancer using immunohistochemical methods. The aim of this study is to investigate the expression of the standard form of CD44 (CD44s) in colorectal cancer tissues as compared to adjacent normal colonic tissues. Furthermore, the level of expression of CD44s in colorectal cancer tissues was correlated with the degree of histological differentiation, Duke s classification, sex, size and site of the tumor. Immunohistochemical analysis for CD44s was carried out in 49 paraffin-fixed sections of neoplastic colorectal tissues and non-neoplastic ones adjacent to the lesion, by the standard peroxidase-antiperoxidase method. Expression of these antigens were compared in normal and malignant epithelium and stromal cells. The results show that the level of CD44s in the epithelial and stromal cells was significantly higher in the colorectal cancer tissues than the normal ones. However, there was no association between the percentages of expressions of CD44s and the degree of histological differentiation, Duke s classification, sex or size of the tumor. There was however, a significantly higher expression of CD44s in the epithelium of rectal cancer than that of colonic cancer. This study indicates that the expression of CD44s is significantly higher in colorectal cancer tissues. However, further studies are required to understand its role in tumor progression and metastasis of this disease.

Plasma concentrations of alpha-tocopherol and urate in patients with different types of cancer.

OBJECTIVE: To measure plasma concentrations of alpha-tocopherol and urate to determine whether there is any relationship with different types of cancer before treatment. METHOD: Plasma concentrations of those two antioxidants were measured in cancer patients and sex- and age-matched controls. Plasma total cholesterol concentration was measured to derive an alpha-tocopherol/cholesterol ratio. RESULTS: Alpha-tocopherol and urate concentrations as well as alpha-tocopherol/cholesterol ratios were significantly lower in the cancer patients as whole, in gastrointestinal cancer and in breast cancer compared to the controls. There was no significant relationship between alpha-tocopherol and urate levels in either the plasma of patients (r=0.048; P=0.653) or controls (r=0.073; P=0.406). Alpha-tocopherol was more positively correlated with cholesterol in the plasma of controls (r=0.539; P < 0.0001) in comparison with the patients (r=0.456; P < 0.0001). There was no significant correlation between urate and cholesterol levels in both patient and control plasma samples. CONCLUSION: The data suggest that although alpha-tocopherol and urate provide important antioxidant defence in cancer, the association between their levels is weak.

Plasma micronutrient antioxidant in cancer patients.

The distribution of breast, colon, gastric, thyroid, oral, rectal, pancreatic and renal cancers were determined in 71 Kuwaitis, 45 other Arabs, and 26 Indians. Plasma levels of micronutrient antioxidants, retinol, alpha-tocopherol, lycopene, and beta-carotene were measured in the groups and in 90 matched controls for comparison. Cholesterol was measured to determine its association with the micronutrient antioxidants. Pancreatic cancer occurred exclusively in Kuwaitis, while breast and colon cancers were disproportionately higher in Kuwaitis than in the other groups. Micronutrient antioxidant levels were similar in the groups, except for higher lycopene levels in Kuwaitis. In most instances, the micronutrient antioxidants, except beta-carotene, decreased significantly in levels in patients than in controls. Low levels of retinol, lycopene, and beta-carotene were strongly associated with pancreatic cancer. Compared to controls, significantly increased levels of beta-carotene occurred in breast, colon, thyroid, and renal cancers; increased lycopene occurred in oral cancer, and increased alpha-tocopherol occurred in pancreatic cancer. Alpha-tocopherol strongly correlated with cholesterol. Generally, changes in alpha-tocopherol/ cholesterol ratios mimicked those of alpha-tocopherol levels. Micronutrient antioxidant levels were significantly lower in male patients than female patients. Age showed a negative but statistically insignificant relationship with micronutrient antioxidants. Lycopene strongly correlated with alpha-carotene and alpha-tocopherol with retinol. Among the patients, all micronutrient antioxidants except retinol decreased significantly in levels in smokers than nonsmokers, suggesting susceptibility to cigarette smoke oxidative stress. We conclude that micronutrient antioxidant depletions and altered associations may imply tumor utilization or antioxidant burden in oxidative stress or both. Furthermore, the incidence of pancreatic, colon and breast cancers among Kuwaitis warrants further study.

Serum antioxidant and cholesterol levels in patients with different types of cancer.

Serum antioxidant (urate, alpha-tocopherol) activity and cholesterol concentration in 142 patients of Indian and Arab (Kuwaitis and other Arabs) origin with different types of cancer (breast, colon, stomach, thyroid, oral, rectal, pancreatic, and renal) were compared to 100 age- and sex-matched control subjects. Values were expressed as medians (interquartile range). Urate concentration was significantly decreased in male patients compared to male controls (P < 0.0001) and in female patients and female breast cancer cases compared to female controls; P < 0.0001 and P = 0.001, respectively. Alpha-tocopherol concentration decreased significantly in total cancer, stomach, colon, rectal, and breast cancer cases than the controls; P < 0.0001, P < 0.0001, P < 0.0001, P = 0.012, and P = 0.022, respectively. Cholesterol concentration decreased significantly in stomach, oral, colon, and total cancer cases compared to the controls; P < 0.0001, P < 0.0001, P = 0.002, and P = 0.012, respectively. Among controls, females had significantly (P < 0.0001) lower concentrations of alpha-tocopherol than males. Among patients, cholesterol, urate, and alpha-tocopherol concentrations decreased significantly in smokers than in nonsmokers; P < 0.0001, P = 0.004, and P = 0.047, respectively. Generally, changes in alpha-tocopherol/cholesterol ratios mimicked changes in alpha-tocopherol concentration. Concentrations of all parameters decreased significantly in male patients compared to male controls. Age was positively associated with all three analytes with respect to the controls. Alpha-tocopherol correlated with cholesterol in cancer patients (r = 0.367; P < 0.0001) and with urate in the controls (r = 0.342; P < 0.0001). The data suggest cancer-related diminished synthesis of cholesterol and, generally, a greater antioxidant burden for alpha-tocopherol than urate in cancer-generated oxidative stress. The increased incidence of pancreatic cancer in Kuwaitis warrants further study.

Cholangiocarcinoma and liver cirrhosis in relation to changes due to thioacetamide.

Different doses of thioacetamide (0.05%, 0.1% and 0.15%) were used to induce liver cirrhosis in Wistar rats. Thioacetamide at 0.5% caused cirrhosis by the twelfth week of treatment. A severe bile duct proliferation and cholangiocarcinoma was seen at longer intervals. Animals treated with higher doses (0.1% and 0.15%) of thioacetamide developed more severe intense degenerative changes in the liver and died in the twelfth and eighth week respectively. The serum and tissue contents of Zn and Cu changed in a characteristic fashion that was consistent with the severity of the liver damage. Serum Zn and Cu concentrations were at their lowest in the animals that developed severe degenerative liver and died at higher dose (0.15%) of thioacetamide. This study indicates that treatment of rats with 0.05% thiocetamide is more effective and appropriate for the induction of liver cirrhosis. Continued administration of the drug at this dosage led to the development of further changes in the liver. This model may be suitable for studying these long term changes that occur in the liver and lead to cirrhosis. Events that precede the development of severe bile duct proliferation and cholangiocarcinoma may also be studied.

Thioacetamide toxicity and the spleen: histological and biochemical analysis.

Exposure to thioacetamide is associated with the development of liver cirrhosis in experimental animals. In addition to liver, thioacetamide toxicity has been observed in other organs. In this study, the toxic effect of thioacetamide on the spleen was investigated at 0, 4, 8 and 12 weeks post-treatment durations. The level of tissue copper and selenium increased until the eighth week when a significant drop was observed. The zinc level was also increased but returned back to normal by week 8, thereafter it showed further increase. Calculation of the copper/zinc ratio showed an increase, but, recovered and returned to normal value by week 12. The level of manganese fluctuated until the eighth week. It then increased rapidly. Histological studies of the spleen tissue showed a significant increase in extramedullary haematopoiesis in the red pulp region and marked hyperplasia in the marginal zone and follicles. The results of this study, demonstrate an intimate association between trace element levels and spleen pathology, as observed in studies of other organs.

Prognostic significance of CEA and CA 19-9 in colorectal cancer in Kuwait.

Preoperative CEA and CA 19-9 levels have been used in the past as prognostic indicators in colorectal cancer, but Dukes' stage is still considered to be the most important prognostic factor. Recent survival estimates may have been influenced by the fact that in the last decade adjuvant chemotherapy and postoperative irradiation have been included in the routine management of advanced-stage disease. In a heterogeneous Kuwaiti population higher reference levels (95th percentile) of CEA and CA 19-9 have been found than those usually employed. In the present study 62 patients with Dukes' stage B + C could be analyzed for two-year disease-free survival (DFS). Relapse was observed in 19 patients, 28 patients were disease free and 15 patients with censored observations were included. No significant difference in DFS was observed in Dukes' B (69%) versus Dukes' C (48%) patients (p = 0.09). On the other hand, Dukes' stage B + C patients with elevated preoperative levels of CEA or CA 19-9 had a significantly poorer DFS than patients with normal levels. For CEA levels below or above the cutoff the DFS was 74% versus 23% (p = 0.003); for CA 19-9 levels below or above the cutoff the DFS was 71% versus 33% (p = 0.004). In 54 patients with Dukes' stage B + C for whom preoperative levels of both CEA and CA 19-9 were available multivariate analysis revealed a decreasing risk of relapse in the following order: CEA and/or CA 19-9 elevated (chi-square 7.09; p = 0.008), CA 19-9 elevated (chi-square 6.27; p = 0.01), CEA elevated (chi-square 5.47; p = 0.02), and Dukes' C (chi-square 2.08; p = 0.15 n.s.). Hence, novel treatment protocols may have improved the disease-free survival, but the use of adjuvant chemotherapy and/or radiotherapy is of questionable benefit in patients who have elevated levels of CEA and/or CA 19-9 prior to treatment.

Antimicrobial susceptibility profile of soil isolates of Nocardia asteroides from Kuwait.

OBJECTIVES: To find the antimicrobial susceptibility profile of 42 soil isolates of Nocardia asteroides against 14 antimicrobial agents representing beta-lactams, aminoglycosides, ciprofloxacin, minocycline, erythromycin and third generation cephalosporins. METHODS: The antimicrobial susceptibility was determined by the disk diffusion method using Mueller-Hinton agar medium. A homogeneous suspension giving an inoculum of 106-108 CFU/mL was used to streak the plates. The zone of inhibition was read after 36-48 h of incubation at 37 degrees C. RESULTS: All the soil isolates of N. asteroides were susceptible to amikacin, imipenem and tobramycin. Susceptibility to cephalosporins was quite variable; 86% of the isolates were susceptible to cefotaxime, 57% to ceftriaxone and 40% to cefamandole. Fifty-seven per cent of the isolates showed intermediate susceptibility to cefamandole, 33% to ceftriaxone and 5% to cefotaxime. Ninety-three per cent of the isolates were resistant to sulfamethoxazole alone or in combination with trimethoprim. CONCLUSIONS: The study reports a wide variation in the antimicrobial susceptibility profile of soil isolates of N. asteroides originating from a single geographical area. Of interest is the finding that over 90% of N. asteroides isolates were resistant to sulfamethoxazole without any previous exposure to this drug. This may have serious therapeutic implications as sulphonamides or the combination of trimethoprim-sulfamethoxazole is the therapy of choice for nocardiosis. Demonstration of resistance to beta-lactam antibiotics may be attributed to the presence of beta-lactamases which was detectable in > 90% of the soil strains of N. asteroides. The study underscores the importance of antimicrobial susceptibility testing for clinical isolates of Nocardia since individual strains show considerable differences in their susceptibility patterns necessitating therapeutic adjustments.

A profile of tumor markers in the population of Kuwait.

The tumour markers CEA, AFP, CA 125 and CA 199 were analyzed in a group of apparently healthy subjects in Kuwait. The sample (n = 394) included both genders in the population with a mean age of 38 (S.d. 12.0) years. The distribution of CEA levels values was significant different (Mann-Whitney U test) between Kuwaiti and non-Kuwaiti. The distribution of AFP levels was found to be the same in all groups. The distribution of CA 125 levels was significantly higher in females than in males, both in Kuwaiti and non-Kuwaiti. The distribution of CA 19-9 values was found to be significantly higher in the Kuwaiti female group when compared to the males. The upper reference level was defined as the 95 percentile of the normal values in each group. In the total population the reference level of AFP was 5.6 micrograms/l and of CA 19.9 43 kU/l. The reference level of CA 125 was 16 U/l in males and 24 kU/l in females, respectively. The CEA reference level in Kuwaitis was 6.9 micrograms/l and in non-Kuwaitis 4.4 micrograms/l. The results indicated the importance of determining the reference levels of tumour markers for each individual laboratory. It was also emphasized that care should be taken on the impact of 95 percentiles of normal and benign disease groups.

Elevated levels of IL-8 in dengue hemorrhagic fever.

Dengue virus causes dengue fever, a mild febrile illness, and at times dengue hemorrhagic fever (DHF), a severe illness the pathogenesis of which is not fully understood. Given the crucial roles played by interleukin-8 (IL-8) as a chemoattractant cytokine and in inflammatory processes, levels of circulating IL-8 in the sera and IL-8 mRNA in the peripheral blood mononuclear cells (PBMC) were measured in 99 patients of a recent dengue epidemic that occurred in India in 1996 and in 21 normal healthy controls. Twenty-six of the patients had dengue fever (DF) and the remaining 73 were diagnosed as having different grades of DHF. All the control normal sera were negative for IL-8, so were their PBMC for IL-8 mRNA. Increased levels of IL-8 in the sera and IL-8 mRNA in their PBMC were observed in patients with severe illness of DHF grades III and IV. Only two out of 26 patients of DF and one out of 10 DHF grade I patient were positive for IL-8 and all three deteriorated to DHF grade IV within 24 hr. All six patients of DHF grade IV who died had higher serum level of IL-8 above 200 pg/ml, the highest being 5,568 pg/ml in one patient; the presence of mRNA for IL-8 was very high in all patients. A striking correlation was observed between increased levels of IL-8 and severe DHF, with greater levels in patients with increased grade of the disease and death. These results suggest that IL-8 may have an important role and may be an indicator of increasing severity of the disease and death.

Nocardia asteroides in the soil of Kuwait.

A pilot study was undertaken to determine the occurrence and distribution of pathogenic nocardiae in Kuwaiti soil. A total of 102 soil samples collected from two localities were investigated by the paraffin bait technique. Nocardia asteroides was the only species isolated from 42 (41%) soil samples. None of the isolates fulfilled the criteria required for identification of N. farcinica or N. nova. Thirty one (73.8%) isolates showed equivalent growth at 45 degrees C and 35 degrees C, 17 (40.4%) isolates utilized acetamide for carbon and nitrogen requirements and 3 (7.1%) isolates showed delayed arylsulphatase activity. Only a solitary isolate was resistant to cefamandole. Soil samples originating from the Kuwait University Campus, Shuwaikh, which were rich in humus/organic matter, were more productive for N. asteroides (67%) than the samples which were devoid of it but were mixed with crude oil (39%). Sand samples that lacked organic matter and crude oil samples were least productive of N. asteroides. These preliminary findings do not suggest that massive oil contamination of soil in the Ahmadi oil field area during the Gulf war promoted the natural occurrence of N. asteroides. However, isolation of N. asteroides in as many as 41% of the soil sample is a significant observation warranting further epidemiologic studies including its possible role in the operation desert storm sickness syndrome. This is the first report on the natural occurrence of N. asteroides in Kuwait.

Unusual presentations of abdominal tuberculosis.

OBJECTIVE: To review unusual presenting features and diagnostic difficulties of abdominal tuberculosis in an endemic region. DESIGN: Retrospective clinical study from 1984 to 1989, illustrated by case reports. SETTING: A single hospital in Kuwait. PATIENTS: Fifty patients with abdominal tuberculosis established by the standard histologic and bacteriologic demonstration of acid-fast bacilli or tuberculous granulomas. MAIN OUTCOME MEASURES: Site of disease and unusual features at presentation. RESULTS: Tubercular lesions are most commonly seen in the ileocecal region. They are also common in the ileum but are less common in the appendix and jejunum. Involvement of the ascending colon, rectum and upper gastrointestinal tract is rare. Abdominal tuberculosis presents in many ways depending on the degrees of ulceration, fibrous healing, infection and caseating abscess formation. CONCLUSIONS: Abdominal tuberculosis should be considered in immigrants from regions where this disease is endemic who present with abdominal signs and symptoms. Imaging studies, endoscopy and laparoscopy may preclude laparotomy for the diagnosis of abdominal tuberculosis. Antituberculosis chemotherapy is the mainstay of treatment.

Liver cirrhosis induced by carbon tetrachloride and the effect of superoxide dismutase and xanthine oxidase inhibitor treatment.

Repeated administration of carbon tetrachloride (CCl4) induces liver cirrhosis, possibly because it involves the production of free radicals. In order to evaluate the effect of free radical scavengers such as superoxide dismutase (SOD) and allopurinol in the pathogenesis of liver cirrhosis, rats were subjected to repeated CCl4 administration with and without scavengers. Four groups of animals were studied: CCl4 plus SOD (group 1), CCl4 plus allopurinol (group 2), CCl4 alone (group 3) and olive oil (group 4, normal controls). Analysis of plasma and tissue concentrations of trace elements was performed and histopathological patterns were studied in all groups after 7 weeks of repeated intraperitoneal administration of the solutions. Plasma levels of zinc and selenium were significantly lower in all experimental groups, with reciprocal elevation of manganese and copper. Copper and manganese content in the liver tissue was significantly higher in all three experimental groups. The zinc content was elevated in groups receiving CCl4 alone (group 3) or with allopurinol (group 2). The liver selenium, however, was significantly lower in these two groups. The copper:zinc ratio for plasma was 0.78 in the control group, 1.6 in the CCl4 group, 1.3 in the allopurinol group and 1.5 in the SOD group. For liver tissue, the ratio was 0.07 for controls, 0.17 for CCl4, 0.11 for allopurinol and 0.28 for the SOD group. The changes in trace element content correlated with the severity of cellular damage observed microscopically in the liver. The higher the copper:zinc ratio, the more advanced and extensive was the microscopic evidence of liver injury after CCl4 challenge.

Conserving blood in preparation for elective surgery.

A prospective study was carried out for a period of 6 months (September 1987 to 28 February 1988) to evaluate the possible misuse of blood transfusion service in the department of surgery, Amiri Teaching Hospital, Kuwait. There was a monthly wastage of 45 +/- 13 units of blood. Five hundred and eleven units of blood were crossmatched but never transfused. The time taken by the blood bank technicians in crossmatching blood which was never used amounted to 54.4% of the normal working hours. An annual loss of about US$25000.00 was calculated to have occurred.

Necrotizing fasciitis.

Ten cases of necrotizing fasciitis are reviewed. Three patients died but only two of these deaths were due to uncontrolled septicaemia. All isolated organisms were sensitive to a combination of piperacillin and ampicillin which we now regard as the initial antibiotic combination of choice. Prompt and aggressive surgical debridement remains the cornerstone of management.

Seasonality of disease in Kuwait.

To compare the seasonal variation in total mortality and deaths from cardiovascular, respiratory, and malignant disease, data were collected from North-East Scotland (Grampian region) and Kuwait. Seasonal differences were similar, in both timing and degree, for total mortality and deaths from circulatory disease, but were greater in Kuwait for respiratory disease. Peak mortality was during winter in both areas: in Grampian, when the climate is most uncomfortable, and in Kuwait, when the climate is at its most comfortable. Socioeconomic changes in Kuwait have been accompanied by a rapid fall in the degree of seasonality (deseasonality) for both total and infant mortality. These findings suggest that mortality peaks in winter, not because of a seasonally low temperature, but because of a seasonal fall in mean temperature irrespective of the annual mean temperature.

PIP: Seasonality of total mortality in Kuwait and causes of death from cardiovascular, respiratory, malignancy, injuries and poisoning, and all other diseases was analyzed by the cosinor method, and compared to data from Grampian, East Scotland as an example of an industrialized area. Data for Kuwait were taken from Ministries of Public Health and of Planning. For cosinor analysis, the mean mortality from each cause was computed, and the percent change for each month is called amplitude. For Kuwait the total mortality peaks in winter, with a declining amplitude, from 20% in the mid-1970s, to about 10% in the mid 1980s. Improved public health typically causes this reduction in seasonal amplitude, called deseasonality. Kuwait's seasonal deaths are largely due to 40% seasonality in cardiovascular deaths. Deaths due to malignancy, injuries and poisonings, and all other deaths are not seasonal. In comparison, in Grampian, 60% of total mortality is cardiovascular and is seasonal, and injuries and all other diseases are also seasonal, while malignancies are not seasonal. The phasing of seasonal cardiovascular deaths is similar in both locations, with similar peaks of about 20% in January. For both areas the timing of respiratory deaths peaks in February, but the amplitude is 46% for Kuwait compared to 33% for Grampian. Kuwait also had significant winter peaks for infectious and parasitic diseases, congenital anomalies and perinatal deaths, accounting for 27% of all deaths, while these causes made up only 2% of deaths in Scotland. Kuwait has a relatively higher proportion of infant deaths, 24.7%, with seasonality, while Grampian has more deaths of elderly 75, 48%, also seasonal. Both locations are in the northern hemisphere, with lowest temperatures in the winter. Grampian's July mean temperatures, however are similar to Kuwait's January mean. Grampian also differs from Kuwait in a much wider variation in photoperiodicity, or day length. The reasons why mortality peaks in warm climates in pleasant winter conditions is not known.